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Li M, Gao X, Lin X, Zhang Y, Peng W, Sun T, Shu W, Shi Y, Guan Y, Xia X, Yi X, Li Y, Jia J. Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers. Cancer Lett 2025; 620:217637. [PMID: 40118241 DOI: 10.1016/j.canlet.2025.217637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/27/2025] [Accepted: 03/11/2025] [Indexed: 03/23/2025]
Abstract
Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.
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Affiliation(s)
- Mintao Li
- Department of Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Xuan Gao
- Geneplus-Shenzhen Clinical Laboratory, Shenzhen, China
| | - Xiangchun Lin
- Department of Gastroenterology, Peking University International Hospital, Beijing, China
| | - Yan Zhang
- Geneplus-Beijing Institute, Beijing, China
| | - Wenying Peng
- The Second Department of Oncology, Yunnan Cancer Hospital & the Third Affiliated Hospital of Kunming Medical University & Yunnan Cancer Center, Kunming, China
| | - Tao Sun
- General Surgery Department, Peking University Third Hospital, Beijing, China
| | - Weiyang Shu
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Yanyan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | | | | | - Xin Yi
- Geneplus-Beijing Institute, Beijing, China.
| | - Yuan Li
- Department of Gastroenterology, Peking University International Hospital, Beijing, China; Department of Gastroenterology, Peking University Third Hospital, Beijing, China.
| | - Jinzhu Jia
- Department of Biostatistics, School of Public Health, Peking University, Beijing, China; Center for Statistical Science, Peking University, Beijing, China.
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Xu XX, Gao YH, Du CZ, Gao XX, Chen P, Fan RF, Li HT, Qiao Z. Molecular surveillance-informed personalized multidisciplinary therapy achieves prolonged survival in a patient with Lynch syndrome-associated colorectal cancer: A case report. World J Gastrointest Oncol 2025; 17:106316. [DOI: 10.4251/wjgo.v17.i6.106316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/27/2025] [Accepted: 04/22/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Lynch syndrome (LS), an autosomal dominant genetic disorder, is distinguished by germline mutations in the DNA mismatch repair genes, including MLH1. These mutations confer an elevated risk for the development of colorectal cancer (CRC) and an array of other malignancies. Timely detection, facilitated by genetic profiling and stringent molecular surveillance, is crucial. It enables the implementation of customized therapeutic strategies, which have the potential to markedly enhance patient outcomes. Despite its significant public health impact, LS is frequently underdiagnosed, underscoring the necessity for increased vigilance and the adoption of precision medicine tactics.
CASE SUMMARY This case presentation focuses on a 54-year-old male patient with a strong familial predisposition to colon cancer, who was identified to have LS-associated multiple colorectal neoplasms. Utilizing a comprehensive, multidisciplinary therapeutic strategy that encompassed precision medicine, immunotherapy with pembrolizumab, and stringent molecular residual disease monitoring, we effectively managed his advanced CRC. This tailored approach led to the achievement of sustained clinical remission exceeding 30 months, illustrating the promise of personalized treatment protocols in optimizing outcomes for individuals with LS and associated colorectal malignancies.
CONCLUSION A synergistic, multidisciplinary approach is essential for managing LS-associated CRC, advocating for personalized care pathways in precision medicine.
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Affiliation(s)
- Xin-Xin Xu
- Department of General Surgery & Institute of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Yun-He Gao
- Department of General Surgery & Institute of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Cheng-Zhou Du
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Xiao-Xin Gao
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Peng Chen
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Rui-Fang Fan
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Hong-Tao Li
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou 730050, Gansu Province, China
| | - Zhi Qiao
- Department of General Surgery & Institute of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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Battistuzzi L, Blondeaux E, Puccini A, Boni L, Grillo F, Trevisan L, Varesco L, Sciallero MS. Barriers and Facilitators in Diagnostic Pathways That Align Universal Tumor Screening and Mainstream Genetic Testing for Lynch Syndrome in Colorectal Cancer: Protocol for a Scoping Review With a Narrative Synthesis. JMIR Res Protoc 2025; 14:e70831. [PMID: 40492649 DOI: 10.2196/70831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/11/2025] [Accepted: 03/21/2025] [Indexed: 06/12/2025] Open
Abstract
BACKGROUND Approximately 3% of colorectal cancers (CRCs) are due to Lynch syndrome (LS), a hereditary cancer syndrome caused by pathogenic variants (PVs) in the mismatch repair (MMR) genes. Patients with CRC and LS have elevated lifetime risks for a range of cancers and require personalized treatment and targeted surveillance. Relatives of people affected by LS who share the same PV also have elevated cancer risks and can benefit from preventive measures and/or risk-reducing surgeries. Despite this, LS remains vastly underdiagnosed. Universal tumor screening (UTS) for deficient MMR is recommended in diagnosing LS in patients with CRC. This process, when combined with genetic testing (GT) offered within routine cancer care (termed "mainstream GT"), aims to identify individuals at risk efficiently, but integrating UTS and mainstream GT for LS in CRC is a complex endeavor. OBJECTIVE The aim of the proposed scoping review will be to comprehensively explore the literature on diagnostic pathways comprising UTS and mainstream GT for LS among patients with CRC and barriers and facilitators in their implementation. METHODS The scoping review will follow Arksey and O'Malley's expanded framework. Results will be reported following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines and summarized quantitatively. A narrative synthesis will also be performed using the Theoretical Domains Framework. RESULTS The results will be presented in a forthcoming scoping review, which we expect to publish in a peer-reviewed journal by early 2026. CONCLUSIONS Aligning UTS with mainstream GT for LS in CRC may boost early diagnosis and prevention while reducing waiting times and other patient burdens. By addressing barriers to and facilitators in diagnostic pathways, health care systems can improve the identification and management of LS, ultimately leading to better outcomes for patients and their families. The insights gained from this scoping review will inform the development of a mixed methods study about implementing diagnostic pathways for LS in CRC that integrate UTS and mainstream GT in Italy. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/70831.
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Affiliation(s)
- Linda Battistuzzi
- Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Eva Blondeaux
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Alberto Puccini
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Milan, Italy
| | - Luca Boni
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federica Grillo
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Surgical and Integrated Diagnostic Sciences, University of Genova, Genova, Italy
| | - Lucia Trevisan
- Hereditary Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Liliana Varesco
- Hereditary Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Zuo H, Yuan Z, Gu MH, Xu W, Zhou JH, Zhang Y, Gu XH. Nutritional and inflammatory indicators differ among patients with colorectal cancer with distinct microsatellite stability statuses. World J Gastrointest Surg 2025; 17:104394. [DOI: 10.4240/wjgs.v17.i5.104394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Nutritional and inflammatory indicators are crucial in assessing the nutritional health and immune function of patients with cancer, which are factors closely associated with the diagnosis and treatment of colorectal cancer (CRC).
AIM To explore the relationship between nutritional and inflammatory indicators and microsatellite stability (MSS) status in CRC.
METHODS The clinical data of 56 patients who underwent surgical treatment for CRC were collected. Furthermore, the expressions of nutritional (levels of serum albumin, triglycerides, serum cholesterol, and body mass index) and inflammatory response indicators (absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio) as well as their correlation with microsatellite instability (MSI) status were investigated in patients with CRC.
RESULTS Compared to the patients with MSS tumors, those with MSI tumors demonstrated significantly lower levels of two nutritional indicators, namely serum albumin and body mass index (P < 0.05). Moreover, patients in the MSI group demonstrated significantly lower absolute lymphocyte counts and higher neutrophil-to-lymphocyte ratio than those in the MSS group (P < 0.05), indicating pronounced differences in inflammatory responses and immune states between the two groups.
CONCLUSION Certain nutritional and inflammatory indicators exhibit significant differences among patients with MSI and MSS CRC, highlighting their potential role in the clinical treatment and health management of this specific population.
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Affiliation(s)
- Hao Zuo
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Zheng Yuan
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Meng-Hui Gu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Wei Xu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Jia-Hui Zhou
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Yan Zhang
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
| | - Xin-Hua Gu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu school of Nanjing Medical University, Suzhou 215000, Jiangsu Province, China
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Fischer AK, Kroesen A, Büttner R. [Secondary malignant neoplasms with underlying Lynch syndrome and coincidental ulcerative colitis]. CHIRURGIE (HEIDELBERG, GERMANY) 2025; 96:415-420. [PMID: 40029372 PMCID: PMC12014831 DOI: 10.1007/s00104-025-02251-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 03/05/2025]
Affiliation(s)
- Anne Kristin Fischer
- Institut für Pathologie, Universität zu Köln, Kerpener Str. 62, 50937, Köln, Deutschland.
| | - Anton Kroesen
- Krankenhaus Porz am Rhein, Urbacher Weg 19, 51149, Köln, Deutschland
| | - Reinhard Büttner
- Institut für Pathologie, Universität zu Köln, Kerpener Str. 62, 50937, Köln, Deutschland
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Huang Q, Zheng X, Xu W. Case Report: A long-term response of immunotherapy combined with anti-angiogenesis therapy in a patient with dMMR metastatic colorectal cancer after ICI failure. Front Oncol 2025; 15:1553380. [PMID: 40270608 PMCID: PMC12014423 DOI: 10.3389/fonc.2025.1553380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/13/2025] [Indexed: 04/25/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in patients with metastatic colorectal cancer (mCRC) characterized by high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). However, most patients experience intrinsic or acquired resistance. The need for treatment for patients with MSI-H/dMMR mCRC remains unmet. Here, we report the case of a patient with dMMR mCRC who achieved a durable therapeutic benefit from the combination of ICI and angiogenesis inhibitor after ICI failure. Case presentation A 40-year-old Chinese woman diagnosed with cT4N2M1b mCRC characterized by dMMR attributed to MLH-1 and PMS-2 deficiency, along with KRAS mutation. Primarily, the patient was treated with a combination of Chinese medicine and XELOX and underwent disease progression. Due to dMMR status, this patient then received single-agent camrelizumab. Unfortunately, disease progression was observed after two cycles of treatment. Subsequently, she received camrelizumab combined with bevacizumab. After treatment, the patient achieved a complete response, and the disease was sustainably controlled with a progression-free survival (PFS) of 3 years and counting. Conclusions This report demonstrates that the combination of ICI and anti-angiogenesis therapy can induce a powerful and durable antitumor response in patients with ICI-resistant MSI-H/dMMR mCRC, which is worthy of further research.
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Affiliation(s)
- Qianwen Huang
- Department of Medical Oncology, Boluo County People’s Hospital, Huizhou, China
| | - Xiaoling Zheng
- Department of Pharmacy, Boluo County People’s Hospital, Huizhou, China
| | - Wenshen Xu
- Department of Medical Oncology, Boluo County People’s Hospital, Huizhou, China
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Krause MJ, Sinkala M, Ramesar R. Distinct dysregulated pathways in sporadic and Lynch syndrome-associated colorectal cancer offer insights for targeted treatment. FEBS Lett 2025; 599:1006-1028. [PMID: 39973357 PMCID: PMC11995676 DOI: 10.1002/1873-3468.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/21/2025]
Abstract
Lynch syndrome (LS) is a hereditary disorder that increases the risk of colorectal cancer (CRC) due to constitutional pathogenic variants in mismatch repair (MMR) genes. When coupled with somatic mutations in the same gene, MMR deficiency occurs. However, the mechanisms driving cancer development remain unclear. This study aimed to identify distinct molecular drivers in LS-associated and sporadic CRC. We found that PI3K-Akt signalling is dysregulated in LS-associated CRC, while Wnt signalling predominates in sporadic CRC. Moreover, our findings highlight the therapeutic potential of PI3K-Akt pathway inhibitors, such as taselisib, for LS-associated CRC patients with high pathway dependency. Similarly, Wnt signalling pathway inhibitors, such as XAV939, offer a promising therapeutic approach for sporadic CRC. These findings underscore the importance of understanding the biological basis of disease for developing targeted therapies tailored to CRC subtype-specific oncogenic pathways.
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Affiliation(s)
- May J. Krause
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular MedicineFaculty of Health Sciences, University of Cape TownSouth Africa
| | - Musalula Sinkala
- Computational Biology Division, Department of Integrative Biomedical Sciences, School of Health SciencesUniversity of Cape TownSouth Africa
| | - Raj Ramesar
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular MedicineFaculty of Health Sciences, University of Cape TownSouth Africa
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Shen Q, Zhou Y, Liu X, Li J, Pan S, Xie N, Lin X, Zhou L, Zhou J, Li T. Clinical and Genetic Characteristics of Pediatric Colorectal Cancer. Pediatr Blood Cancer 2025; 72:e31569. [PMID: 39887884 DOI: 10.1002/pbc.31569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 12/21/2024] [Accepted: 01/18/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Compared to colorectal cancer (CRC) in adults, CRC in children is extremely rare. Although its incidence has increased recently, there is a lack of clinical research on the disease. Inherited cancer susceptibility syndromes (ICSS), a group of disorders in which patients are predisposed to susceptibility to a wide range of tumors as a result of pathogenic mutations in genes in their germ line, are an important cause of CRC in children. Delayed diagnosis due to atypical clinical presentation, as well as limited awareness of ICSS among doctors, contributes to poor outcomes in juvenile CRC patients. Therefore, improving clinicians' understanding of the diagnosis and treatment of the disease is crucial to enhancing children's prognosis with CRC. METHODS Clinical data and laboratory reports were collected from eight pediatric patients diagnosed with CRC at the Children's Hospital of Nanjing Medical University between 2020 and 2023. The clinical and genetic characteristics of these patients were evaluated and compared with other patients with early-onset CRC in the literature. RESULTS A total of 8 children with CRC were enrolled in the study, including 5 male and 3 female children, with a median age of 140 (73-177) months. The main clinical manifestations were unexplained abdominal pain, abdominal distension, vomiting, and hematochezia. Three cases of intestinal obstruction and two cases of intestinal intussusception occurred among the patients. All eight children underwent surgical treatment, including one case of snare resection of rectal polyp, five cases of subtotal colectomy, and two cases of radical resection of CRC. One case of radical resection of CRC utilized laparoscopic and colonoscopic combined resection guided by indocyanine green (ICG) fluorescence navigation system. Postoperative combination of pathological pictures and immunohistochemical (IHC) staining results confirmed high-grade squamous intraepithelial lesion (HSIL) in Case 1, and mucinous adenocarcinoma in the remaining seven cases. Out of eight pediatric patients with CRC, except for Case 1 and Case 7, who did not undergo chemotherapy, the remaining six patients all received postoperative chemotherapy; among them, the patients in Cases 1, 6, 7, and 8 achieved complete remission, whereas the patients in Cases 2 and 4 died due to postoperative recurrence and distant metastasis, the patient in Case 3 is still undergoing chemotherapy, and the patient in Case 5 was lost to follow-up after surgery. The results of the genetic test report showed that two children had ICSS caused by mismatch gene repair system defects (deficient MMR, dMMR); in Case 3, the child's genetic test results showed heterozygous mutation of MSH2 in the MMR gene, with high microsatellite instability (MSI-H), and the results of the methylation test of the MLH1 gene were negative, which, combined with the family history of heterozygous mutation of the MSH2 gene, ruled out sporadic CRC and led to the diagnosis of Lynch syndrome (LS); Case 8 genetic testing showed two heterozygous mutations in the MMR gene PMS2 with microsatellite stabilization (MSS), and a diagnosis of constitutional mismatch repair deficiency (CMMRD) was considered. CONCLUSION Pediatric CRC is confronted with delayed diagnosis and poor clinical prognosis, mainly due to nonspecific clinical presentation and the low index of suspicion among clinicians. Early detection and diagnosis is the fundamental guarantee to improve the prognosis of pediatric CRC patients, and pediatric surgeons enhance the understanding of pediatric CRC and standardize the surgery as much as possible.
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Affiliation(s)
- Qiyang Shen
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Yong Zhou
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Xingyu Liu
- Department of Pediatric Surgery, First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Jian Li
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Sirui Pan
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Nan Xie
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Xinrong Lin
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Li Zhou
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Jianfeng Zhou
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
| | - Tao Li
- Department of Oncology, Children's Hospital of Nanjing Medical University, Jiangsu, China
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Wang X, Ni H, Zhu L, Huang H, Deng A, Hu J, Cai W, Li J. Analyzing pathogenic variants in mismatch repair genes: personalized prevention strategies for lynch syndrome in Chinese families. Front Med (Lausanne) 2025; 12:1527249. [PMID: 40160320 PMCID: PMC11949903 DOI: 10.3389/fmed.2025.1527249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/11/2025] [Indexed: 04/02/2025] Open
Abstract
Background This study aimed to analyze the pathogenic variants in one family with colorectal cancer and another with endometrial cancer and provide appropriate personalized prevention strategies for carriers of these genetic mutations. Methods One proband with colorectal cancer and another with endometrial cancer and their family members were enrolled in this study. Whole-exome sequencing was used to identify pathogenic gene mutations in both families. We compared the structural difference between the wild-type and mutant MSH2 proteins using SWISS-MODEL and PyMOL visualization software. Results We identified one novel mutation (NM_000251.2:c.1486delT:p.L496*) in the MSH2 gene in Family I and a known mutation (NM_001258271.1:c.884 + 4A > G) in the MLH1 gene in Family II. The novel mutation (NM_000251.2:c.1486delT:p.L496*) caused a stop gain mutation, resulting in the absence of amino acids 496-934 in the mutant MSH2 protein. This led to the loss of Domain 5 and alterations in the sequences of Domain 3 and Domain 4 regions, resulting in premature termination of MSH2 protein coding. The known mutation (NM_001258271.1:c.884 + 4A > G) in MLH1 causes the skipping of exon 10, producing a truncated protein and undergoing nonsense-mediated decay based on literature reports. Thus, 5-fluorouracil-based adjuvant chemotherapy is not recommended for patients with lynch syndrome. Conclusion The novel stop gain mutant (NM_000251.2:c.1486delT:p.L496*) in MSH2 is deemed pathogenic for LS, and the mutant (NM_001258271.1:c.884 + 4A > G) in MLH1 has been further confirmed to be pathogenic. These findings expand the spectrum of mismatch repair gene variations in the ethnic group Han of China and reaffirm the importance of genetic testing for LS.
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Affiliation(s)
- Xiufang Wang
- Department of Pain, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haichun Ni
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin Zhu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Huang
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Aiping Deng
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jifa Hu
- Department of Scientific Research, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Cai
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juyi Li
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ben David C, Siegler Y, Linder R, Amit A, Matanes E. Screening and prevention of gynecologic malignancies in patients with lynch syndrome: following the guidelines. Front Oncol 2025; 15:1563022. [PMID: 40144212 PMCID: PMC11936791 DOI: 10.3389/fonc.2025.1563022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Lynch syndrome (LS), a hereditary condition caused by germline mutations in mismatch repair (MMR) genes, significantly elevates the lifetime risk of endometrial cancer (EC) (40-60%) and ovarian cancer (8-10%) in affected women. Despite advances in colorectal cancer screening for LS patients, optimal strategies for gynecologic cancer prevention remain under debate. Current recommendations for EC surveillance, including annual transvaginal ultrasound and endometrial biopsy starting at age 30-35, lack robust evidence for effectiveness. Risk-reducing hysterectomy with bilateral salpingo-oophorectomy (BSO) is frequently advised after childbearing to mitigate cancer risk. Emerging data suggest that hormonal interventions, such as oral contraceptives and progestin-based therapies, may reduce EC risk by up to 50%, offering non-surgical preventive options. Lifestyle modifications, including weight management and physical activity, further complement risk reduction strategies. Molecular diagnostic advancements, including immunohistochemistry and microsatellite instability testing, enhance early identification of LS-associated gynecologic malignancies. For patients with advanced or recurrent EC, the integration of immunotherapy into treatment regimens has demonstrated significant efficacy. Agents such as pembrolizumab and dostarlimab, particularly in combination with carboplatin and paclitaxel, have improved progression-free and overall survival rates for patients with MMR-deficient tumors. This review highlights the need for personalized, evidence-based approaches to gynecologic cancer screening and prevention in LS, emphasizing the importance of integrating genetic testing, patient education, and novel therapeutic options. Future research should focus on refining screening protocols and expanding non-invasive preventive strategies to improve outcomes for this high-risk population.
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Affiliation(s)
- Chen Ben David
- Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Yoav Siegler
- Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Revital Linder
- Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Amnon Amit
- Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Emad Matanes
- Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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11
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Wu D, Song QY, Dai BS, Li J, Wang XX, Liu JY, Xie TY. Colorectal cancer early screening: Dilemmas and solutions. World J Gastroenterol 2025; 31:98760. [PMID: 40061594 PMCID: PMC11886035 DOI: 10.3748/wjg.v31.i9.98760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 01/03/2025] [Accepted: 01/13/2025] [Indexed: 02/18/2025] Open
Abstract
Colorectal cancer (CRC) is a prevalent malignancy worldwide, posing a significant public health concern. Mounting evidence has confirmed that timely early screening facilitates the detection of incipient CRC, thereby enhancing patient prognosis. Obviously, non-participation of asymptomatic individuals in screening programs hampers early diagnosis and may adversely affect long-term outcomes for CRC patients. In this letter, we provide a comprehensive overview of the current status of early screening practices, while also thoroughly examine the dilemmas and potential solutions associated with early screening for CRC. In response to these issues, we proffer a set of recommendations directed at governmental authorities and the general public, which focus on augmenting financial investment, establishing standardized screening protocols, advancing technological capabilities, and bolstering public awareness campaigns. The importance of collaborative efforts from various stakeholders cannot be overstated in the quest to enhance early detection rates and alleviate the societal burden of CRC.
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Affiliation(s)
- Di Wu
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Qi-Ying Song
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Bai-Shu Dai
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Jie Li
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Xin-Xin Wang
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Jia-Yu Liu
- Department of Neurosurgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
| | - Tian-Yu Xie
- Department of General Surgery, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
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12
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Lehtonen TM, Koskenvuo LE, Lepistö AH. Early-onset rectal cancer: Experience of a single-center, high-volume unit. Scand J Surg 2025; 114:22-34. [PMID: 39396124 DOI: 10.1177/14574969241282543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2024]
Abstract
BACKGROUND AND OBJECTIVE The incidence of early-onset colorectal cancer among the young (<50 years) has been reported to have risen in last decades. This retrospective study aimed to investigate the characteristics of early-onset rectal cancers (EO-RCs) and potential changes in proportion of EO-RCs, and further to report the mortality and recurrence rates of EO-RCs. METHODS In the years 2007-2021, 2557 rectal cancer (RC) patients were operated in Helsinki University Hospital and of them 147 were 18-49 years old. Cumulative overall survival (OS), disease-specific survival, and disease-free survival were calculated using the Kaplan-Meier analysis. RESULTS The percentual amount of the EO-RCs varied between 2.5% and 11.3% annually and there was no perceivable trend. Majority were adenocarcinomas (98.7%), of which 8.8% were mucinous. Predisposing factors such as Lynch syndrome, polyposis, or ulcerative colitis were seen in 26 patients (17.7%) and in 10 of 22 patients (45.5%) under 35 years. The cumulative 5-year OS was 91.9% in stage I, 93.3% in stage II, 86.7% in stage III, and 50.0% in stage IV disease. Metastatic recurrence was found in 22 cases (18.4%) and local recurrence in 8 patients (5.4%) and 6 patients had both. CONCLUSIONS In our cohort of 147 EO-RC patients, OS was good and the clinical course did not seem to differ much from the course of RC in general population.
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Affiliation(s)
- Taru M Lehtonen
- Department of Surgery HUS Helsinki University Hospital and University of Helsinki, Jorvi Hospital,Espoo 20540, Finland
| | - Laura E Koskenvuo
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Jorvi, Finland
| | - Anna H Lepistö
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Jorvi, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Helsinki, Finland
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13
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Storandt MH, Shi Q, Eng C, Lieu C, George T, Stoppler MC, Mauer E, Yilma B, Fragkogianni S, Teslow EA, Mahipal A, Jin Z. Genomic Landscapes of Early-Onset Versus Average-Onset Colorectal Cancer Populations. Cancers (Basel) 2025; 17:836. [PMID: 40075683 PMCID: PMC11899610 DOI: 10.3390/cancers17050836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Rates of early-onset colorectal cancer (eoCRC), defined as disease diagnosed at <50 years of age, are increasing. The incidence and spectrum of somatic and pathogenic germline variants (PGV) in this population are not well understood. METHODS This cross-sectional study leveraged Tempus' clinicogenomic database, including de-identified records of patients diagnosed with CRC between 2000-2022, to analyze and compare eoCRC and average-onset colorectal cancer (aoCRC, disease diagnosed ≥50 years of age) patients. The frequency and spectrum of somatic mutations and PGVs in patients with eoCRC and aoCRC were evaluated and compared. RESULTS Among 11,006 participants in this study, 57% were male, 76% were white, and 80% had stage 4 disease. Within the total cohort, 2379 had eoCRC and 8627 had aoCRC. Among patients with eoCRC, 4.2% had a tumor with high microsatellite instability and/or deficient mismatch repair (MSI-H/dMMR) and 6.8% with aoCRC had an MSI-H/dMMR tumor (p < 0.001). The most frequent somatic mutations involved TP53, APC, and KRAS, with the most significant difference in BRAF, which was more frequently mutated in aoCRC (9.8% vs. 4.7%, p < 0.0001). In total, 1413 (59.4%) eoCRC and 4898 (56.8%) aoCRC patients had matched normal specimen (blood or saliva) sequencing and a PGV was identified in 6.9% of eoCRC and 5.0% of aoCRC patients. CONCLUSIONS Somatic and germline mutation profiles were similar for eoCRC and aoCRC patients and may not adequately explain differences in tumor behavior and age of disease onset.
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Affiliation(s)
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Cathy Eng
- Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA
| | - Christopher Lieu
- Division of Medical Oncology, University of Colorado Health Cancer Center, Aurora, CO 80045, USA
| | - Thomas George
- Division of Hematology and Oncology, University of Florida, Gainesville, FL 32603, USA
| | | | | | - Binyam Yilma
- Tempus AI, Inc., Chicago, IL 60654, USA (E.A.T.)
| | | | | | - Amit Mahipal
- Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA;
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14
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Ke H, Li P, Li Z, Zeng X, Zhang C, Luo S, Chen X, Zhou X, Dong S, Chen S, Huang J, Yuan M, Yu R, Ye S, Hu T, Tang Z, Liu D, Wu K, Wu X, Lan P. Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells. Clin Transl Med 2025; 15:e70175. [PMID: 39934971 PMCID: PMC11813809 DOI: 10.1002/ctm2.70175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 10/01/2024] [Accepted: 12/29/2024] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients. METHODS Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour-adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining. RESULTS Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell-cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8+ T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8+ T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy. CONCLUSIONS Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response. KEY POINTS Distinct immunotypes are identified in the CRC macroenvironment. TLS and immunotherapy exert influence on the immune macroenvironment. TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.
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Affiliation(s)
- Haoxian Ke
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Peisi Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Zhihao Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Xian Zeng
- Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
| | - Chi Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Shuzhen Luo
- HIM‐BGI Omics Center, Hangzhou Institute of Medicine (HIM)Chinese Academy of Sciences, BGI ResearchHangzhouChina
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of GenomicsBGI ResearchShenzhenChina
- BGI GenomicsHarbinChina
| | - Xiaofang Chen
- HIM‐BGI Omics Center, Hangzhou Institute of Medicine (HIM)Chinese Academy of Sciences, BGI ResearchHangzhouChina
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of GenomicsBGI ResearchShenzhenChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Xinlan Zhou
- HIM‐BGI Omics Center, Hangzhou Institute of Medicine (HIM)Chinese Academy of Sciences, BGI ResearchHangzhouChina
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of GenomicsBGI ResearchShenzhenChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Shichen Dong
- BGI ResearchShenzhenChina
- Shenzhen Key Laboratory of Single‐Cell OmicsBGI ResearchShenzhenChina
| | - Shaopeng Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Junfeng Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Ming Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Runfeng Yu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Shubiao Ye
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Tuo Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Zhonghui Tang
- Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
| | - Dongbin Liu
- HIM‐BGI Omics Center, Hangzhou Institute of Medicine (HIM)Chinese Academy of Sciences, BGI ResearchHangzhouChina
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of GenomicsBGI ResearchShenzhenChina
- BGI GenomicsHarbinChina
| | - Kui Wu
- HIM‐BGI Omics Center, Hangzhou Institute of Medicine (HIM)Chinese Academy of Sciences, BGI ResearchHangzhouChina
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of GenomicsBGI ResearchShenzhenChina
- BGI GenomicsHarbinChina
| | - Xianrui Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Ping Lan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Biomedical Innovation CenterThe Sixth Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Colorectal Surgery, Department of General SurgeryThe Sixth Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
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15
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Chikatani K, Chika N, Tanabe N, Mori Y, Suzuki O, Matsuyama T, Ishibashi K, Eguchi H, Okazaki Y, Yamaguchi T, Ishida H. Frequency and Molecular Characteristics of Mismatch Repair-deficient Status among Multiple Synchronous Colorectal Cancers. J Anus Rectum Colon 2025; 9:145-155. [PMID: 39882230 PMCID: PMC11772799 DOI: 10.23922/jarc.2024-092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 10/30/2024] [Indexed: 01/31/2025] Open
Abstract
Objectives Mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC) have been largely categorized into three subtypes: MLH1-methylated, Lynch syndrome (LS)-associated, and Lynch-like syndrome (LLS)-associated. No studies have examined the prevalence and subtypes of synchronously diagnosed dMMR CRCs in detail. Therefore, this study aimed to examine the frequency and molecular characteristics of the dMMR status among multiple synchronous CRCs to clarify the clinical significance of identifying patients with such tumors. Methods Immunohistochemistry (IHC) of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed for surgically and endoscopically resected (in conjunction with surgical resection) lesions from consecutive patients with initially diagnosed multiple synchronous CRCs between July 2014 and June 2020. When necessary, MLH1-methylation analysis and testing of germline and somatic MMR genes were performed. Results In total, 133 patients (33 females) had 309 lesions. The combinations of synchronous tumor sites were the left-sided colon/rectum only (n=67, 50.4%), both the right-sided colon and left-sided colon/rectum (n=42, 31.6%), and the right-sided colon only (n=24, 18.0%). IHC showed a loss of expression of at least one MMR protein in 10 (7.5%) of 133 patients and 17 (5.5%) of 309 lesions. Molecular analysis revealed that these 10 patients were categorized as having MLH1-methylated (n=5, 3.8% of all patients), LS-associated (n=4, 3.0%), or LLS-associated (n=1, 0.8%) CRC. Conclusions Our data will be useful for genetic counseling in patients with synchronous CRCs suspected of having LS. Screening for LS using IHC for MMR proteins in individuals with multiple synchronous CRCs is an effective approach.
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Affiliation(s)
- Kenichi Chikatani
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Noriyasu Chika
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Noriko Tanabe
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yoshiko Mori
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Takatoshi Matsuyama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Hidetaka Eguchi
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasushi Okazaki
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tatsuro Yamaguchi
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
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16
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Pasqualotto E, Pompeu BF, Braga MAP, Delgado LM, Chavez MP, Morgado Ferreira RO, Pasqualotto T, Morbach V, Formiga FB. Segmental versus extended colectomy for colorectal cancer in patients with lynch syndrome: A systematic review and meta-analysis. World J Surg 2025; 49:24-33. [PMID: 39631798 DOI: 10.1002/wjs.12443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 11/23/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND The decision to perform segmental or extended colectomy in Lynch syndrome (LS) patients with colorectal cancer (CRC) is still controversial. Therefore, this systematic review and meta-analysis aims to provide updated evidence for segmental versus extended colectomy in LS carriers with CRC. METHODS PubMed, Embase, and Cochrane Library were systematically searched for studies published until January 2024 comparing segmental and extended colectomies for CRC in patients with LS. Risk ratio (RR) was used to evaluate binary endpoints with 95% confidence intervals (CIs). Heterogeneity was assessed with the Cochran's Q test and I2 statistics. Statistical analysis was performed using the R Software, version 4.2.3. RESULTS A total of 14 studies comprising 2303 LS carriers with CRC, of whom 1724 (74.9%) patients underwent segmental colectomy and 579 (25.1%) patients underwent extended colectomy. Segmental colectomy significantly increased metachronous CRC (mCRC) (RR 2.87; 95% CI 2.03-4.07; and p < 0.01). There were no significant differences between groups for 5-year overall survival (OS) (RR 0.92; 95% CI 0.82-1.03; and p = 0.14), 10-year OS (RR 0.99; 95% CI 0.96-1.04; and p = 0.80), and mortality (RR 1.63; 95% CI 0.90-2.97; and p = 0.11). There were no significant linear associations between the outcome of mCRC and age at the time of primary CRC, sex, primary CRC location, and pathogenic LS variant. CONCLUSION In this meta-analysis, segmental colectomy significantly increased mCRC compared with extended colectomy after the first surgery for CRC in patients with LS. However, there were no significant differences between groups for 5- and 10-year OS and mortality.
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17
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Rodrigues C, Irving SC, Alves P, Dinis-Ribeiro M, Brandão C, Correia M. The Influence of Diet and Obesity in Lynch Syndrome: What Do We Know So Far. Nutrients 2024; 16:4352. [PMID: 39770972 PMCID: PMC11677193 DOI: 10.3390/nu16244352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Of all new cases of colorectal cancer, Lynch syndrome (LS) accounts for approximately 3%. This syndrome is the most common hereditary cancer syndrome and is caused by pathogenic variants in the genes responsible for DNA mismatch repair. Although the relationship between colorectal cancer risk and diet is well established, little is known regarding the influence of diet and nutritional characteristics on LS's clinical evolution. There is some evidence suggesting that individuals living with LS should follow general guidelines for diet and alcohol restriction/moderation, so as to achieve and maintain a favorable weight status and overall health and quality of life. However, more research is needed, preferentially from clinical studies of a prospective nature with robust designs, to better inform diet and behavioral patterns targeting cancer prevention in LS.
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Affiliation(s)
- Cláudio Rodrigues
- Gastroenterology Department, Unidade Local de Saúde de Viseu Dão Lafões, 3504-509 Viseu, Portugal;
| | - Susana Couto Irving
- Nutrition–Medicine Department, Instituto Português de Oncologia, Francisco Gentil E.P.E., 4200-072 Porto, Portugal; (S.C.I.); (P.A.)
| | - Paula Alves
- Nutrition–Medicine Department, Instituto Português de Oncologia, Francisco Gentil E.P.E., 4200-072 Porto, Portugal; (S.C.I.); (P.A.)
| | - Mário Dinis-Ribeiro
- IRISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal;
- MEDCIDS-Department of Community Medicine, Information and Decision in Health, Faculty of Porto, University of Medicine, 4200-072 Porto, Portugal
- Department of Gastroenterology, Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Catarina Brandão
- IRISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal;
- Department of Gastroenterology, Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Marta Correia
- Laboratório Associado, Escola Superior de Biotecnologia, Centro de Biotecnologia e Química Fina, Universidade Católica Portuguesa, CBQF, Rua Diogo Botelho 1327, 4169-005 Porto, Portugal;
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18
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Gupta P, Zhan PL, Leeds I, Mongiu A, Reddy V, Pantel HJ. Practice Patterns and Trends in the Surgical Management of Mismatch Repair Deficient Colon Cancer. J Surg Res 2024; 304:371-382. [PMID: 39615154 DOI: 10.1016/j.jss.2024.10.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 10/11/2024] [Accepted: 10/26/2024] [Indexed: 12/15/2024]
Abstract
INTRODUCTION Defects in the DNA mismatch repair (MMR) pathway can predispose individuals to colorectal cancer (CRC), with germline mutations in this pathway leading to Lynch syndrome. Consequently, universal MMR testing is recommended for all newly diagnosed CRC patients to detect mismatch repair deficient (MMR-D) tumors, enabling informed treatment decisions. Given the increased potential for metachronous disease in patients with Lynch syndrome, the current guidelines for surgical management of Lynch-associated colon cancer recommend extended resection in patients under age 60. METHODS A retrospective analysis of nonmetastatic CRC was performed from the National Cancer Database to evaluate the current trends and practice patterns in the surgical management of MMR-D colon cancer, as well as assess the factors influencing choice of surgical procedure. RESULTS From 2018 to 2020, 98,112 nonmetastatic CRC patients were identified, with 19.93% being MMR-D. MMR-D colon cancer patients were more likely to undergo extended resection than those with mismatch repair proficient tumors (9.4% versus 4.2%, P < 0.001). When accounting for approximately one-fourth of MMR-D colon cancers being attributable to Lynch syndrome, the frequency of extended resection was less than expected (9.4% versus 25%, P < 0.001). MMR-D patients under age 60 were more likely to undergo extended resection than those over age 60 (9% versus 3%) (odds ratio [OR] 3.57, 95% confidence interval [CI] 3.06-4.15). Several factors were associated with decreased rate of extended resection: uninsured (OR 0.42, 95% CI 0.21-0.84), Black race (OR 0.54, 95% CI 0.35-0.82), treatment at nonacademic centers (OR 0.74, 95% CI 0.56-0.97), and crowfly distance >25 miles (OR 1.98, 95% CI 1.14-3.45). CONCLUSIONS These findings provide valuable insight into the current surgical practice patterns in the management of MMR-D colon cancers and possibly colon cancers associated with Lynch syndrome.
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Affiliation(s)
- Princy Gupta
- Division of Colon and Rectal Surgery, Yale School of Medicine, New Haven, Connecticut.
| | - Peter L Zhan
- Division of General Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Ira Leeds
- Division of Colon and Rectal Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Anne Mongiu
- Division of Colon and Rectal Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Vikram Reddy
- Division of Colon and Rectal Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Haddon J Pantel
- Division of Colon and Rectal Surgery, Yale School of Medicine, New Haven, Connecticut
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19
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Feng X, Yao Q, Xu Y, Zhang J, Jia L, Wang Q, Cai X, Xu Y, Liu F, Huang D, Sheng W, Bai Q, Zhu X, Zhou X. Approaches for Lynch syndrome screening and characteristics of subtypes with mismatch repair deficiency in patients with colorectal carcinoma. Int J Cancer 2024; 155:1780-1791. [PMID: 39109916 DOI: 10.1002/ijc.35085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 11/18/2024]
Abstract
To evaluate different Lynch syndrome (LS) screening approaches and establish an efficient and sensitive strategy are critical for clinical practice. In total, 583 patients with colorectal carcinoma (CRC) at Fudan University Shanghai Cancer Center were enrolled. Patient samples were examined by immunohistochemistry (IHC) and next-generation sequencing (NGS), and MLH1 promoter hypermethylation (MPH) was detected in MLH1-deficient cases. Germline genetic testing was performed in cases with deleterious variants and large genomic rearrangements (LGRs) of tumor MMR genes were detected in cases with dMMR or MSI-H cases with no MMR germline variants. Our results showed that triage with IHC and followed by BRAF/MLH1 methylation testing (Strategy 1) identified 93.3% (70/75) of LS cases. IHC followed by germline NGS (Strategy 2) or direct tumor NGS (Strategy 3) both identified 98.7% (74/75) of LS cases. The proportion of LGRs in LS cases was 16.0% (12/75), while 84.0% (63/75) showed SNV/Indel. The average cost per patient was ¥6010.81, ¥6058.48, and ¥8029.98 for Strategy 1, Strategy 2 and Strategy 3, respectively. The average time spent on different strategies was 4.74 days (Strategy 1), 4.89 days (Strategy 2), and 14.50 days (Strategy 3) per patient, respectively. LS and Lynch-like syndrome (LLS) were associated with an earlier onset age than MPH. In conclusion, we compared different workflows for LS screening and IHC plus germline NGS is recommended for LS screening when taking sensitivity, time, and cost into account. Moreover, multiplex ligation-dependent probe amplification made up for the shortcoming of NGS and should be incorporated into routine screening.
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Affiliation(s)
- Xu Feng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Qianlan Yao
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Yuyin Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Jing Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Liqin Jia
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Qian Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xu Cai
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Ye Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University, Shanghai Cancer Center, Shanghai, China
| | - Fangqi Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University, Shanghai Cancer Center, Shanghai, China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Qianming Bai
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xiaoli Zhu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
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20
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Chou AJ, Bing RS, Ding DC. Endometrial Atypical Hyperplasia and Risk of Endometrial Cancer. Diagnostics (Basel) 2024; 14:2471. [PMID: 39594136 PMCID: PMC11593242 DOI: 10.3390/diagnostics14222471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/04/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Endometrial atypical hyperplasia (EAH) is a premalignant condition with a substantial risk of progression to endometrial cancer (EC), with the endometrioid subtype being the most common. EAH is characterized by abnormal endometrial gland proliferation and cellular atypia, often resulting from prolonged unopposed estrogen exposure. This review aims to explore the clinical significance of EAH, its risk of progression to EC, and the current approaches to management. The risk of EAH progressing to EC ranges from 20 to 50%, influenced by factors such as histopathology and genetic mutations including PTEN and KRAS. Key risk factors include obesity, polycystic ovary syndrome, and postmenopausal status. Abnormal uterine bleeding is a hallmark symptom of EAH and early-stage EC, necessitating diagnostic evaluation through endometrial biopsy and transvaginal ultrasonography. Therapeutic management strategies depend on patient risk and fertility considerations. Hormonal therapy, particularly progestins, is the mainstay for fertility preservation, while hysterectomy is preferred for higher-risk patients. Regular monitoring with biopsies is essential for those undergoing conservative treatment. Recent advancements in the management of EAH and EC have shifted towards incorporation of molecular diagnostics and targeted therapies, enabling better risk stratification and individualized care. Biomarkers and minimally invasive surgical techniques are emerging as promising approaches in improving outcomes for women with EAH. This review underscores the importance of early diagnosis and personalized management in preventing the progression of EAH to EC, highlighting current clinical practices and potential future developments in this field.
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Affiliation(s)
- An-Ju Chou
- Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, New Taipei City 231, Taiwan; (A.-J.C.); (R.-S.B.)
| | - Ruo-Shi Bing
- Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, New Taipei City 231, Taiwan; (A.-J.C.); (R.-S.B.)
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
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21
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Huang W, Zhang S. A watch-and-wait approach for metachronous multiple colon cancer following neoadjuvant immunotherapy: a case report. Front Immunol 2024; 15:1391038. [PMID: 39430753 PMCID: PMC11486642 DOI: 10.3389/fimmu.2024.1391038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 09/06/2024] [Indexed: 10/22/2024] Open
Abstract
The application of immunotherapy for treating colorectal cancer (CRC) is currently a research hotspot, and neoadjuvant immunotherapy has shown initial success in treating CRC. The watch-and-wait (W&W) approach is often used after achieving a clinical complete response (cCR) following preoperative treatment of low rectal cancer. However, thus far, the W&W approach has not been reported for patients with colon cancer. Here, we report the case of a 64-year-old patient with heterogeneous multigenic CRC who achieved cCR after five sessions of neoadjuvant immunotherapy before surgery. A W&W approach was used to spare the patient from surgery. A 64-year-old male presented with intermittent abdominal pain. A colonoscopy examination detected an irregular cauliflower-like mass near the hepatic flexure of the ascending colon. The biopsy results indicated adenocarcinoma of the ascending colon. The patient was administered pembrolizumab (200 mg, ivgtt, q3w). After one cycle of treatment, the intestinal obstruction symptoms disappeared, and the treatment was continued for additional three sessions. After complete clinical remission of the tumor was confirmed, the W&W approach was adopted. Follow-up CT scans and colonoscopy examinations confirmed no local tumor regeneration or metastasis. Neoadjuvant immunotherapy is effective for patients with DNA mismatch repair gene deficiency and/or microsatellite instability high with a high rate of cCR or pathologic complete response. The W&W approach may also be suitable for patients with colon cancer. The safety and feasibility of watch and wait in patients with colon cancer need to be verified by more clinical data.
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Affiliation(s)
| | - Shouru Zhang
- Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing, ;China
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22
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Capalbo A, de Wert G, Mertes H, Klausner L, Coonen E, Spinella F, Van de Velde H, Viville S, Sermon K, Vermeulen N, Lencz T, Carmi S. Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations. Hum Reprod Update 2024; 30:529-557. [PMID: 38805697 PMCID: PMC11369226 DOI: 10.1093/humupd/dmae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/25/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing. OBJECTIVE AND RATIONALE This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom. SEARCH METHODS We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms 'polygenic embryo screening', 'polygenic preimplantation', and 'PGT-P'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant. OUTCOMES The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for 'designer babies', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling. WIDER IMPLICATIONS The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling.
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Affiliation(s)
- Antonio Capalbo
- Juno Genetics, Department of Reproductive Genetics, Rome, Italy
- Center for Advanced Studies and Technology (CAST), Department of Medical Genetics, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Guido de Wert
- Department of Health, Ethics & Society, CAPHRI-School for Public Health and Primary Care and GROW School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Heidi Mertes
- Department of Philosophy and Moral Sciences, Ghent University, Ghent, Belgium
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
| | - Liraz Klausner
- Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Edith Coonen
- Departments of Clinical Genetics and Reproductive Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School for Oncology and Developmental Biology, GROW, Maastricht University, Maastricht, The Netherlands
| | - Francesca Spinella
- Eurofins GENOMA Group Srl, Molecular Genetics Laboratories, Department of Scientific Communication, Rome, Italy
| | - Hilde Van de Velde
- Research Group Genetics Reproduction and Development (GRAD), Vrije Universiteit Brussel, Brussel, Belgium
- Brussels IVF, UZ Brussel, Brussel, Belgium
| | - Stephane Viville
- Laboratoire de Génétique Médicale LGM, Institut de Génétique Médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg, France
- Laboratoire de Diagnostic Génétique, Unité de Génétique de l’infertilité (UF3472), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Karen Sermon
- Research Group Genetics Reproduction and Development (GRAD), Vrije Universiteit Brussel, Brussel, Belgium
| | | | - Todd Lencz
- Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Departments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Shai Carmi
- Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
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23
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Qin PF, Yang L, Hu JP, Zhang JY. Breast cancer and rectal cancer associated with Lynch syndrome: A case report. World J Clin Oncol 2024; 15:1215-1221. [PMID: 39351452 PMCID: PMC11438856 DOI: 10.5306/wjco.v15.i9.1215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 07/28/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND The development mechanisms of Lynch syndrome (LS)-related breast cancer (BC) and rectal cancer are complex and variable, leading to personalized variations in diagnosis and treatment plans. CASE SUMMARY This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer. Moreover, screening data and management guidelines, as well as relevant literature on LS, are included in this report. This study summarizes the molecular pathogenesis, clinicopathological features, and screening and management protocols for LS-associated BC and rectal cancer. CONCLUSION Implementing early screening, prevention, and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer.
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Affiliation(s)
- Pei-Fang Qin
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Ling Yang
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Jun-Ping Hu
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Jing-Yue Zhang
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
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24
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Nowak M, Jabbar F, Rodewald AK, Gneo L, Tomasevic T, Harkin A, Iveson T, Saunders M, Kerr R, Oein K, Maka N, Hay J, Edwards J, Tomlinson I, Sansom O, Kelly C, Pezzella F, Kerr D, Easton A, Domingo E, Koelzer VH, Church DN. Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer. Cell Rep Med 2024; 5:101727. [PMID: 39293403 PMCID: PMC11525017 DOI: 10.1016/j.xcrm.2024.101727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/16/2024] [Accepted: 08/15/2024] [Indexed: 09/20/2024]
Abstract
Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.
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Affiliation(s)
- Marta Nowak
- Department of Pathology and Molecular Pathology, Zurich, Zurich, Switzerland
| | - Faiz Jabbar
- Cancer Genomics and Immunology Group, The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Ann-Katrin Rodewald
- Department of Pathology and Molecular Pathology, Zurich, Zurich, Switzerland
| | - Luciana Gneo
- Cancer Genomics and Immunology Group, The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Tijana Tomasevic
- Cancer Genomics and Immunology Group, The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Andrea Harkin
- CRUK Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, UK
| | - Tim Iveson
- University of Southampton, Southampton, UK
| | | | - Rachel Kerr
- Department of Oncology, University of Oxford, Oxford, UK
| | - Karin Oein
- Glasgow Tissue Research Facility, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
| | - Noori Maka
- Glasgow Tissue Research Facility, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
| | - Jennifer Hay
- Glasgow Tissue Research Facility, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
| | - Joanne Edwards
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Ian Tomlinson
- Department of Oncology, University of Oxford, Oxford, UK
| | - Owen Sansom
- CRUK Beatson Institute of Cancer Research, Garscube Estate, Glasgow, UK
| | - Caroline Kelly
- CRUK Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, UK
| | | | - David Kerr
- Nuffield Department of Clinical and Laboratory Sciences, University of Oxford, Oxford, UK
| | | | - Enric Domingo
- Department of Oncology, University of Oxford, Oxford, UK
| | - Viktor H Koelzer
- Department of Pathology and Molecular Pathology, Zurich, Zurich, Switzerland; Department of Oncology, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - David N Church
- Cancer Genomics and Immunology Group, The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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25
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Xue C, Zhu D, Wang X, Jiao L, Lu Y, Zhang S, Lv J, Cui L, Ruan M, Xu D, Liu Q, Feng Y, Mei S. Durable response to pembrolizumab in hepatic metastasis from colonic carcinoma with Lynch syndrome: a case report. Front Immunol 2024; 15:1455907. [PMID: 39247185 PMCID: PMC11377275 DOI: 10.3389/fimmu.2024.1455907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/07/2024] [Indexed: 09/10/2024] Open
Abstract
Pembrolizumab and other immunotherapies have become central in treating metastatic colon cancer, particularly effective in patients with mismatch repair deficiencies. We report a case involving a man who initially underwent radical surgery for sigmoid colon cancer on April 27, 2011, followed by hepatic tumor resection on September 21, 2017. Post-surgery, he received eight cycles of adjuvant chemotherapy with the CAPEOX regimen and was regularly monitored through CT and MRI scans. On August 24, 2022, liver metastases were detected, and he was diagnosed with Lynch syndrome (LS) due to germline mutation in the MSH2 and EPCAM genes. He commenced treatment with 200mg of pembrolizumab intravenously every three weeks on September 2, 2022, and demonstrated a sustained response. However, after 17 cycles, he developed a treatment related adverse event (TRAE) of pancreatic endocrine dysfunction, leading to type 1 diabetes, managed with subcutaneous insulin injections. After 30 cycles of treatment, no evidence of disease was observed. This case underscores the significant clinical benefits of first-line pembrolizumab in managing hepatic metastasis in colonic carcinoma associated with LS, despite the occurrence of TRAEs. It raises critical questions regarding the optimal duration of immunotherapy following a complete or partial response and whether treatment should be discontinued upon the emergency of TRAEs. Continued research and forthcoming clinical trials with checkpoint inhibitors are expected to refine treatment protocols for LS-associated carcinoma.
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Affiliation(s)
- Cheng Xue
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Dongqing Zhu
- Department of Radiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xin Wang
- Department of Health Management Center, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lina Jiao
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yunhui Lu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Sanli Zhang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Jiayi Lv
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Linlin Cui
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Mengna Ruan
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Dechao Xu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Qingyang Liu
- Department of Radiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yun Feng
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuqin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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26
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Durhuus JA, Galanakis M, Maltesen T, Therkildsen C, Rosthøj S, Klarskov LL, Lautrup CK, Andersen O, Nilbert MC. A registry-based study on universal screening for defective mismatch repair in colorectal cancer in Denmark highlights disparities in screening uptake and counselling referrals. Transl Oncol 2024; 46:102013. [PMID: 38824875 PMCID: PMC11170276 DOI: 10.1016/j.tranon.2024.102013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/15/2024] [Accepted: 05/27/2024] [Indexed: 06/04/2024] Open
Abstract
Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4-2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5-6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1-17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1-1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2-5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8-4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2-37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8-15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics.
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Affiliation(s)
- Jon Ambæk Durhuus
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Kettegårds Allé 30, Copenhagen 2630, Denmark; Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.
| | - Michael Galanakis
- Danish Cancer Institute, Statistics and Data Analysis, Copenhagen, Denmark
| | - Thomas Maltesen
- Danish Cancer Institute, Statistics and Data Analysis, Copenhagen, Denmark
| | - Christina Therkildsen
- The Danish HNPCC Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
| | - Susanne Rosthøj
- Danish Cancer Institute, Statistics and Data Analysis, Copenhagen, Denmark
| | - Louise Laurberg Klarskov
- Department of Pathology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - Ove Andersen
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Kettegårds Allé 30, Copenhagen 2630, Denmark
| | - Mef Christina Nilbert
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Kettegårds Allé 30, Copenhagen 2630, Denmark; Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, Sweden
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Puccini A, Nardin S, Trevisan L, Lastraioli S, Gismondi V, Ricciotti I, Damiani A, Bregni G, Murialdo R, Pastorino A, Martelli V, Gandini A, Mastracci L, Varesco L, Dono M, Battistuzzi L, Grillo F, Sciallero S. Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: a 10-year experience in a single Italian Cancer Center. Eur J Cancer Prev 2024; 33:355-362. [PMID: 38190337 DOI: 10.1097/cej.0000000000000870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
BACKGROUND Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). METHODS Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. RESULTS Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. CONCLUSION Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.
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Affiliation(s)
- Alberto Puccini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Hematology Unit, Rozzano, Milan
| | - Simone Nardin
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
- Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino
| | - Lucia Trevisan
- Medical Genetics Unit, IRCCS Ospedale Policlinico San Martino
| | - Sonia Lastraioli
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino
| | | | - Ilaria Ricciotti
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
| | - Azzurra Damiani
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
| | - Giacomo Bregni
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
| | | | | | | | - Annalice Gandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa
| | - Luca Mastracci
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino
- Department of Surgical and Integrated Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
| | - Liliana Varesco
- Medical Genetics Unit, IRCCS Ospedale Policlinico San Martino
| | - Maria Dono
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino
| | | | - Federica Grillo
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino
- Department of Surgical and Integrated Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
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Power RF, Doherty DE, Horgan R, Fahey P, Gallagher DJ, Lowery MA, Cadoo KA. Modifiable risk factors for cancer among people with lynch syndrome: an international, cross-sectional survey. Hered Cancer Clin Pract 2024; 22:10. [PMID: 38877502 PMCID: PMC11177364 DOI: 10.1186/s13053-024-00280-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 05/14/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Lynch syndrome is the most common cause of hereditary colorectal and endometrial cancer. Lifestyle modification may provide an opportunity for adjunctive cancer prevention. In this study, we aimed to characterise modifiable risk factors in people with Lynch syndrome and compare this with international guidelines for cancer prevention. METHODS A cross-sectional study was carried out utilizing survey methodology. Following public and patient involvement, the survey was disseminated through patient advocacy groups and by social media. Self-reported demographic and health behaviours were collected in April 2023. Guidelines from the World Cancer Research Fund (WCRF) were used to compare percentage adherence to 9 lifestyle recommendations, including diet, physical activity, weight, and alcohol intake. Median adherence scores, as a surrogate for lifestyle risk, were calculated and compared between groups. RESULTS 156 individuals with Lynch syndrome participated from 13 countries. The median age was 51, and 54% were cancer survivors. The mean BMI was 26.7 and the mean weekly duration of moderate to vigorous physical activity was 90 min. Median weekly consumption of ethanol was 60 g, and 3% reported current smoking. Adherence to WCRF recommendations for cancer prevention ranged from 9 to 73%, with all but one recommendation having < 50% adherence. The median adherence score was 2.5 out of 7. There was no significant association between median adherence scores and age (p = 0.27), sex (p = 0.31), or cancer history (p = 0.75). CONCLUSIONS We have characterised the modifiable risk profile of people living with Lynch syndrome, outlining targets for intervention based on lifestyle guidelines for the general population. As evidence supporting the relevance of modifiable factors in Lynch syndrome emerges, behavioural modification may prove an impactful means of cancer prevention.
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Affiliation(s)
- Robert F Power
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Cancer Genetics service, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Damien E Doherty
- Mater Misericordiae University Hospital, Eccles Street, Dublin, Ireland
| | | | - Pat Fahey
- Lynch syndrome Ireland, Dublin, Ireland
| | - David J Gallagher
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Cancer Genetics service, Trinity St James's Cancer Institute, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Maeve A Lowery
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Karen A Cadoo
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- Cancer Genetics service, Trinity St James's Cancer Institute, Dublin, Ireland.
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland.
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Zhu B, Liu M, Mu T, Li W, Ren J, Li X, Liang Y, Yang Z, Niu Y, Chen S, Lin J. Quadruple primary tumors in a lynch syndrome patient surviving more than 26 years with genetic analysis: a case report and literature review. Front Oncol 2024; 14:1382154. [PMID: 38894864 PMCID: PMC11184617 DOI: 10.3389/fonc.2024.1382154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/07/2024] [Indexed: 06/21/2024] Open
Abstract
The incidence of multiple primary tumors(MPTs) is on the rise in recent years, but patients having four or more primary tumors is still rare. Lynch syndrome (LS) patients have a high risk of developing MPTs. NGS sequencing could identify the genetic alterations in different tumors to make a definite diagnosis of uncommon cases in clinical practice. Here, we report the case of a 66-year-old female patient who develops four MPTS between the ages of 41 and 66, that is sigmoid colon cancer, acute non-lymphocytic leukemia, urothelial carcinoma and ascending colon cancer. She has survived for more than 26 years since the first discovery of tumor. Targeted sequencing indicates that she has a pathogenic germline mutation in the exon 13 of MSH2, and her 2020 ureteral cancer sample and 2023 colon cancer sample have completely different mutation profiles. To the best of our knowledge, this is the first case of multiple primary tumors with an acute non-lymphocytic leukemia in LS patients.
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Affiliation(s)
- Bosen Zhu
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ming Liu
- Research and Development Division, HaploX Biotechnology, Shenzhen, China
| | - Tianhao Mu
- Research and Development Division, HaploX Biotechnology, Shenzhen, China
| | - Wentao Li
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Junqi Ren
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiangtao Li
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yi Liang
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ziyi Yang
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yulin Niu
- Research and Development Division, HaploX Biotechnology, Shenzhen, China
| | - Shifu Chen
- Research and Development Division, HaploX Biotechnology, Shenzhen, China
| | - Junqiong Lin
- Department of Gastroenteroanal Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Boeri M, Signoroni S, Ciniselli CM, Gariboldi M, Zanutto S, Rausa E, Segale M, Zanghì A, Ricci MT, Verderio P, Sozzi G, Vitellaro M. Detection of (pre)cancerous colorectal lesions in Lynch syndrome patients by microsatellite instability liquid biopsy. Cancer Gene Ther 2024; 31:842-850. [PMID: 38332046 PMCID: PMC11192631 DOI: 10.1038/s41417-023-00721-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 02/10/2024]
Abstract
Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close endoscopic surveillance is the only option available to reduce CRC morbidity and mortality. However, it may fail to intercept interval cancers and patients' compliance to such an invasive procedure may decrease over the years. The development of a minimally invasive test able to detect (pre)cancerous colorectal lesions, could thus help tailor surveillance programs in LS patients. Taking advantage of an endoscopic surveillance program, we retrospectively assessed the instability of five microsatellites (BAT26, BAT25, NR24, NR21, and Mono27) in liquid biopsies collected at baseline and possibly at two further endoscopic rounds. For this purpose, we tested a new multiplex drop-off digital polymerase chain reaction (dPCR) assay, reaching mutant allele frequencies (MAFs) as low as 0.01%. Overall, 78 plasma samples at the three time-points from 18 patients with baseline (pre)cancerous lesions and 18 controls were available for molecular analysis. At baseline, the MAFs of BAT26, BAT25 and NR24 were significantly higher in samples of patients with lesions but did not differ with respect to the grade of dysplasia or any other clinico-pathological characteristics. When all markers were combined to determine MSI in blood, this test was able to discriminate lesion-bearing patients with an AUC of 0.80 (95%CI: 0.66; 0.94).
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Affiliation(s)
- Mattia Boeri
- Epigenomics and Biomarkers of Solid Tumors Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Stefano Signoroni
- Unit of Hereditary Digestive Tract Tumors, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Chiara Maura Ciniselli
- Bioinformatics and Biostatistics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Manuela Gariboldi
- Molecular Epigenomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Susanna Zanutto
- Molecular Epigenomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Emanuele Rausa
- Unit of Hereditary Digestive Tract Tumors, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Miriam Segale
- Epigenomics and Biomarkers of Solid Tumors Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Anna Zanghì
- Epigenomics and Biomarkers of Solid Tumors Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Teresa Ricci
- Unit of Hereditary Digestive Tract Tumors, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Verderio
- Bioinformatics and Biostatistics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Gabriella Sozzi
- Epigenomics and Biomarkers of Solid Tumors Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marco Vitellaro
- Unit of Hereditary Digestive Tract Tumors, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Colorectal Surgery Division, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Wang P, Zhong W, Huang Q, Zhu Y, Chen L, Ye K. Liposome Nanomedicine Based on Tumor Cell Lysate Mitigates the Progression of Lynch Syndrome-Associated Colon Cancer. ACS Biomater Sci Eng 2024; 10:3136-3147. [PMID: 38663028 DOI: 10.1021/acsbiomaterials.3c01531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2024]
Abstract
Treatment with immune checkpoint inhibitors (ICIs) has shown efficacy in some patients with Lynch syndrome-associated colon cancer, but some patients still do not benefit from it. In this study, we adopted a combination strategy of tumor vaccines and ICIs to maximize the benefits of immunotherapy. Here, we obtained tumor-antigen-containing cell lysate (TCL) by lysing MC38Mlh1 KD cells and prepared liposome nanoparticles (Lipo-PEG) with a typical spherical morphology by thin-film hydration. Anti-PD-L1 was coupled to the liposome surface by the amidation reaction. As observed, anti-PD-L1/TCL@Lipo-PEG was not significantly toxic to mouse intestinal epithelial cells (MODE-K) in the safe concentration range and did not cause hemolysis of mouse red blood cells. In addition, anti-PD-L1/TCL@Lipo-PEG reduced immune escape from colon cancer cells (MC38Mlh1 KD) by the anti-PD-L1 antibody, restored the killing function of CD8+ T cells, and targeted more tumor antigens to bone marrow-derived dendritic cells (BMDCs), which also expressed PD-L1, to stimulate BMDC antigen presentation. In syngeneic transplanted Lynch syndrome-associated colon cancer mice, the combination of anti-PD-L1 and TCL provided better cancer suppression than monoimmunotherapy, and the cancer suppression effect of anti-PD-L1/TCL@Lipo-PEG treatment was even better than that of the free drug. Meanwhile anti-PD-L1/TCL@Lipo-PEG enhanced the immunosuppressive tumor microenvironment. In vivo fluorescence imaging and H&E staining showed that the nanomedicine was mainly retained in the tumor site and had no significant toxic side effects on other major organs. The anti-PD-L1/TCL@Lipo-PEG prepared in this study has high efficacy and good biosafety in alleviating the progression of Lynch syndrome-associated colon cancer, and it is expected to be a therapeutic candidate for Lynch syndrome-associated colon cancer.
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Affiliation(s)
- Pengcheng Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Wenjin Zhong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Qiaozhen Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Yuejia Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Liquan Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Kai Ye
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
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Xu Y, Liu K, Li C, Li M, Zhou X, Sun M, Zhang L, Wang S, Liu F, Xu Y. Microsatellite instability in mismatch repair proficient colorectal cancer: clinical features and underlying molecular mechanisms. EBioMedicine 2024; 103:105142. [PMID: 38691939 PMCID: PMC11070601 DOI: 10.1016/j.ebiom.2024.105142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 05/03/2024] Open
Abstract
BACKGROUND Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).
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Affiliation(s)
- Yun Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Kai Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China
| | - Cong Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Minghan Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, PR China
| | - Menghong Sun
- Department of Pathology, Tissue Bank, Fudan University Shanghai Cancer Center, Shanghai, PR China
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Sheng Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China.
| | - Fangqi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Lawler T, Parlato L, Warren Andersen S. The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1349572. [PMID: 38737895 PMCID: PMC11082351 DOI: 10.3389/fonc.2024.1349572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes. Methods We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC. Results In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent. Discussion A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.
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Affiliation(s)
- Thomas Lawler
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Shaneda Warren Andersen
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
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Dosunmu GT, Shergill A. Colorectal Cancer: Genetic Underpinning and Molecular Therapeutics for Precision Medicine. Genes (Basel) 2024; 15:538. [PMID: 38790167 PMCID: PMC11120657 DOI: 10.3390/genes15050538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/16/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Colorectal cancer (CRC) accounts for about 10% of all cancer cases and 9% of cancer-related deaths globally. In the United States alone, CRC represents approximately 12.6% of all cancer cases, with a mortality rate of about 8%. CRC is now the first leading cause of cancer death in men younger than age 50 and second in women younger than age 50. This review delves into the genetic landscape of CRC, highlighting key mutations and their implications in disease progression and treatment. We provide an overview of the current and emerging therapeutic strategies tailored to individual genomic profiles.
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Affiliation(s)
| | - Ardaman Shergill
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA;
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35
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Patel A, Gulhati P. Molecular Landscape and Therapeutic Strategies against Colorectal Cancer. Cancers (Basel) 2024; 16:1551. [PMID: 38672633 PMCID: PMC11049251 DOI: 10.3390/cancers16081551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Although the overall incidence of CRC is decreasing, the incidence of young-onset CRC, characterized by a diagnosis of CRC before age 50, is increasing. Outcomes for CRC patients are improving, partly due to comprehensive molecular characterization of tumors and novel therapeutic strategies. Advances in genomic and transcriptomic analyses using blood- and tumor-tissue-based sequencing have facilitated identification of distinct tumor subtypes harboring unique biological characteristics and therapeutic vulnerabilities. These insights have led to the development and incorporation of targeted therapies and immunotherapy in CRC treatment. In this review, we discuss the molecular landscape and key oncogenes/tumor suppressors contributing to CRC tumorigenesis, metastasis, and therapeutic resistance. We also discuss personalized therapeutic strategies for subsets of CRC patients and provide an overview of evolving novel treatments being evaluated in clinical trials.
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Affiliation(s)
- Aakash Patel
- Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
| | - Pat Gulhati
- Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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Zhang M, Li X, Herman JG, Gao A, Wang Q, Yao Y, Shen F, He K, Guo M. Methylation of NRIP3 Is a Synthetic Lethal Marker for Combined PI3K and ATR/ATM Inhibitors in Colorectal Cancer. Clin Transl Gastroenterol 2024; 15:e00682. [PMID: 38235705 PMCID: PMC10962901 DOI: 10.14309/ctg.0000000000000682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/10/2024] [Indexed: 01/19/2024] Open
Abstract
INTRODUCTION The aim of this study was to investigate the epigenetic regulation and underlying mechanism of NRIP3 in colorectal cancer (CRC). METHODS Eight cell lines (SW480, SW620, DKO, LOVO, HT29, HCT116, DLD1, and RKO), 187 resected margin samples from colorectal cancer tissue, 146 cases with colorectal adenomatous polyps, and 308 colorectal cancer samples were used. Methylation-specific PCR, Western blotting, RNA interference assay, and a xenograft mouse model were used. RESULTS NRIP3 exhibited methylation in 2.7% (5/187) of resected margin samples from colorectal cancer tissue, 32.2% (47/146) of colorectal adenomatous polyps, and 50.6% (156/308) of CRC samples, and the expression of NRIP3 was regulated by promoter region methylation. The methylation of NRIP3 was found to be significantly associated with late onset (at age 50 years or older), poor tumor differentiation, lymph node metastasis, and poor 5-year overall survival in CRC (all P < 0.05). In addition, NRIP3 methylation was an independent poor prognostic marker ( P < 0.05). NRIP3 inhibited cell proliferation, colony formation, invasion, and migration, while induced G1/S arrest. NRIP3 suppressed CRC growth by inhibiting PI3K-AKT signaling both in vitro and in vivo . Methylation of NRIP3 sensitized CRC cells to combined PI3K and ATR/ATM inhibitors. DISCUSSION NRIP3 was frequently methylated in both colorectal adenomatous polyps and CRC. The methylation of NRIP3 may potentially serve as an early detection, late-onset, and poor prognostic marker in CRC. NRIP3 is a potential tumor suppressor. NRIP3 methylation is a potential synthetic lethal marker for combined PI3K and ATR/ATM inhibitors.
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Affiliation(s)
- Meiying Zhang
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyun Li
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - James G. Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
| | - Aiai Gao
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qian Wang
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuanxin Yao
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fangfang Shen
- Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Kunlun He
- Key Laboratory of Ministry of Industry and Information Technology of Biomedical Engineering and Translational Medicine, Chinese PLA General Hospital, Beijing, China
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
- National Key Laboratory of Kidney Diseases, the First Medical Center, Chinese PLA General Hospital, Beijing, China
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Dal Buono A, Puccini A, Franchellucci G, Airoldi M, Bartolini M, Bianchi P, Santoro A, Repici A, Hassan C. Lynch Syndrome: From Multidisciplinary Management to Precision Prevention. Cancers (Basel) 2024; 16:849. [PMID: 38473212 DOI: 10.3390/cancers16050849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. METHODS PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. RESULTS Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. CONCLUSIONS Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies.
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Affiliation(s)
- Arianna Dal Buono
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Alberto Puccini
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Gianluca Franchellucci
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Marco Airoldi
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Michela Bartolini
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Paolo Bianchi
- Clinical Analysis Laboratory, Oncological Molecular Genetics Section, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Armando Santoro
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Alessandro Repici
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Cesare Hassan
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
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Sadeghi M, Mestivier D, Carbonnelle E, Benamouzig R, Khazaie K, Sobhani I. Loss of symbiotic and increase of virulent bacteria through microbial networks in Lynch syndrome colon carcinogenesis. Front Oncol 2024; 13:1313735. [PMID: 38375206 PMCID: PMC10876293 DOI: 10.3389/fonc.2023.1313735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/14/2023] [Indexed: 02/21/2024] Open
Abstract
Purpose Through a pilot study, we performed whole gut metagenomic analysis in 17 Lynch syndrome (LS) families, including colorectal cancer (CRC) patients and their healthy first-degree relatives. In a second asymptomatic LS cohort (n=150) undergoing colonoscopy-screening program, individuals with early precancerous lesions were compared to those with a normal colonoscopy. Since bacteria are organized into different networks within the microbiota, we compared related network structures in patients and controls. Experimental design Fecal prokaryote DNA was extracted prior to colonoscopy for whole metagenome (n=34, pilot study) or 16s rRNA sequencing (validation study). We characterized bacteria taxonomy using Diamond/MEGAN6 and DADA2 pipelines and performed differential abundances using Shaman website. We constructed networks using SparCC inference tools and validated the construction's accuracy by performing qPCR on selected bacteria. Results Significant differences in bacterial communities in LS-CRC patients were identified, with an enrichment of virulent bacteria and a depletion of symbionts compared to their first-degree relatives. Bacteria taxa in LS asymptomatic individuals with colonic precancerous lesions (n=79) were significantly different compared to healthy individuals (n=71). The main bacterial network structures, constructed based on bacteria-bacteria correlations in CRC (pilot study) and in asymptomatic precancerous patients (validation-study), showed a different pattern than in controls. It was characterized by virulent/symbiotic co-exclusion in both studies and illustrated (validation study) by a higher Escherichia/Bifidobacterium ratio, as assessed by qPCR. Conclusion Enhanced fecal virulent/symbiotic bacteria ratios influence bacterial network structures. As an early event in colon carcinogenesis, these ratios can be used to identify asymptomatic LS individual with a higher risk of CRC.
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Affiliation(s)
- Mohammad Sadeghi
- EA7375 –EC2M3: Early detection of Colonic Cancer by using Microbial & Molecular Markers Paris East Créteil University (UPEC), Créteil, France
| | - Denis Mestivier
- EA7375 –EC2M3: Early detection of Colonic Cancer by using Microbial & Molecular Markers Paris East Créteil University (UPEC), Créteil, France
| | - Etienne Carbonnelle
- Bacteriology, Virology, Hygiene Laboratory, Assistance Publique–Hôpitaux de Paris (APHP), Avicenne Hospital, Bobigny, France
| | - Robert Benamouzig
- Department of Gastroenterology, Assistance Publique–Hôpitaux de Paris (APHP), Avicenne Hospital, Bobigny, France
| | | | - Iradj Sobhani
- EA7375 –EC2M3: Early detection of Colonic Cancer by using Microbial & Molecular Markers Paris East Créteil University (UPEC), Créteil, France
- Department of Gastroenterology, Assistance Publique–Hôpitaux de Paris (APHP), Henri Mondor Hospital, Créteil, France
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Panier S, Wang S, Schumacher B. Genome Instability and DNA Repair in Somatic and Reproductive Aging. ANNUAL REVIEW OF PATHOLOGY 2024; 19:261-290. [PMID: 37832947 DOI: 10.1146/annurev-pathmechdis-051122-093128] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.
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Affiliation(s)
- Stephanie Panier
- Institute for Genome Stability in Aging and Disease and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne and University Hospital of Cologne, Cologne, Germany;
- Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Siyao Wang
- Institute for Genome Stability in Aging and Disease and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne and University Hospital of Cologne, Cologne, Germany;
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Institute of Molecular Biology (IMB), Mainz, Germany
| | - Björn Schumacher
- Institute for Genome Stability in Aging and Disease and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne and University Hospital of Cologne, Cologne, Germany;
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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Heymer EJ, Jóźwiak K, Kremer LC, Winter DL, de Vathaire F, Sunguc C, Sugden E, Kok JL, van der Pal HJH, Hjorth L, Jakab Z, Maule MM, Haupt R, Bagnasco F, Terenziani M, Diallo I, Gunnes MW, Sommer G, Zadravec Zaletel L, Kuehni CE, Winther JF, Lähteenmäki PM, Gudmundsdottir T, Allodji RS, Skinner R, Ronckers CM, Hawkins MM, Reulen RC, Teepen JC. Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study. J Clin Oncol 2024; 42:336-347. [PMID: 37972325 DOI: 10.1200/jco.23.00452] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 09/12/2023] [Accepted: 09/26/2023] [Indexed: 11/19/2023] Open
Abstract
PURPOSE Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.
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Affiliation(s)
- Emma J Heymer
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Katarzyna Jóźwiak
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Leontien C Kremer
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
| | - David L Winter
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Florent de Vathaire
- Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Gustave Roussy, University Paris Saclay, Villejuif, France
| | - Ceren Sunguc
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Elaine Sugden
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Judith L Kok
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | | | - Lars Hjorth
- Department of Clinical Sciences Lund, Paediatrics,Skane University Hospital, Lund University, Lund, Sweden
| | - Zsuzsanna Jakab
- Hungarian Childhood Cancer Registry, 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Milena M Maule
- Childhood Cancer Registry of Piedmont, Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Riccardo Haupt
- Division of Hematology/Oncology, IRCCS Istituto Giannina Gaslini, DOPO Clinic, Genova, Italy
| | | | - Monica Terenziani
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Ibrahima Diallo
- Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Gustave Roussy, University Paris Saclay, Villejuif, France
| | - Maria W Gunnes
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Registration, Cancer Registry of Norway, Oslo, Norway
| | - Grit Sommer
- Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | | | - Claudia E Kuehni
- Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
- Division of Pediatric Hematology/Oncology, Department of Paediatrics, University Children's Hospital of Bern, University of Bern, Bern, Switzerland
| | - Jeanette F Winther
- Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark
| | - Päivi M Lähteenmäki
- Department of Pediatrics and Adolescent Medicine, Turku University and Turku University Hospital, Turku, Finland
| | - Thorgerdur Gudmundsdottir
- Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark
- Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland
| | - Rodrigue S Allodji
- Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Gustave Roussy, University Paris Saclay, Villejuif, France
| | - Roderick Skinner
- Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Cécile M Ronckers
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Health Services Research, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Michael M Hawkins
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Raoul C Reulen
- Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
| | - Jop C Teepen
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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Power RF, Doherty DE, Parker I, Gallagher DJ, Lowery MA, Cadoo KA. Modifiable Risk Factors and Risk of Colorectal and Endometrial Cancers in Lynch Syndrome: A Systematic Review and Meta-Analysis. JCO Precis Oncol 2024; 8:e2300196. [PMID: 38207227 DOI: 10.1200/po.23.00196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 09/21/2023] [Accepted: 09/23/2023] [Indexed: 01/13/2024] Open
Abstract
PURPOSE Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancers. Modifiable risk factors, including obesity, physical activity, alcohol intake, and smoking, are well-established in sporadic cancers but are less studied in Lynch syndrome. METHODS Searches were conducted on MEDLINE, Embase, and Web of Science for cohort studies that investigated the association between modifiable risk factors and the risk of colorectal or endometrial cancer in people with Lynch syndrome. Adjusted hazard ratios (HRs) and 95% CIs for colorectal and endometrial cancers were pooled using a random effects model. The protocol was prospectively registered on PROSPERO (CRD 42022378462), and the meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. RESULTS A total of 770 citations were reviewed. Eighteen studies were identified for qualitative synthesis, with seven colorectal cancer (CRC) studies eligible for meta-analysis. Obesity (HR, 2.38 [95% CI, 1.52 to 3.73]) was associated with increased CRC risk. There was no increased CRC risk associated with smoking (HR, 1.04 [95% CI, 0.82 to 1.32]) or alcohol intake (HR, 1.32 [95% CI, 0.97 to 1.81]). Type 2 diabetes mellitus (T2DM) and some dietary factors might increase risk of CRC although more studies are needed. In a qualitative synthesis of three endometrial cancer cohort studies, female hormonal risk factors and T2DM may affect the risk of endometrial cancer, but obesity was not associated with an increased risk. CONCLUSION Lifestyle recommendations related to weight and physical activity may also be relevant to cancer prevention for individuals with Lynch syndrome. Further high-quality prospective cohort studies, in particular, including endometrial cancer as an end point, are needed to inform evidence-based cancer prevention strategies in this high-risk population.
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Affiliation(s)
- Robert F Power
- Mater Misericordiae University Hospital, Dublin, Ireland
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
| | | | - Imelda Parker
- Department of Biostatistics, Cancer Trials Ireland, Dublin, Ireland
| | - David J Gallagher
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Maeve A Lowery
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Karen A Cadoo
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
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Lu M, Zhang X, Chu Q, Chen Y, Zhang P. Susceptibility Genes Associated with Multiple Primary Cancers. Cancers (Basel) 2023; 15:5788. [PMID: 38136334 PMCID: PMC10741435 DOI: 10.3390/cancers15245788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/29/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of next-generation sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.
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Affiliation(s)
| | | | | | | | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.L.)
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Emiloju OE, Sinicrope FA. Neoadjuvant Immune Checkpoint Inhibitor Therapy for Localized Deficient Mismatch Repair Colorectal Cancer: A Review. JAMA Oncol 2023; 9:1708-1715. [PMID: 37676680 DOI: 10.1001/jamaoncol.2023.3323] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Importance Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease. Observations Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy. Conclusions and Relevance While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.
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Affiliation(s)
| | - Frank A Sinicrope
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
- Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, Minnesota
- Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota
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Eikenboom EL, Moen S, van Leerdam ME, Papageorgiou G, Doukas M, Tanis PJ, Dekker E, Wagner A, Spaander MCW. Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study. Lancet Gastroenterol Hepatol 2023; 8:1106-1117. [PMID: 37865103 DOI: 10.1016/s2468-1253(23)00228-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. METHODS For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. FINDINGS Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). INTERPRETATION The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. FUNDING None.
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Affiliation(s)
- Ellis L Eikenboom
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Sarah Moen
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Grigorios Papageorgiou
- Department of Biostatistics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Pieter J Tanis
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
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Liepert M, Brundler MA, Galante GJ. A Rare Presentation of Pediatric Lynch Syndrome Presenting with Recurrent Adenomatous Polyps. JPGN REPORTS 2023; 4:e354. [PMID: 38034465 PMCID: PMC10684175 DOI: 10.1097/pg9.0000000000000354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/07/2023] [Indexed: 12/02/2023]
Abstract
Lynch syndrome (LS) is the most common cause of inherited colorectal cancer and the increases risk of developing extracolonic cancers. We present the first case of pediatric-onset LS with recurrent adenomatous colonic polyps presenting with rectal prolapse. This case highlights the importance of considering polyposis syndromes such as LS as possible diagnoses for pediatric patients who present with colorectal adenomatous polyps, as well as the need to consider immunohistochemical staining of polyps for mismatch repair protein expression in pediatric populations to rule out LS as a diagnosis. We demonstrate the need to consider pediatric patients in LS guidelines.
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Affiliation(s)
- Maryah Liepert
- From the Department of Internal Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Marie-Anne Brundler
- Department of Pathology & Laboratory Medicine and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Gary J Galante
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
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Xu Y, Liu K, Li C, Li M, Liu F, Zhou X, Sun M, Ranganathan M, Zhang L, Wang S, Hu X, Xu Y. The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major Genetic Risk Factor for Colorectal Cancer with Heterogeneous Clinical Phenotypes. RESEARCH (WASHINGTON, D.C.) 2023; 6:0249. [PMID: 37854294 PMCID: PMC10581333 DOI: 10.34133/research.0249] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/25/2023] [Indexed: 10/20/2023]
Abstract
While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk.
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Affiliation(s)
- Yun Xu
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Kai Liu
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Cong Li
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Minghan Li
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Fangqi Liu
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Xiaoyan Zhou
- Department of Pathology,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Menghong Sun
- Department of Pathology, Tissue Bank,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Megha Ranganathan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine,
University of California, Los Angeles, CA, USA
| | - Sheng Wang
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Xin Hu
- Precision Cancer Medical Center,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Ye Xu
- Department of Colorectal Surgery,
Fudan University Shanghai Cancer Center, Shanghai, P.R. China
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Keivanlou MH, Amini-Salehi E, Joukar F, Letafatkar N, Habibi A, Norouzi N, Vakilpour A, Aleali MS, Rafat Z, Ashoobi MT, Mansour-Ghanaei F, Hassanipour S. Family history of cancer as a potential risk factor for colorectal cancer in EMRO countries: a systematic review and meta-analysis. Sci Rep 2023; 13:17457. [PMID: 37838786 PMCID: PMC10576738 DOI: 10.1038/s41598-023-44487-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/09/2023] [Indexed: 10/16/2023] Open
Abstract
The current meta-analysis aims to investigate the existing articles that evaluated the implications of a positive family history of cancer on the risk of colorectal cancer (CRC) within the EMRO countries. We employed PubMed, Scopus, and Web of Science as search databases for this study. To assess the quality of the selected articles, we utilized the Newcastle-Ottawa (NCO) checklist. In comparing the impact of a family history of cancer between the case and control groups, we computed the odds ratio (OR) along with its corresponding 95% confidence interval (CI). Finally, 27 articles were selected for meta-analysis. The result of the meta-analysis showed a significant association between the presence of a family history of CRC or any cancers and CRC (OR 2.21; 95% CI 1.54-3.17; P < 0.001, OR 1.76; 95% CI 1.27-2.42; P = 0.001, respectively). Our findings underscore the critical importance of timely screening and early identification for individuals with a family history of cancer. By fostering close coordination among healthcare facilities and actively promoting the adoption of screening methods for early detection, we have the potential to significantly reduce both mortality rates and financial burdens of CRC on the general public, ultimately leading to enhanced patient outcomes.
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Affiliation(s)
- Mohammad-Hossein Keivanlou
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ehsan Amini-Salehi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Negin Letafatkar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arman Habibi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Naeim Norouzi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Maryam Sadat Aleali
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Zahra Rafat
- Department of Medical Parasitology and Mycology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Taghi Ashoobi
- Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht, Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Soheil Hassanipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran.
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Alvarez SJA, Pencheva B, Westfall E, Mwalija C, Parsell M, Greenleaf M, Porter CC, Lam WA, Mannino RG, Mitchell SG. A novel mobile health application to support cancer surveillance needs of patients and families with cancer predisposition syndromes. Pediatr Blood Cancer 2023; 70:e30537. [PMID: 37415085 PMCID: PMC11075126 DOI: 10.1002/pbc.30537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND At least 5%-10% of malignancies occur secondary to an underlying cancer predisposition syndrome (CPS). For these families, cancer surveillance is recommended with the goal of identifying malignancy earlier, in a presumably more curable form. Surveillance protocols, including imaging studies, bloodwork, and procedures, can be complex and differ based on age, gender, and syndrome, which adversely affect adherence. Mobile health (mHealth) applications (apps) have been utilized in oncology and could help to facilitate adherence to cancer surveillance protocols. METHODS Applying a user-centered mobile app design approach, patients with a CPS and/or primary caregivers were interviewed to identify current methods for care management and barriers to compliance with recommended surveillance protocols. Broad themes from these interviews informed the design of the mobile app, HomeTown, which was subsequently evaluated by usability experts. The design was then converted into software code in phases, evaluated by patients and caregivers in an iterative fashion. User population growth and app usage data were assessed. RESULTS Common themes identified included general distress surrounding surveillance protocol scheduling and results, difficulty remembering medical history, assembling a care team, and seeking resources for self-education. These themes were translated into specific functional app features, including push reminders, syndrome-specific surveillance recommendations, ability to annotate visits and results, storage of medical histories, and links to reliable educational resources. CONCLUSIONS Families with CPS demonstrate a desire for mHealth tools to facilitate adherence to cancer surveillance protocols, reduce related distress, relay medical information, and provide educational resources. HomeTown may be a useful tool for engaging this patient population.
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Affiliation(s)
- Santiago J Arconada Alvarez
- Emory University School of Medicine, Atlanta, Georgia, USA
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Bojana Pencheva
- Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Eleanor Westfall
- Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Comfort Mwalija
- Global Health Informatics Institute, Lilongwe Malawi
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Maren Parsell
- Emory University School of Medicine, Atlanta, Georgia, USA
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Morgan Greenleaf
- Emory University School of Medicine, Atlanta, Georgia, USA
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Christopher C Porter
- Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Wilbur A Lam
- Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Robert G Mannino
- Emory University School of Medicine, Atlanta, Georgia, USA
- AppHatchery, Georgia Clinical and Translational Science Alliance, Atlanta, Georgia, USA
| | - Sarah G Mitchell
- Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
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Choudhury H, Pandey M, Saravanan V, Mun ATY, Bhattamisra SK, Parikh A, Garg S, Gorain B. Recent progress of targeted nanocarriers in diagnostic, therapeutic, and theranostic applications in colorectal cancer. BIOMATERIALS ADVANCES 2023; 153:213556. [PMID: 37478770 DOI: 10.1016/j.bioadv.2023.213556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/28/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023]
Abstract
Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.
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Affiliation(s)
- Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
| | - Vilashini Saravanan
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Amanda Tan Yee Mun
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ankit Parikh
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Sanjay Garg
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
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