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Fukuya H, Sasaki T, Ihara E, Yoshimura D, Okitsu R, Ohkubo A, Matsushita Y, Hasuda H, Sakaguchi Y, Harada N. A case of gastric-localized juvenile polyposis syndrome with SMAD4 mosaic variant presenting as a slowly progressive phenotype. Clin J Gastroenterol 2025:10.1007/s12328-025-02146-7. [PMID: 40372668 DOI: 10.1007/s12328-025-02146-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 05/02/2025] [Indexed: 05/16/2025]
Abstract
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder caused by pathogenic variants in the mothers against decapentaplegic homolog 4 (SMAD4) and bone morphogenetic protein receptor type 1A (BMPR1A) genes. It is characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. We report a case of a 73-year-old Japanese male with sporadic, gastric-localized JPS harboring a SMAD4 mosaic variant who presented with slowly progressive endoscopic lesions. Endoscopy at the age of 55 revealed erythematous and edematous mucosa in the gastric fundus. During the following 18 years, the patient developed progressive gastric polyposis, leading to refractory anemia and hypoalbuminemia. Genetic testing identified a SMAD4 frameshift mosaic variant (c.1245_1248del (p.Asp415Glufs)) with an allele frequency of 23%. A total gastrectomy with D1 lymphadenectomy was performed, confirming the JPS diagnosis and the identification of a localized gastric adenocarcinoma without lymph node metastasis. This case highlights the unique natural history of JPS with a SMAD4 mosaic variant, which potentially contributes to a slowly progressive phenotype.
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Affiliation(s)
- Hiroki Fukuya
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan.
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
| | - Taisuke Sasaki
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Daisuke Yoshimura
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Ryota Okitsu
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Akito Ohkubo
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yuki Matsushita
- Department of Pediatrics, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
- Department of Clinical genomics, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hirofumi Hasuda
- Department of Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoshihisa Sakaguchi
- Department of Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Naohiko Harada
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Fukuoka, 810-8563, Japan
- Institute of Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
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Aoun RJN, Kalady MF. Hereditary Colorectal Cancer: From Diagnosis to Surgical Options. Clin Colon Rectal Surg 2025; 38:179-190. [PMID: 40292001 PMCID: PMC12020645 DOI: 10.1055/s-0044-1787884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Hereditary colorectal cancer (CRC) syndromes account for up to 5% of CRC. Patients have an increased risk of CRC and extracolonic cancers, both of which develop at an early age. The main polyposis syndromes include familial adenomatous polyposis, MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. The non-polyposis syndromes include Lynch syndrome and familial colorectal cancer type X. Each of the syndromes have distinct but sometimes overlapping phenotypes. Clinical evaluation and ultimately the underlying germline genetic pathogenic variants define the syndromes. Each syndrome has polyp, CRC, and extracolonic risks and management is based on early and timely surveillance with therapeutic and often extended prophylactic surgery. Surgical intervention strategies are individualized, considering not only the earlier onset of malignancies and heightened risks for metachronous cancers but also the patient's needs and quality of life. This article reviews the different diagnostic approaches to hereditary CRC and highlights subsequent disease-specific management and surgical decision-making strategies.
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Affiliation(s)
- Rami James N. Aoun
- Division of Colon and Rectal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Matthew F. Kalady
- Division of Colon and Rectal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
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Li D, Morgan DR, Corral JE, Montgomery EA, Riquelme A, Shah SC. Gastric Cancer Screening in the United States: A Review of Current Evidence, Challenges, and Future Perspectives. Am J Gastroenterol 2025; 120:765-777. [PMID: 40072512 DOI: 10.14309/ajg.0000000000003301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 12/18/2024] [Indexed: 03/14/2025]
Abstract
Gastric cancer remains a leading cause of cancer-related mortality worldwide. In the United States, gastric cancer incidence and mortality are substantially higher among non-White racial and ethnic groups and new immigrants from high-incidence countries. This is in large part related to the higher prevalence of Helicobacter pylori -associated gastric premalignant changes in these populations. Apart from primary prevention, early detection of gastric cancer is the principal strategy to reduce gastric cancer mortality and improve survival. Extensive evidence in Asian countries has demonstrated the benefits of endoscopic screening in detecting early-stage gastric cancer and reducing gastric cancer-related mortality. By contrast, direct, high-quality US-based data, such as from large clinical trials or observational studies, on important outcomes of gastric cancer screening are still lacking. In this review, we evaluate and summarize the latest global evidence on the epidemiology and predisposing factors of gastric cancer as well as the efficacy, benefits vs. risks, and cost-effectiveness of gastric cancer screening. We further discuss the critical knowledge gaps and challenges in promoting gastric cancer screening in the United States. Dedicated research is urgently needed to enrich the US-based data on gastric cancer primary and secondary prevention to inform clinical practice and reduce gastric cancer-related morbidity and mortality in a cost and resource efficient manner.
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Affiliation(s)
- Dan Li
- Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, California, USA
- Kaiser Permanente Northern California Division of Research, Oakland, California, USA
| | - Douglas R Morgan
- Division of Gastroenterology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Juan E Corral
- Division of Gastroenterology, Prisma Health, Greenville, South Carolina, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Arnoldo Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Control and Prevention of Cancer (CECAN), Santiago, Chile
| | - Shailja C Shah
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Gastroenterology Section, Jennifer Moreno Department of Veterans Affairs Medical Center, La Jolla, California, USA
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Yang M, Tong Z, Yuan Z, Jiang B, Zhao Y, Xu D, Yuan Y. A Novel Missense Variant of BMPR1A in Juvenile Polyposis Syndrome: Assessment of Structural and Functional Alternations. Hum Mutat 2025; 2025:7317429. [PMID: 40226309 PMCID: PMC11919155 DOI: 10.1155/humu/7317429] [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: 08/22/2024] [Accepted: 01/27/2025] [Indexed: 04/15/2025]
Abstract
Juvenile polyposis syndrome (JPS) is a rare precancerous condition associated with a high susceptibility to colorectal cancer. The genetic basis of JPS has been reported to lie in germline mutations in BMPR1A or SMAD4, resulting in diverse clinical manifestations and an elusive underlying mechanism. We firstly utilized a 139-gene next-generation sequencing (NGS) panel to detect the germline variants and further employed various prediction tools to assess the pathogenicity and functional alternations. Consequently, we identified a novel pathogenic BMPR1A missense variant (c.355C>T; p.R119C). More importantly, we proposed for the first time that the missense variant would lead to a decrease in molecular weight, potentially associated with reduced protein stability, diminished posttranslational modifications, and aberrant alternative splicing. These findings may provide novel perspectives for further exploration into the role of BMPR1A in JPS development. Also, we hope to encourage clinicians to underscore the importance of genetic testing and analysis in facilitating the diagnosis and treatment of diseases.
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Affiliation(s)
- Mengyuan Yang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ziyan Tong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhijun Yuan
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Bingjing Jiang
- Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yingxin Zhao
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dong Xu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
- Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China
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Matsubara Y, Nakamura Y, Nakayama Y, Yano T, Ishikawa H, Kumagai H, Umeno J, Uchida K, Jimbo K, Yamamoto T, Ishida H, Suzuki O, Okamoto K, Kakuta F, Koike Y, Kawasaki Y, Sakamoto H. Prevalence and Incidence of Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome in Japan: A Nationwide Epidemiological Survey in 2022. J Gastroenterol Hepatol 2025; 40:473-481. [PMID: 39623880 DOI: 10.1111/jgh.16839] [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: 06/27/2024] [Revised: 10/17/2024] [Accepted: 11/17/2024] [Indexed: 02/11/2025]
Abstract
BACKGROUND AND AIM Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) are autosomal dominant diseases associated with high cancer risk. In Japan, knowledge about the prevalence and incidence of PJS and JPS is lacking despite being crucial for providing appropriate medical support. We aimed to determine the prevalence and incidence of these diseases. METHODS In 2022, a nationwide questionnaire survey was conducted to determine the number of patients with PJS or JPS by sex and the number of newly confirmed cases from 2019 to 2021. The target facilities included gastroenterology, pediatrics, and pediatric surgery departments, which were stratified into seven classes on the basis of the total number of beds. We randomly selected target facilities using different extraction rates in each class, resulting in 1748/2912 facilities (extraction rate: 60%) as the final sample. We calculated the estimated number of patients using the response and extraction rates. RESULTS A total of 1077 facilities responded to the survey. The estimated numbers of patients with PJS and JPS were 701 (95% confidence interval [CI]: 581-820) and 188 (95% CI: 147-230), respectively. The 3-year period prevalences of PJS and JPS were 0.6/100000 and 0.15/100000, whereas the incidences in 2021 were 0.07/100000 and 0.02/100000, respectively. Male patients constituted 53.5% and 59.6% in the PJS and JPS groups, respectively. CONCLUSIONS We determined the prevalence and incidence of PJS and JPS in Japan for the first time. Further research is needed to obtain more detailed information, including the clinical differences and outcomes in Japan.
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Affiliation(s)
- Yuri Matsubara
- Department of Public Health, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | | | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonori Yano
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideki Kumagai
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichi Uchida
- Department of Pediatric Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Keisuke Jimbo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, 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
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Fumihiko Kakuta
- Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Japan
| | - Yuhki Koike
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yuko Kawasaki
- College of Nursing Art and Science, University of Hyogo, Akashi, Japan
| | - Hirotsugu Sakamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
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Li J, Yao H, Lu Y, Zhang S, Zhang Z. Chinese national clinical practice guidelines on prevention, diagnosis and treatment of early colorectal cancer. Chin Med J (Engl) 2024; 137:2017-2039. [PMID: 39104005 PMCID: PMC11374253 DOI: 10.1097/cm9.0000000000003253] [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] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND The incidence and mortality of colorectal cancer (CRC) in China are increasing in recent years. The clarified pathogenesis and detectable precancerous lesions of CRC make it possible to prevent, screen, and diagnose CRC at an early stage. With the development of endoscopic and surgical techniques, the choice of treatment for early CRC is also worth further discussion, and accordingly, a standard follow-up program after treatment needs to be established. METHODS This clinical practice guideline (CPG) was developed following the recommended process of the World Health Organization, adopting Grading of Recommendations Assessment, Development and Evaluation (GRADE) in assessing evidence quality, and using the Evidence to Decision framework to formulate clinical recommendations, thereby minimizing bias and increasing transparency of the CPG development process. We used the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement and Appraisal of Guidelines for Research and Evaluation II (AGREE II) as reporting and conduct guides to ensure the guideline's completeness and transparency. RESULTS This CPG comprises 46 recommendations concerning prevention, screening, diagnosis, treatment, and surveillance of CRC. In these recommendations, we have indicated protective and risk factors for CRC and made recommendations for chemoprevention. We proposed a suitable screening program for CRC based on the Chinese context. We also provided normative statements for the diagnosis, treatment, and surveillance of CRC based on existing clinical evidence and guidelines. CONCLUSIONS The 46 recommendations in this CPG are formed with consideration for stakeholders' values and preferences, feasibility, and acceptability. Recommendations are generalizable to resource-limited settings with similar CRC epidemiology pattern as China.
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Affiliation(s)
- Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Hongwei Yao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Yun Lu
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266555, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing 100050, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China
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Costa D, Ramai D, Tringali A. Novel classification of gastric polyps: The good, the bad and the ugly. World J Gastroenterol 2024; 30:3640-3653. [PMID: 39192997 PMCID: PMC11346164 DOI: 10.3748/wjg.v30.i31.3640] [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: 05/22/2024] [Revised: 07/19/2024] [Accepted: 08/02/2024] [Indexed: 08/13/2024] Open
Abstract
Gastric polyps (GPs) are increasingly common. On upper endoscopy, they should be examined with white light and occasionally chromoendoscopy, and their morphology classified according to the Paris classification. Most GPs have a typical endoscopic appearance and can be associated with diseases like Helicobacter pylori infection. Histological examination is necessary for an accurate diagnosis. While most polyps are non-neoplastic and do not require treatment, some carry a risk of malignancy or are already malignant. Therefore, understanding the diagnosis, classification, and management of GPs is crucial for patient prognostication. Our new classification categorizes GPs into "good", "bad", and "ugly" based on their likelihood of becoming malignant. We aim to provide descriptions of the endoscopic appearance, pathology, treatment, and follow-up for different GPs, as well as clinical management flowcharts.
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Affiliation(s)
- Deborah Costa
- Department of Digestive Endoscopy and Gastroenterology, AULSS2, Conegliano Hospital, Conegliano 31015, Italy
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, United States
| | - Alberto Tringali
- Department of Digestive Endoscopy and Gastroenterology, AULSS2, Conegliano Hospital, Conegliano 31015, Italy
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Costa D, Ramai D, Tringali A. Novel classification of gastric polyps: The good, the bad and the ugly. World J Gastroenterol 2024; 30:3640-3653. [DOI: doi 10.3748/wjg.v30.i31.3640 pmid: 39192997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
Gastric polyps (GPs) are increasingly common. On upper endoscopy, they should be examined with white light and occasionally chromoendoscopy, and their morphology classified according to the Paris classification. Most GPs have a typical endoscopic appearance and can be associated with diseases like Helicobacter pylori infection. Histological examination is necessary for an accurate diagnosis. While most polyps are non-neoplastic and do not require treatment, some carry a risk of malignancy or are already malignant. Therefore, understanding the diagnosis, classification, and management of GPs is crucial for patient prognostication. Our new classification categorizes GPs into "good", "bad", and "ugly" based on their likelihood of becoming malignant. We aim to provide descriptions of the endoscopic appearance, pathology, treatment, and follow-up for different GPs, as well as clinical management flowcharts.
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Forte G, Buonadonna AL, Fasano C, Sanese P, Cariola F, Manghisi A, Guglielmi AF, Lepore Signorile M, De Marco K, Grossi V, Disciglio V, Simone C. Clinical and Molecular Characterization of SMAD4 Splicing Variants in Patients with Juvenile Polyposis Syndrome. Int J Mol Sci 2024; 25:7939. [PMID: 39063183 PMCID: PMC11276957 DOI: 10.3390/ijms25147939] [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: 06/14/2024] [Revised: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer.
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Affiliation(s)
- Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Antonia Lucia Buonadonna
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Filomena Cariola
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Andrea Manghisi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Anna Filomena Guglielmi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (A.L.B.); (C.F.); (P.S.); (F.C.); (A.M.); (A.F.G.); (M.L.S.); (K.D.M.); (V.G.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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Cohen S, Yerushalmy-Feler A, Rojas I, Phen C, Rudnick DA, Flahive CB, Erdman SH, Magen-Rimon R, Copova I, Attard T, Latchford A, Hyer W. Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden. J Pediatr Gastroenterol Nutr 2024; 79:161-167. [PMID: 38801072 DOI: 10.1002/jpn3.12257] [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: 03/24/2024] [Revised: 05/09/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
OBJECTIVE A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS. METHODS Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group. RESULTS A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. CONCLUSIONS This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.
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Affiliation(s)
- Shlomi Cohen
- Tel Aviv Sourasky Medical Center, affiliated to the Faculty of Medicine, Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv University, Tel Aviv, Israel
| | - Anat Yerushalmy-Feler
- Tel Aviv Sourasky Medical Center, affiliated to the Faculty of Medicine, Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv University, Tel Aviv, Israel
| | - Isabel Rojas
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Claudia Phen
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - David A Rudnick
- Departments of Pediatrics and Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Colleen B Flahive
- Department of Pediatrics, Division of Gastroenterology Hepatology and Nutrition, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Steven H Erdman
- Department of Pediatrics, Division of Gastroenterology Hepatology and Nutrition, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Ramit Magen-Rimon
- Rambam Medical Center, Faculty of Medicine, Pediatric Gastroenterology and Nutrition Institute, Ruth Children's Hospital of Haifa, Technion, Haifa, Israel
| | - Ivana Copova
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University Hospital Motol and 2nd Faculty of Medicine, Prague, Czech Republic
| | - Thomas Attard
- Division of Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital Kansas City, The University of Missouri in Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Andrew Latchford
- St Mark's Centre for Familial Intestinal Cancer, St Mark's Hospital, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Warren Hyer
- St Mark's Hospital, National Bowel Hospital, London, UK
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11
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Fernández Aceñero MJ, Díaz del Arco C. Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes. Curr Issues Mol Biol 2024; 46:6440-6471. [PMID: 39057027 PMCID: PMC11275188 DOI: 10.3390/cimb46070385] [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: 05/27/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.
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Affiliation(s)
- María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Cristina Díaz del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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12
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Zohud O, Midlej K, Lone IM, Nashef A, Abu-Elnaaj I, Iraqi FA. Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models. Int J Mol Sci 2024; 25:5812. [PMID: 38891999 PMCID: PMC11172477 DOI: 10.3390/ijms25115812] [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: 03/28/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.
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Affiliation(s)
- Osayd Zohud
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Kareem Midlej
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Iqbal M. Lone
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Aysar Nashef
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya Tebaria 42310, Israel; (A.N.); (I.A.-E.)
- Department of Oral and Maxillofacial Surgery, Meir Medical Center, Faculty of Medicine and Health Sciences, Tel-Aviv University, Kfar-Saba 69978, Israel
| | - Imad Abu-Elnaaj
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya Tebaria 42310, Israel; (A.N.); (I.A.-E.)
- Azrieli Faculty of Medicine, Bar-Ilan University, Tsaft 33241, Israel
| | - Fuad A. Iraqi
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
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13
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Matsuyama S, Fukuda A, Matsumoto A, Eguchi H, Ueo T, Ohana M, Seno H. Sporadic gastric juvenile polyposis with a novel SMAD4 nonsense mutation in a mosaic pattern. Clin J Gastroenterol 2024; 17:23-28. [PMID: 37950802 DOI: 10.1007/s12328-023-01884-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/19/2023] [Indexed: 11/13/2023]
Abstract
A 50-year-old female was diagnosed with gastric hyperplastic polyps 7 years before and was followed up at another hospital. She was referred to our hospital because of the growth of gastric polyps and progression of anemia. She had no family history of polyposis. The polyps were observed only in the stomach, increased in size and number, and the erythematous edema got worse. Endoscopic mucosal resection (EMR) of the gastric polyp was performed. Pathologically, the gastric polyp was hamartomatous polyp, and the intervening mucosa between polyps showed no atypical structure without inflammation. Given that gastric juvenile polyposis (GJP) was clinically suspected, a genetic test using peripheral blood was performed. Target resequencing and Sanger sequencing analysis revealed a nonsense mutation in the SMAD4 gene at codon 169. The mutation was detected at a low frequency of 11%, and considered a mosaic mutation. Therefore, she was diagnosed with a sporadic GJP, and total gastrectomy was performed. Immunostaining of SMAD4 for the resected specimen showed a mixture of stained and unstained area in the epithelium of the polyp, indicating partial loss of SMAD4 expression. To our knowledge, this is the first reported case of GJP with a nonsense SMAD4 mutation at codon 169 in a mosaic pattern.
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Affiliation(s)
- Sho Matsuyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
- Department of Gastroenterology, Tenri Hospital, 200 Mishima-Cho, Tenri, Nara, 632-8552, Japan.
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Atsushi Matsumoto
- Department of Gastroenterology, Tenri Hospital, 200 Mishima-Cho, Tenri, Nara, 632-8552, Japan
| | - Hidetaka Eguchi
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, 113-8431, Japan
| | - Taro Ueo
- Department of Gastroenterology, Tenri Hospital, 200 Mishima-Cho, Tenri, Nara, 632-8552, Japan
| | - Masaya Ohana
- Department of Gastroenterology, Tenri Hospital, 200 Mishima-Cho, Tenri, Nara, 632-8552, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
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14
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Nakamura K, Kubota K, Shimizu A, Notake T, Ikehara T, Umemura K, Kamachi A, Goto T, Tomida H, Takahashi Y, Nagaya T, Umemura T, Soejima Y. Juvenile polyposis syndrome with gastric and duodenal polyposis presenting with refractory anemia and protein-leakage gastroenteropathy in a patient with SMAD4 mutation: a case report. Surg Case Rep 2024; 10:11. [PMID: 38191939 PMCID: PMC10774325 DOI: 10.1186/s40792-023-01796-4] [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: 10/28/2023] [Accepted: 12/18/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder characterized by multiple hyperproliferative polyps of the gastrointestinal tract, particularly of the colon, rectum, and stomach. SMAD4 mutations are frequently associated with multiple polyposis of the stomach; the condition causes severe bleeding and hypoproteinemia, which may progress to severe dysplasia and adenocarcinoma formation. We report our experience with the first case of total gastrectomy with pancreaticoduodenectomy following two partial jejunectomies for JPS, who presented with refractory anemia and protein-losing gastroenteropathy due to polyposis of the stomach and duodenum. CASE PRESENTATION A 33-year-old Japanese man presented with the chief complaint of shortness of breath on exertion. His family history included gastric polyposis (mother, aunt, and cousin) and cerebral infarction (grandmother). Blood testing at the initial visit indicated iron-deficiency anemia, whereas endoscopy revealed multiple polyps in the duodenum and jejunum. Genetic testing revealed a 4 bp deletion (TGAA) in exon 5 of the SMAD4 gene; two partial small bowel resections were performed, but polyps grew in the remaining stomach, duodenum, and small intestine. The patient developed hypoalbuminemia and anemia, and required central venous nutrition and blood transfusion. However, because the hyponutrition and anemia remained poorly controlled, a total gastrectomy with concomitant pancreaticoduodenectomy was performed. Malnutrition and anemia improved, and there was no polyp recurrence in the remaining intestinal tract at 18 months after the surgery. CONCLUSIONS We report a case of JPS with refractory anemia and protein-losing gastroenteropathy that was treated with total gastrectomy with concomitant pancreaticoduodenectomy. Although the surgery was highly invasive, the patient's nutritional status and anemia improved postoperatively, and the treatment was successful. However, to determine the appropriate surgical procedure, a detailed examination of the gastrointestinal lesions and the effects of the surgical invasion on nutritional status must be undertaken.
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Affiliation(s)
- Kenya Nakamura
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Koji Kubota
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Akira Shimizu
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Tsuyoshi Notake
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Tomohiko Ikehara
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Kentaro Umemura
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Atsushi Kamachi
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Takamune Goto
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Hidenori Tomida
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yoshiyuki Takahashi
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tadanobu Nagaya
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Soejima
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
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15
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [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: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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16
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Jelsig AM, Wullum L, Kuhlmann TP, Ousager LB, Burisch J, Karstensen JG. Risk of Cancer and Mortality in Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome-A Nationwide Cohort Study With Matched Controls. Gastroenterology 2023; 165:1565-1567.e2. [PMID: 37659672 DOI: 10.1053/j.gastro.2023.08.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/22/2023] [Accepted: 08/27/2023] [Indexed: 09/04/2023]
Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
| | | | | | | | - Johan Burisch
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Wu MY, Toon C, Field M, Wong M. Polyposis found on index colonoscopy in a 56-year-old female - BMPR1A variant in juvenile polyposis syndrome: A case report. World J Gastrointest Endosc 2023; 15:623-628. [PMID: 37900118 PMCID: PMC10600688 DOI: 10.4253/wjge.v15.i10.623] [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: 05/10/2023] [Revised: 07/21/2023] [Accepted: 07/31/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Juvenile polyposis syndrome (JPS) is a rare hereditary polyposis disease frequently associated with an autosomal-dominant variant of the SMAD4 or BMPR1A gene. It often manifests with symptoms in children and adolescents and is infrequently diagnosed in asymptomatic adults. Establishing the diagnosis is important as patients with JPS have a high risk of developing gastrointestinal cancer and require genetic counselling and close routine follow-up. CASE SUMMARY We report on the case of a 56-year-old female diagnosed with JPS after genetic testing revealed a rare variant of the BMPR1A gene BMPR1A c.1409T>C (p.Met470Thr). She was initially referred for colonoscopy by her general practitioner after testing positive on a screening faecal immunochemical test and subsequently found to have polyposis throughout the entire colorectum on her index screening colonoscopy. The patient was asymptomatic with a normal physical examination and no related medical or family history. Blood tests revealed only mild iron deficiency without anemia. To date, there has only been one other reported case of JPS with the same genetic variant. Subsequent colonoscopies were organised for complete polyp clearance and the patient was returned for surveillance follow-up. CONCLUSION JPS patients can present with no prior symptoms or family history. Genetic testing plays an important diagnostic role guiding management.
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Affiliation(s)
- Michael Yulong Wu
- Department of Gastroenterology and Hepatology, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
- Northern Clinical School, The University of Sydney, Sydney 2065, New South Wales, Australia
| | - Christopher Toon
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
| | - Michael Field
- Clinical Genetics, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
| | - May Wong
- Department of Gastroenterology and Hepatology, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
- Northern Clinical School, The University of Sydney, Sydney 2065, New South Wales, Australia
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18
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Jelsig AM, van Overeem Hansen T, Gede LB, Qvist N, Christensen LL, Lautrup CK, Ljungmann K, Christensen LT, Rønlund K, Tørring PM, Bertelsen B, Sunde L, Karstensen JG. Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study. Fam Cancer 2023; 22:429-436. [PMID: 37354305 PMCID: PMC10542306 DOI: 10.1007/s10689-023-00338-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/23/2023] [Indexed: 06/26/2023]
Abstract
Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.
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Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
| | - Thomas van Overeem Hansen
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lene Bjerring Gede
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Niels Qvist
- Research Unit for Surgery, Odense University Hospital, Odense, Denmark
- University of Southern Denmark, Odense, Denmark
| | | | | | - Ken Ljungmann
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
| | | | - Karina Rønlund
- Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark
| | | | - Birgitte Bertelsen
- Center for Genomic Medicine, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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19
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Foda ZH, Dharwadkar P, Katona BW. Preventive strategies in familial and hereditary colorectal cancer. Best Pract Res Clin Gastroenterol 2023; 66:101840. [PMID: 37852714 DOI: 10.1016/j.bpg.2023.101840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/05/2023] [Accepted: 05/17/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. While most cases are sporadic, a significant proportion of cases are associated with familial and hereditary syndromes. Individuals with a family history of colorectal cancer have an increased risk of developing the disease, and those with hereditary syndromes such as Lynch syndrome or familial adenomatous polyposis have a significantly higher risk. In these populations, preventive strategies are critical for reducing the incidence and mortality of colorectal cancer. This review provides an overview of current preventive strategies for individuals at increased risk of colorectal cancer due to familial or hereditary factors. The manuscript includes a discussion of risk assessment and genetic testing, highlighting the importance of identifying at-risk individuals and families. This review describes various preventive measures, including surveillance colonoscopy, chemoprevention, and prophylactic surgery, and their respective benefits and limitations. Together, this work highlights the importance of preventive strategies in familial and hereditary colorectal cancer.
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Affiliation(s)
- Zachariah H Foda
- The Sidney Kimmel Comprehensive Cancer Center and Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Pooja Dharwadkar
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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20
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Papadopulos ME, Plazzer JP, Macrae FA. Genotype-phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome. Hered Cancer Clin Pract 2023; 21:12. [PMID: 37400896 DOI: 10.1186/s13053-023-00255-3] [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: 10/10/2022] [Accepted: 06/07/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Juvenile Polyposis Syndrome (JPS) is an autosomal dominant condition with hamartomatous polyps in the gastrointestinal tract, associated with an increased risk of gastrointestinal malignancy. Disease causing variants (DCVs) in BMPR1a or SMAD4 account for 45-60% of JPS cases, with BMPR1a DCVs accounting for 17-38% of JPS cases. Within those with either a BMPR1a or SMAD4 DCV, there is phenotypic variability in location of polyps, risk of malignancy and extra-intestinal manifestations with limited published reports of gene-phenotype association or genotype-phenotype correlation. We aimed to identify any gene-phenotype association or genotype-phenotype correlation in BMPR1a to inform surveillance recommendations, and gene-specific modification to the ACMG classification of pathogenicity of DCVs. METHODS A literature search was performed through EMBASE, MEDLINE and PubMed. Studies that were included explored BMPR1a DCV-related JPS or contiguous deletion of PTEN and BMPR1a. Data was also drawn from the BMPR1a specific databases on LOVD and ClinVar. RESULTS There were 211 DCVs in BMPR1a identified, 82 from patients with JPS in the literature, and 17 from LOVD and 112 from ClinVar classified as pathogenic or likely pathogenic. These included missense, nonsense and frameshift variants and large deletions, occurring across all functional domains of the gene. Unlike in SMAD4 carriers, gastric polyposis and malignancy were not identified in our review in BMPR1a carriers, but colonic polyposis and malignancy occurred in carriers of either BMPR1a or SMAD4 DCVs. Those with contiguous deletion of PTEN and BMPR1a can present with JPS of infancy, with a severe phenotype of GI bleeding, diarrhoea, exudative enteropathy and rectal prolapse. No specific BMPR1a genotype-phenotype correlation could be ascertained including by variant type or functional domain. CONCLUSION Phenotypic characteristics cannot be used to inform variant location in BMPR1a. However, the phenotypic characteristics of BMPR1a DCV carriers, being almost exclusively related to the colon and rectum, can assist in pathogenicity assessment of BMPR1a variants. Given these findings, we propose that carriers of BMPR1a DCVs should only require surveillance for colorectal polyps and malignancy, and that surveillance for gastric polyps and malignancy may be unnecessary. However variant location within BMPR1a does not support differential surveillance recommendations.
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Affiliation(s)
- M E Papadopulos
- Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australia.
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.
| | - J P Plazzer
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
| | - F A Macrae
- Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australia
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
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21
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Lucaciu L, Yano T, Saurin JC. Updates in the diagnosis and management of non-ampullary small-bowel polyposis. Best Pract Res Clin Gastroenterol 2023; 64-65:101852. [PMID: 37652652 DOI: 10.1016/j.bpg.2023.101852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Advances in endoscopic instruments and techniques changed the strategy of diagnosis and management for non-ampullary small-bowel polyposis. In patients with Peutz-Jeghers syndrome, gastrointestinal surveillance using capsule endoscopy should commence no later than eight years old. Small bowel polyps >15 mm should be treated to prevent intussusception. Recently, endoscopic ischemic polypectomy and endoscopic reduction of intussusception were described. In patients with familial adenomatous polyposis, the first endoscopic screening using a lateral viewing and a longer endoscope to check the proximal jejunum should be performed around 25 years. Some experts recommend a first duodenal examination with a first colonoscopy (13 years). The surveillance intervals for duodenal polyposis should be adjusted individually. ESGE recommended the resection of every adenoma larger than 1 cm. Cold snare polypectomy has the potential to change the threshold of size for endoscopic resection. In patients with Juvenile polyposis syndrome, small bowel involvement seems infrequent and mostly located in the duodenal part. There is no indication for distal small bowel investigation.
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Affiliation(s)
- Laura Lucaciu
- Royal Free Unit for Endoscopy, The Royal Free Hospital and UCL Institute for Liver and Digestive Health, London, UK
| | - Tomonori Yano
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan.
| | - Jean Christophe Saurin
- Gastroenterology and Endoscopy Unit, Hospices Civils de Lyon, Hôpital E. Herriot, Lyon, France
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22
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Attard TM, Cohen S, Durno C. Polyps and Polyposis Syndromes in Children: Novel Endoscopic Considerations. Gastrointest Endosc Clin N Am 2023; 33:463-486. [PMID: 36948756 DOI: 10.1016/j.giec.2022.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Polypectomy is the most common therapeutic endoscopic intervention in children. Management of sporadic juvenile polyps is limited to polypectomy to resolve symptoms, whereas polyposis syndromes pose a multidisciplinary challenge with broader ramifications. In preparation for polypectomy, there are key patient, polyp, endoscopy unit, and provider characteristics that factor into the likelihood of success. Younger age and multiple medical comorbidities increase the risk of adverse outcomes, classified as intraoperative, immediate postoperative, and delayed postoperative complications. Novel techniques, including cold snare polypectomy, can significantly decrease adverse events but a more structured training process for polypectomy in pediatric gastroenterology is needed.
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Affiliation(s)
- Thomas M Attard
- Division of Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA; The University of Missouri in Kansas City School of Medicine, Kansas City, MO, USA.
| | - Shlomi Cohen
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Carol Durno
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; The Zane Cohen Centre for Digestive Diseases, 60 Murray Street, Toronto, Ontario M5T 3L9, Canada; Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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23
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Dang Y, Xu Q, Liu X, Wang L, Lin C. Clinical and functional characterisation of the SMAD4 germline variant c.1035C > A in a family with juvenile polyposis syndrome by whole-exome sequencing. Med Mol Morphol 2023; 56:78-83. [PMID: 35851413 DOI: 10.1007/s00795-022-00333-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: 05/15/2022] [Accepted: 07/04/2022] [Indexed: 11/28/2022]
Abstract
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant inherited disease characterised by multiple juvenile polyps. Genes with JPS-associated mutations and their correlation with the phenotype are currently unknown. Gastrointestinal endoscopy results of a 31-year-old female patient showed multiple polyps in the digestive tract, and the presence of juvenile polyps was confirmed by pathological examination. During follow-up, the patient underwent total gastrectomy and polypectomy several times. Five members of this family were diagnosed with JPS, of which two died and three survived. Full exon gene sequencing of eight members of this family revealed a SMAD4 (NM-005359.3) c.1035C > A (p.Cys345*) mutation. This mutation leads to premature codon termination, causing protein truncation. SMAD4 is a pathogenic gene associated with JPS. This is the first report of an association between the c.1035C > A mutation and JPS pathogenesis. Detection of JPS-related mutations in family members with a genetic predisposition for JPS is very important for genetic counselling, surgical intervention, long-term monitoring and follow-up, and drug treatment.
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Affiliation(s)
- Yuan Dang
- Department of General Surgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, 350025, Fujian, China.,Innovation Center for Cancer Research, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fujian Cancer Hospital, Fuzhou, China
| | - Qianhui Xu
- Department of General Surgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, 350025, Fujian, China.,Department of General Surgery, 900th hospital of Joint Logistics Support Force, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China.,Department of General Surgery, Dongfang Hospital of Xiamen university, School of Medicine, Xiamen University, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China
| | - Xiaofang Liu
- Department of General Surgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, 350025, Fujian, China.,Department of General Surgery, 900th hospital of Joint Logistics Support Force, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China.,Department of General Surgery, Dongfang Hospital of Xiamen university, School of Medicine, Xiamen University, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China
| | - Lie Wang
- Department of General Surgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, 350025, Fujian, China. .,Department of General Surgery, 900th hospital of Joint Logistics Support Force, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China. .,Department of General Surgery, Dongfang Hospital of Xiamen university, School of Medicine, Xiamen University, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China.
| | - Chen Lin
- Department of General Surgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, 350025, Fujian, China. .,Department of General Surgery, 900th hospital of Joint Logistics Support Force, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China. .,Department of General Surgery, Dongfang Hospital of Xiamen university, School of Medicine, Xiamen University, 156 Xierhuan Road, Fuzhou, 350025, Fujian, China.
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24
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Singh AD, Gupta A, Mehta N, Heald B, Macaron C, Liska D, Bhatt A, Burke CA. Occurrence of gastric cancer in patients with juvenile polyposis syndrome: a systematic review and meta-analysis. Gastrointest Endosc 2023; 97:407-414.e1. [PMID: 36265529 DOI: 10.1016/j.gie.2022.10.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/15/2022] [Accepted: 10/10/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS The true rate of gastric cancer (GC) in juvenile polyposis syndrome (JPS) is unknown because of its rarity and ascertainment bias in published literature. To better assess this, we conducted a systematic review and meta-analysis. METHODS MEDLINE, Embase, and Scopus databases were searched for the key words juvenile polyposis syndrome, juvenile polyps, stomach cancer, GC, SMAD4, BMPR1A, hamartomatous polyposis syndrome, hamartomas, and hereditary cancers for studies reporting upper GI manifestations in JPS. The primary outcome was the reported occurrence of GC in JPS. We then compared GC occurrence based on the presence or absence of pathogenic germline variants (PGVs) and in untested patients. RESULTS Eleven studies including 637 patients were included. The pooled occurrence of GC was 3.5% (95% confidence interval [CI], 1.8-5.2; I2 = 12.3%) at a median age of 42.5 years (range, 15-57.6). The pooled occurrence of GC in patients with SMAD4 PGV was 10.1% (95% CI, 3.2-16.8%; I2 = 54.7%). GC was reported in only 1 BMPR1A PGV carrier and was not reported in patients without an identifiable PGV. In patients with prior germline testing, the risk of GC was higher in SMAD4 PGV carriers (odds ratio, 11.6; 95% CI, 4.6-29.4; I2 = 18.3%) compared with patients without SMAD4 PGV. In JPS patients with unknown status of germline testing, pooled occurrence of GC was 7.5% (95% CI, 0-15.5). There was an overall moderate risk of bias in the studies. CONCLUSIONS GC is highest in SMAD4-associated JPS and was not reported in patients without identifiable PGVs. The value of GC surveillance in BMPR1A PGV carriers and JPS patients without an identifiable PGV is questionable. Germline testing should be performed in all JPS patients to inform GC risk discussion and utility of surveillance.
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Affiliation(s)
- Achintya D Singh
- Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Akshita Gupta
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Neal Mehta
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Brandie Heald
- Center for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, Ohio, USA; Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Carole Macaron
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - David Liska
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Amit Bhatt
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Carol A Burke
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
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25
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Gorji L, Albrecht P. Hamartomatous polyps: Diagnosis, surveillance, and management. World J Gastroenterol 2023; 29:1304-1314. [PMID: 36925460 PMCID: PMC10011967 DOI: 10.3748/wjg.v29.i8.1304] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/08/2022] [Accepted: 02/16/2023] [Indexed: 02/28/2023] Open
Abstract
Hereditary polyposis syndrome can be divided into three categories: Ade-nomatous, serrated, and hamartomatous polyps. Hamartomatous polyps, malformations of normal tissue presenting in a disorganized manner, are characterized by an autosomal dominant inheritance pattern. These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations, which require conscientious and diligent monitoring. Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS). Diagnosis can be pursued with molecular testing and endoscopic sampling. Early identification of these autosomal dominant pathologies allows to optimize malignancy sur-veillance, which helps reduce morbidity and mortality in both the affected patient population as well as at-risk family members. Endoscopic surveillance is an important pillar of prognosis and monitoring, with many patients eventually requiring surgical intervention. In this review, we discuss the diagnosis, surveillance, and management of HPS.
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Affiliation(s)
- Leva Gorji
- Department of Surgery, Kettering Health Dayton, Dayton, OH 45405, United States
| | - Peter Albrecht
- Department of Surgery, Kettering Health Dayton, Dayton, OH 45405, United States
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26
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Yehia L, Heald B, Eng C. Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes. Gastroenterology 2023; 164:800-811. [PMID: 36717037 DOI: 10.1053/j.gastro.2023.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023]
Abstract
The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. Although the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables presymptomatic cancer surveillance and management before symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.
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Affiliation(s)
- Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | | | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Center for Personalized Genetic Healthcare, Community Care, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio; Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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27
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Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test? Int J Mol Sci 2023; 24:ijms24032137. [PMID: 36768460 PMCID: PMC9916931 DOI: 10.3390/ijms24032137] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
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28
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Zhao ZY, Lei Y, Wang ZM, Han H, Xing JJ, Xu XD, Gao XH, Zhang W, Yu ED. Re-recognition of BMPR1A-related polyposis: beyond juvenile polyposis and hereditary mixed polyposis syndrome. Gastroenterol Rep (Oxf) 2023; 11:goac082. [PMID: 36632626 PMCID: PMC9825710 DOI: 10.1093/gastro/goac082] [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: 05/04/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 01/09/2023] Open
Abstract
Background Bone morphogenetic protein receptor type 1A (BMPR1A) is responsible for two individual Mendelian diseases: juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2, which have overlapping phenotypes. This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes. Methods We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer, and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations. Results BMPR1A germline mutations were found in six probands and their three available relatives. The numbers of frameshift, nonsense, splice-site, and missense mutations were one, one, two, and two, respectively; two of the six mutations were novel. Typical juvenile polyps were found in only three patients. Two patients had colorectal cancer rather than any polyps. Conclusions Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer, and typical juvenile polyps do not always occur in these carriers. The variety of phenotypes reflected the features of BMPR1A-mutation carriers, which should be recognized as a spectrum of one syndrome. Genetic testing may be a good approach to identifying BMPR1A-related syndromes.
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Affiliation(s)
| | | | | | - Huan Han
- Department of Pathology, Changhai Hospital, Shanghai, P. R. China
| | - Jun-Jie Xing
- Department of Colorectal Surgery and Hereditary Colorectal Cancer Registry, Changhai Hospital, Shanghai, P. R. China
| | - Xiao-Dong Xu
- Department of Colorectal Surgery and Hereditary Colorectal Cancer Registry, Changhai Hospital, Shanghai, P. R. China
| | - Xian-Hua Gao
- Department of Colorectal Surgery and Hereditary Colorectal Cancer Registry, Changhai Hospital, Shanghai, P. R. China
| | - Wei Zhang
- Department of Colorectal Surgery and Hereditary Colorectal Cancer Registry, Changhai Hospital, Shanghai, P. R. China
| | - En-Da Yu
- Corresponding author. Department of Colorectal Surgery, Changhai Hospital, 168 Changhai Rd., Shanghai 200433, China. Tel: +86-13901688626;
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29
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Mogere E, Mwaura E, Waithaka M, Mutua V, Mugao M, von Csefalvay C, Mukamati D. Juvenile polyposis syndrome: A case report. Clin Case Rep 2023; 11:e6798. [PMID: 36619487 PMCID: PMC9810833 DOI: 10.1002/ccr3.6798] [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: 09/30/2022] [Revised: 11/29/2022] [Accepted: 12/14/2022] [Indexed: 01/05/2023] Open
Abstract
Juvenile polyposis syndrome (JPS) is an autosomal dominant disease that is characterized by multiple hamartomatous polyps. Patients with JPS are at increased risk for developing colorectal and gastric cancer. JPS was diagnosed by endoscopy and histology, and the patient underwent surgery, total proctocolectomy and ileal pouch-anal anastomosis.
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Affiliation(s)
| | | | | | - Victor Mutua
- P.C.E.A Chogoria Mission HospitalTharaka NithiKenya
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30
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Micolonghi C, Piane M, Germani A, Sadeghi S, Libi F, Savio C, Fabiani M, Mancini R, Ranieri D, Pizzuti A, Corleto VD, Parisi P, Visco V, Di Nardo G, Petrucci S. A New SMAD4 Splice Site Variant in a Three-Generation Italian Family with Juvenile Polyposis Syndrome. Diagnostics (Basel) 2022; 12:2684. [PMID: 36359527 PMCID: PMC9689379 DOI: 10.3390/diagnostics12112684] [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: 09/30/2022] [Revised: 10/28/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life.
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Affiliation(s)
- Caterina Micolonghi
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
| | - Maria Piane
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
- S. Andrea University Hospital, 00189 Rome, Italy
| | - Aldo Germani
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Soha Sadeghi
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
| | - Fabio Libi
- S. Andrea University Hospital, 00189 Rome, Italy
| | | | - Marco Fabiani
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- ALTAMEDICA, Human Genetics, 00198 Rome, Italy
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
- S. Andrea University Hospital, 00189 Rome, Italy
| | - Danilo Ranieri
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Antonio Pizzuti
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- Medical Genetics Unit, IRCCS Mendel Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Vito Domenico Corleto
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Medical-Surgical Sciences and Translational Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Pasquale Parisi
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Vincenzo Visco
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
- S. Andrea University Hospital, 00189 Rome, Italy
| | - Giovanni Di Nardo
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Simona Petrucci
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
- S. Andrea University Hospital, 00189 Rome, Italy
- Medical Genetics Unit, IRCCS Mendel Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
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31
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Long JM, Ebrahimzadeh J, Stanich PP, Katona BW. Endoscopic Surveillance in Patients with the Highest Risk of Gastric Cancer: Challenges and Solutions. Cancer Manag Res 2022; 14:2953-2969. [PMID: 36238953 PMCID: PMC9553156 DOI: 10.2147/cmar.s277898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer is one of the most significant causes of cancer-related morbidity and mortality worldwide. Recognized modifiable risk factors include Helicobacter pylori infection, geographic location, select dietary factors, tobacco use and alcohol consumption. In addition, multiple hereditary cancer predisposition syndromes are associated with significantly elevated gastric cancer risk. Endoscopic surveillance in hereditary gastric cancer predisposition syndromes has the potential to identify gastric cancer at earlier and more treatable stages, as well as to prevent development of gastric cancer through identification of precancerous lesions. However, much uncertainty remains regarding use of endoscopic surveillance in hereditary gastric cancer predisposition syndromes, including whether or not it should be routinely performed, the surveillance interval and age of initiation, cost-effectiveness, and whether surveillance ultimately improves survival from gastric cancer for these high-risk individuals. In this review, we outline the hereditary gastric cancer predisposition syndromes associated with the highest gastric cancer risks. Additionally, we cover current evidence and guidelines addressing hereditary gastric cancer risk and surveillance in these syndromes, along with current challenges and limitations that emphasize a need for continued research in this field.
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Affiliation(s)
- Jessica M Long
- Division of Hematology and Oncology, Penn Medicine, Philadelphia, PA, USA
| | | | - Peter P Stanich
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA,Correspondence: Bryson W Katona, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, 751 South Pavilion, Philadelphia, PA, 19104, USA, Tel +1-215-349-8222, Fax +1-215-349-5915, Email
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Mafficini A, Brosens LAA, Piredda ML, Conti C, Mattiolo P, Turri G, Mastrosimini MG, Cingarlini S, Crinò SF, Fassan M, Piccoli P, Simbolo M, Nottegar A, Lawlor RT, Guglielmi A, Scarpa A, Pedrazzani C, Luchini C. Juvenile polyposis diagnosed with an integrated histological, immunohistochemical and molecular approach identifying new SMAD4 pathogenic variants. Fam Cancer 2022; 21:441-451. [PMID: 35075588 PMCID: PMC9636285 DOI: 10.1007/s10689-022-00289-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/12/2022] [Indexed: 01/07/2023]
Abstract
Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4, c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.
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Affiliation(s)
- Andrea Mafficini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Lodewijk A A Brosens
- Department of Pathology, Utrecht, and Department of Pathology, University Medical Center Utrecht, Utrecht University, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maria L Piredda
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Cristian Conti
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Giulia Turri
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Maria G Mastrosimini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Sara Cingarlini
- Department of Medicine, Section of Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Stefano F Crinò
- Digestive Endoscopy Unit, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, and Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Paola Piccoli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Alessia Nottegar
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Rita T Lawlor
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Alfredo Guglielmi
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Corrado Pedrazzani
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, 37134, Verona, Italy.
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy.
- ARC-Net Research Center, University of Verona, Verona, Italy.
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Rosner G, Petel-Galil Y, Laish I, Levi Z, Kariv R, Strul H, Gilad O, Gluck N. Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers. Clin Transl Gastroenterol 2022; 13:e00527. [PMID: 36049049 PMCID: PMC9624493 DOI: 10.14309/ctg.0000000000000527] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/10/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.
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Affiliation(s)
- Guy Rosner
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Petel-Galil
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ido Laish
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Gastroenterology Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Zohar Levi
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Gastroenterology, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - Revital Kariv
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hana Strul
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ophir Gilad
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nathan Gluck
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Abstract
The traditional approach of one-size-fits-all for colorectal cancer has been replaced by personalized interventions to an individual's unique genetic, molecular, and environmental profile, seeking to identify high-risk individuals who would benefit from individualized screening and surveillance. This change in approach is due, in part, to emerging technologies, such as next-generation DNA sequencing.
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Saurin JC, Calavas L, Caillot C. Juvenile polyposis: Focus on less described manifestations. Best Pract Res Clin Gastroenterol 2022; 58-59:101802. [PMID: 35988968 DOI: 10.1016/j.bpg.2022.101802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 06/28/2022] [Accepted: 07/30/2022] [Indexed: 01/31/2023]
Abstract
Juvenile polyposis represents an heterogeneous disease as different genetic dominant backgrounds have been evidenced leading to different clinical presentations. It is associated in some patients with a different syndrome, Hereditary Hemorragic Telangiectasia, justifying a complementary and different management. Recent international recommendations help in managing this very rare disease, and this management should probably be restricted to expert centers able to take care of the multiple manifestations and risks of these patients and families. This paper will focus on the poorly known and evaluated aspects of juvenile polyposis, excluding the colonic involvement and epidemiology that are addressed in a different article of this issue.
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Affiliation(s)
| | - Laura Calavas
- Gastroenterology Unit, Hospices Civils de Lyon, Hôpital E. Herriot, Lyon, France
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36
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Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, Robertson DJ. Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2022; 162:2063-2085. [PMID: 35487791 DOI: 10.1053/j.gastro.2022.02.021] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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Affiliation(s)
- C Richard Boland
- Division of Gastroenterology, University of California-San Diego School of Medicine, San Diego, California
| | - Gregory E Idos
- Divisions of Gastroenterology and Clinical Cancer Genomics, Center for Precision Medicine, City of Hope National Medical Center, Duarte, California
| | - Carol Durno
- The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Francis M Giardiello
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph C Anderson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; University of Connecticut, Farmington, Connecticut
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio
| | - Jason A Dominitz
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington
| | - Seth Gross
- Division of Gastroenterology and Hepatology, New York University Langone Health, New York, New York
| | - Samir Gupta
- Veterans Affairs Medical Center, San Diego, California; University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Brian C Jacobson
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Swati G Patel
- University of Colorado School of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Aasma Shaukat
- Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; University of Minnesota, Minneapolis, Minnesota
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston Massachusetts; Dana-Farber Cancer Institute, Boston Massachusetts; Harvard Medical School, Boston Massachusetts
| | - Douglas J Robertson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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37
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Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, Robertson DJ. Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2022; 95:1025-1047. [PMID: 35487765 DOI: 10.1016/j.gie.2022.02.044] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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Affiliation(s)
- C Richard Boland
- Division of Gastroenterology, University of California-San Diego School of Medicine, San Diego, California.
| | - Gregory E Idos
- Divisions of Gastroenterology and Clinical Cancer Genomics, Center for Precision Medicine, City of Hope National Medical Center, Duarte, California
| | - Carol Durno
- The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Francis M Giardiello
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph C Anderson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; University of Connecticut, Farmington, Connecticut
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio
| | - Jason A Dominitz
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington
| | - Seth Gross
- Division of Gastroenterology and Hepatology, New York University Langone Health, New York, New York
| | - Samir Gupta
- Veterans Affairs Medical Center, San Diego, California; University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Brian C Jacobson
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Swati G Patel
- University of Colorado School of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Aasma Shaukat
- Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; University of Minnesota, Minneapolis, Minnesota
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston Massachusetts; Dana-Farber Cancer Institute, Boston Massachusetts; Harvard Medical School, Boston Massachusetts
| | - Douglas J Robertson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2022; 117:846-864. [PMID: 35471415 DOI: 10.14309/ajg.0000000000001755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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39
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Hampel H, Kalady MF, Pearlman R, Stanich PP. Hereditary Colorectal Cancer. Hematol Oncol Clin North Am 2022; 36:429-447. [DOI: 10.1016/j.hoc.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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40
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Dal Buono A, Gaiani F, Poliani L, Laghi L. Juvenile polyposis syndrome: An overview. Best Pract Res Clin Gastroenterol 2022; 58-59:101799. [PMID: 35988962 DOI: 10.1016/j.bpg.2022.101799] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 03/13/2022] [Accepted: 03/23/2022] [Indexed: 01/31/2023]
Abstract
Juvenile polyposis syndrome (JPS) is a rare precancerous condition that confers an increased risk of developing gastrointestinal cancers. The inheritance pattern is autosomal dominant. JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz- Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations. Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. In JPS a cumulative risk of CRC of 39-68% has been estimated. The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. The aim of this review is to summarize clinical and genetic features of JPS and to elucidate the steps of the clinical management from diagnosis to surveillance.
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Affiliation(s)
- Arianna Dal Buono
- Division of Gastroenterology, Department of Gastroenterology, Humanitas Research Hospital - IRCCs, Rozzano, Milan, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Laura Poliani
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy.
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41
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Khongcharoen N, Laochareonsuk W, Choochuen P, Maneechay W, Sangkhathat S. Sequencing for novel mutation screening in juvenile polyposis syndrome. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2022; 79:102216. [DOI: 10.1016/j.epsc.2022.102216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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42
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Dong J, Ma TS, Xu YH, Li P, Chen WY, Tu JF, Chen YW. Characteristics and potential malignancy of colorectal juvenile polyps in adults: a single-center retrospective study in China. BMC Gastroenterol 2022; 22:75. [PMID: 35189824 PMCID: PMC8862221 DOI: 10.1186/s12876-022-02151-x] [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: 03/14/2021] [Accepted: 02/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Colorectal juvenile polyps are rare and generally considered benign in adults. Carcinogenesis or neoplastic changes are rarely mentioned in the literature. We systematically evaluated the characteristics and potential malignancy of colorectal juvenile polyps in adults. METHODS We retrospectively reviewed the medical records of 103 adults diagnosed with colorectal juvenile polyps from September 2007 to May 2020 at our hospital. The characteristics, endoscopic findings, occurrence of intraepithelial neoplasia, carcinogenesis and diagnostic value of chicken skin mucosa (CSM) were analyzed. RESULTS The average age of patients with juvenile polyps was 43.2 years (range, 19 to 78 years). A total of 101 patients (101/103, 98.1%) had a single juvenile polyp, and two patients had multiple polyps (107 polyps in total). Polyp sizes ranged from 0.5 to 5 cm. One (1/107, 0.9%) juvenile polyp was cancerous, and 7 (7/107, 6.5%) developed low-grade intraepithelial neoplasia. Neoplasia and cancerization did not appear in the two patients with multiple polyps. A 27-year-old female had a 2-cm polyp with well-differentiated adenocarcinoma in the mucosa in the sigmoid colon with erosion on the surface. CSM was observed adjacent to 17 polyps, which were all located in the rectum and sigmoid colon, and one polyp showed low-grade intraepithelial neoplasia. CONCLUSIONS Colorectal juvenile polyps occur in a wide range of locations and in variable sizes and numbers. These polyps are solitary in most patients and have neoplastic potential. CSM is not a tumorigenic marker in colorectal juvenile polyps and usually occurs in the distant colorectum. Colorectal juvenile polyps in adults may progress from low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and then to carcinoma and should be treated when discovered and regularly followed as colorectal adenomas.
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Affiliation(s)
- Jie Dong
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No. 158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China
| | - Tian-Shi Ma
- Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No.158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China
| | - Yuan-Hong Xu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, 519000, Guangdong Province, China
| | - Peng Li
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No. 158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China
| | - Wan-Yuan Chen
- Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No.158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China
| | - Jiang-Feng Tu
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No. 158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China
| | - You-Wei Chen
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), No. 158, Shangtang Road, Hangzhou, 310014, Zhejiang Province, China.
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Abstract
Most patients with colorectal cancer (CRC) were diagnosed in advanced stage and the prognosis is poor. Therefore, early detection and prevention of CRC are very important. As with other cancers, there is also the tertiary prevention for CRC. The primary prevention is etiological prevention, which is mainly the treatment of adenoma or inflammation for preventing the development into cancer. The secondary prevention is the early diagnosis and early treatment for avoiding progressing to advanced cancer. The tertiary prevention belongs to the broad category of prevention, mainly for advanced CRC, through surgical treatment and postoperative adjuvant chemotherapy, radiotherapy, targeted therapy, immunotherapy for preventing tumor recurrence or metastasis. This consensus is based on the recent domestic and international consensus guidelines and the latest progress of international researches in the past five years. This consensus opinion seminar was hosted by the Chinese Society of Gastroenterology and Cancer Collaboration Group of Chinese Society of Gastroenterology, and was organized by the Division of Gastroenterology and Hepatology & Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University. The consensus opinion contains 60 statement clauses, the standard and basis of the evidence-based medicine grade and voting grade of the statement strictly complied with the relevant international regulations and practice.
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Katz LH, Gingold-Belfer R, Vainer E, Hegger S, Laish I, Derazne E, Weintraub I, Reznick-Levi G, Goldberg Y, Levi Z, Cohen S, Half EE. Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background. Hered Cancer Clin Pract 2022; 20:2. [PMID: 35057835 PMCID: PMC8772101 DOI: 10.1186/s13053-021-00207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/07/2021] [Indexed: 11/29/2022] Open
Abstract
Abstract Juvenile polyposis syndrome (JPS), has diverse phenotypes. Aim: To assess mutation rate, clinical features and genotype-phenotype correlation among Israeli JPS kindreds from different ethnicities. Methods Patients’ data were extracted retrospectively from 5 centers. Results Thirty five kindreds (49 patients) were included. Thirty one (89%) Jewish [10 (32%) Ashkenazi; 9 (29%) Sephardi; 11 (35%) non-Russia former Soviet-Union countries (NRFSU), one (3%) unknown]. 40/49 individuals from 27 families underwent genetic testing. Among them 34, from 21 families (85, 78%, respectively) had a pathogenic mutation: BMPR1A n = 15 (71%), SMAD4 n = 6 families (29%). While no SMAD4 mutation was described among Jewish families from NRFSU, 7 NRFSU families carried a founder mutation comprising a large genomic deletion of BMPR1A. GI involvement was reported in 42 patients (86%): colonic polyps (n = 40, 95%, > 50 polyps n = 14, 35%) and 12 underwent colonic resection. Fourteen patients (34%) had gastric or small bowel involvement (n = 5) and 4\14 underwent gastrectomy due to polyp burden. Families from NRFSU had more gastric involvement (66.7% vs. 22.2%- Sephardic and 20%- Ashkenazi Jews; p = 0.038), with more gastric polyps (p = 0.017). Conclusions We demonstrated a high rate of mutation detection in the heterogeneous population of Israel. Patients from NRFSU with BMPR1A mutation had high rate of gastric involvement.
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Kim W, Kidambi T, Lin J, Idos G. Genetic Syndromes Associated with Gastric Cancer. Gastrointest Endosc Clin N Am 2022; 32:147-162. [PMID: 34798983 DOI: 10.1016/j.giec.2021.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although environmental factors such as Helicobacter pylori, tobacco, and diet are major contributors to the development of gastric cancer (GC) worldwide, it is estimated that up to 5% to 10% of GC cases are due to an underlying hereditary susceptibility caused by germline pathogenic variants. Hereditary diffuse gastric cancer (HDGC) caused by germline pathogenic variants in the CDH1 gene is the principal familial GC syndrome. However, other well-established hereditary gastrointestinal syndromes have been associated with an increased risk of GC. In this review, we will discuss the latest insights and advances in our understanding of GC associated with Lynch syndrome (LS), familial adenomatous polyposis (FAP), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). We will also discuss the emergence of new associations of the homologous recombination pathway genes (BRCA1, BRCA2) with GC.
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Affiliation(s)
- Woojin Kim
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Trilokesh Kidambi
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - James Lin
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Gregory Idos
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
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46
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Abstract
Juvenile polyposis syndrome (JPS) is a rare disease with an autosomal dominant inheritance pattern characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. The most frequent signs and symptoms are recurrent abdominal pain, rectal bleeding, anemia, and iron deficiency. The treatment of JPS is symptomatic, requiring serial endoscopic polypectomies or intestinal resections in the most severe cases. We describe the clinical case of a patient with JPS with a childhood juvenile polyposis phenotype because of a mutation on the SMAD4 gene, who received treatment with sirolimus successfully.
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MacFarland SP, Katona BW. Juvenile polyposis without a germline variant in SMAD4/BMPR1A: defining a clinically distinct polyposis syndrome. Oncotarget 2021; 12:1848-1849. [PMID: 34504656 PMCID: PMC8416557 DOI: 10.18632/oncotarget.27999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Indexed: 11/25/2022] Open
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48
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Abstract
Approximately 10% of patients with gastric cancer show familial aggregation and up to 3% are related to an inherited cancer syndrome. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of gastric cancer. Appropriate assessment of familial and genetic risk may allow a personalized approach to gastric cancer prevention through screening and risk-reducing surgeries. The ability to better identify carriers with pathogenic genetic variants associated with gastric cancer before a diagnosis of cancer requires effective genetic risk assessment and testing, followed by optimal screening and surveillance recommendations to further reduce the morbidity and mortality.
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49
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Phull MS, Jadav SS, Gundla R, Mainkar PS. A perspective on medicinal chemistry approaches towards adenomatous polyposis coli and Wnt signal based colorectal cancer inhibitors. Eur J Med Chem 2021; 212:113149. [PMID: 33445154 DOI: 10.1016/j.ejmech.2020.113149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the major causes of carcinogenic mortality in numbers only after lung and breast cancers. The mutations in adenomatous polyposis coli (APC) gene leads to formation of colorectal polyps in the colonic region and which develop as a malignant tumour upon coalition with patient related risk factors. The protein-protein interaction (PPI) of APC with Asef (A Rac specific guanine nucleotide exchange factor) overwhelms the patient's conditions by rapidly spreading in the entire colorectal region. Most mutations in APC gene occur in mutated cluster region (MCR), where it specifically binds with the cytosolic β-catenin to regulate the Wnt signalling pathway required for CRC cell adhesion, invasion, progression, differentiation and stemness in initial cell cycle phages. The current broad spectrum perspective is attempted to elaborate the sources of identification, development of selective APC inhibitors by targeting emopamil-binding protein (EBP) & dehydrocholesterol reductase-7 & 24 (DHCR-7 & 24); APC-Asef, β-catenin/APC, Wnt/β-catenin, β-catenin/TCF4 PPI inhibitors with other vital Wnt signal cellular proteins and APC/Pol-β interface of colorectal cancer. In this context, this perspective would serve as a platform for design of new medicinal agents by targeting cellular essential components which could accelerate anti-colorectal potential candidates.
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Affiliation(s)
- Manjinder Singh Phull
- Department of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, 502329, Telangana, India
| | - Surender Singh Jadav
- Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, Telangana, India
| | - Rambabu Gundla
- Department of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, 502329, Telangana, India
| | - Prathama S Mainkar
- Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Utter Pradesh, India.
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Shen N, Wang X, Lu Y, Xiao F, Xiao J. Importance of early detection of juvenile polyposis syndrome: A case report and literature review. Medicine (Baltimore) 2020; 99:e23494. [PMID: 33327285 PMCID: PMC7738017 DOI: 10.1097/md.0000000000023494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Juvenile polyposis syndrome (JPS) is a rare genetic gastrointestinal disorder with hidden and variable clinical features. Early detection is crucial for good prognosis. PATIENT CONCERNS A 20-year-old female went to hospital for fever, and was unexpectedly diagnosed as JPS during treatment. She reported no clinical signs or family history of JPS. DIAGNOSIS Blood routine examination on hospital admission suggested a moderate anemia. Bone marrow cytology and leukemia fusion gene test were performed to rule out leukemia. Other examinations including ultrasound and computed tomography were also conducted for differential diagnosis. Further electronic colonoscopy identified more than 20 pedicle polyps located at her ileocecum and rectum. Mutation analysis detected a novel de novo pathogenic variant, c.910C>T (p.Gln304Ter) within bone morphogenetic protein receptor type 1A gene, establishing the diagnosis of JPS. INTERVENTIONS The patient was treated with endoscopic interventions. We also provided a genetic counseling for this family. OUTCOMES The patient's polyps were removed, some of which already had adenomatous changes. The patient received surveillance of hereditary colorectal cancer according to guidelines. LESSONS Variable features and lack of family history probably lead to a great underestimation of potential JPS population. It is recommended to perform genetic testing by a multigene panel in individuals who have suspected symptoms of polyposis.
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Affiliation(s)
- Na Shen
- Department of Laboratory Medicine
| | | | | | | | - Juan Xiao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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