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Abudalo R, Alqudah A, Alnajjar R, Abudalo R, Abuqamar A, Oqal M, Qnais E. KRAS/NRAS/BRAF mutational profile and association with clinicopathological characteristics in patients with metastatic colorectal cancer. Oncol Lett 2025; 29:312. [PMID: 40342724 PMCID: PMC12059616 DOI: 10.3892/ol.2025.15058] [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: 11/06/2024] [Accepted: 03/26/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is increasingly prevalent in Jordan and poses a significant public health challenge. The presence of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations is key in CRC diagnostics, as these mutations are associated with resistance to monoclonal antibodies targeting the epidermal growth factor receptor. The present study aimed to identify these mutations in patients with CRC and assess their associations with clinicopathological characteristics. A retrospective analysis was conducted using data from 262 patients with metastatic CRC (mCRC) at the Jordanian Military Cancer Center-Royal Medical Services (Amman, Jordan). Variables such as age, sex, tumor differentiation and the mutational status of KRAS, NRAS and BRAF, along with tumor location, were analyzed statistically to explore associations between mutations and tumor characteristics. Among the included patients, 48.5% had KRAS mutations, 3.8% had NRAS mutations and 0.8% had BRAF mutations. The majority of KRAS mutations were in exon 2 at codons 12 and 13, with the highest mutational rate at 45.8%. In the univariate model, NRAS mutations were significantly associated with moderately differentiated tumors and the multivariate hierarchical regression analysis established that KRAS mutations were significantly associated with histological subtypes [mucinous adenocarcinoma, tubular adenocarcinoma, signet adenocarcinoma and adenocarcinoma (not specified)]. These results highlighted the molecular profiles and clinicopathological characteristics of patients with mCRC, which demonstrated the associations between mutational status and the varying clinicopathological aspects based on the type of RAS mutation. Thus, these specific traits (patient's age, sex, CRC site, histological subtypes and tumor grade) may be taken into account when evaluating the predictive significance of RAS and BRAF status in CRC and tailored treatment strategies.
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Affiliation(s)
- Rawan Abudalo
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa 13133, Jordan
| | - Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa 13133, Jordan
| | - Roaa Alnajjar
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Jordan University, Amman 11942, Jordan
| | - Razan Abudalo
- Department of Radiology, Jordanian Royal Medical Services, Amman 855122, Jordan
| | - Ayman Abuqamar
- Department of Oncology and Hematology, Jordanian Royal Medical Services, Amman 855122, Jordan
| | - Muna Oqal
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa 13133, Jordan
| | - Esam Qnais
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13133, Jordan
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Sugai T, Osakabe M, Uesugi N, Habano W, Yanagawa N, Suzuki H. Comprehensive Analyses of Somatic Copy Number Alterations and Mutations Based on the Adenoma-Carcinoma Sequence. Genes Chromosomes Cancer 2024; 63:e23267. [PMID: 39258844 DOI: 10.1002/gcc.23267] [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: 05/09/2024] [Revised: 07/31/2024] [Accepted: 08/20/2024] [Indexed: 09/12/2024] Open
Abstract
AIMS Identifying molecular alterations in the adenoma and carcinoma components within the same tumor would greatly contribute to understanding the neoplastic progression of early colorectal cancer. METHODS AND RESULTS We examined somatic copy number alterations (SCNAs) and mutations involved in the adenoma and carcinoma components obtained from the same tumor in 46 cases of microsatellite-stable carcinoma in adenoma, using a genome-wide SNP array and gene mutation panel. In addition, we also performed hierarchical clustering to determine the SCNA frequencies in the tumors, resulting in stratification of the samples into two subgroups according to SCNA frequency. Subgroup 1 was characterized by multiple SCNAs and carcinoma components exclusively, while Subgroup 2 was characterized by a low frequency of SCNAs and both the adenoma and carcinoma components. The numbers of total genes and genes with gains were higher in the carcinoma than adenoma components. The three most frequent gains in both components were located at 1p36.33-1q44, 2p25.3-2q37.3, and 3p26.3-3q29. However, no candidate genes mapped to these regions. APC and KRAS mutations were common in both components, whereas the frequency of TP53 mutations was statistically higher in the carcinoma than adenoma component. However, TP53 mutations were not correlated with SCNA frequency. CONCLUSIONS We suggest that considerable SCNAs and TP53 mutations are required for progression from adenoma to carcinoma within the same intramucosal neoplastic lesion.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
- Diagnostic Pathology Center, Southern Tohoku General Hospital, Fukushima, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
- Diagnostic Pathology Center, Southern Tohoku General Hospital, Fukushima, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, School of Medicine, Sapporo, Japan
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Tomuleasa C, Tigu AB, Munteanu R, Moldovan CS, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther 2024; 9:201. [PMID: 39138146 PMCID: PMC11323831 DOI: 10.1038/s41392-024-01899-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/29/2024] [Accepted: 06/14/2024] [Indexed: 08/15/2024] Open
Abstract
Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.
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Affiliation(s)
- Ciprian Tomuleasa
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania.
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania.
| | - Adrian-Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Raluca Munteanu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Cristian-Silviu Moldovan
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - David Kegyes
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Anca Onaciu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gabriel Ghiaur
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Department of Leukemia, Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hermann Einsele
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany
| | - Carlo M Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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Guruvaiah P, Gupta R. IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers. J Transl Med 2024; 22:642. [PMID: 38982514 PMCID: PMC11233160 DOI: 10.1186/s12967-024-05384-4] [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: 03/20/2024] [Accepted: 06/08/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Oncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge. METHODS In this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082. RESULTS We demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition. CONCLUSION Our study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.
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Affiliation(s)
- Praveen Guruvaiah
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Romi Gupta
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
- O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
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Mozibullah M, Eslampanah Seyedi H, Khatun M, Solayman M. Identification and analysis of oncogenic non-synonymous single nucleotide polymorphisms in the human NRAS gene: An exclusive in silico study. J Genet Eng Biotechnol 2024; 22:100378. [PMID: 38797553 PMCID: PMC11087716 DOI: 10.1016/j.jgeb.2024.100378] [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: 12/02/2023] [Accepted: 04/19/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND N-ras protein is encoded by the NRAS gene and operates as GDP-GTP-controlled on/off switching. N-ras interacts with cellular signaling networks that regulate various cellular activities including cell proliferation and survival. The nonsynonymous single nucleotide polymorphism (nsSNPs)-mediated alteration can substantially disrupt the structure and activity of the corresponding protein. N-ras has been reported to be associated with numerous diseases including cancers due to the nsSNPs. A comprehensive study on the NRAS gene to unveil the potentially damaging and oncogenic nsSNPs is yet to be accomplished. Hence, this extensive in silico study is intended to identify the disease-associated, specifically oncogenic nsSNPs of the NRAS gene. RESULTS Out of 140 missense variants, 7 nsSNPs (I55R, G60E, G60R, Y64D, L79F, D119G, and V152F) were identified to be damaging utilizing 10 computational tools that works based on different algorithms with high accuracy. Among those, G60E, G60R, and D119G variants were further filtered considering their location in the highly conserved region and later identified as oncogenic variants. Interestingly, G60E and G60R variants were revealed to be particularly associated with lung adenocarcinoma, rhabdomyosarcoma, and prostate adenocarcinoma. Therefore, D119G could be subjected to detailed investigation for identifying its association with specific cancer. CONCLUSION This in silico study identified the deleterious and oncogenic missense variants of the human NRAS gene that could be utilized for designing further experimental investigation. The outcomes of this study would be worthwhile in future research for developing personalized medicine.
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Affiliation(s)
- Md Mozibullah
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | | | - Marina Khatun
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Md Solayman
- Department of Biochemistry and Molecular Biology, Primeasia University, Bangladesh.
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Devalle S, Aran V, Bastos Júnior CDS, Pannain VL, Brackmann P, Gregório ML, Ferreira Manso JE, Moura Neto V. A panorama of colon cancer in the era of liquid biopsy. THE JOURNAL OF LIQUID BIOPSY 2024; 4:100148. [PMID: 40027146 PMCID: PMC11863817 DOI: 10.1016/j.jlb.2024.100148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/05/2025]
Abstract
Colon cancer (CC) is one of the most frequent cancers worldwide being responsible for over 500 thousand deaths in 2022. Its financial and human burden is expected to increase in the next decades accompanying the growing and aging of the global population. Much of this burden could be alleviated considering that the lethality of CC is mostly due to its late diagnosis and failure in the individualized management of patients. Coordinated government actions and implementation of better diagnostic tools capable of detecting CC earlier and of tracking tumoral evolution are mandatory to achieve a reduction in CC's social impact. CtDNA-based liquid biopsy (LB) has great potential to contribute to patients' screening adhesion, CC earlier detection, and to longitudinal tumor follow-up. In this review, we will discuss the latest epidemiological data on CC disease, diagnostic, subtypes, genetics, and treatment management focusing on the advantages and limitations of ctDNA-based LB, including important bottlenecks and solutions necessary for its clinical translation. The latest ctDNA-directed CC clinical trials will also be examined.
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Affiliation(s)
- Sylvie Devalle
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | | | - Vera Lucia Pannain
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paulo Brackmann
- Clínica de Coloproctologia do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - Marcelo Leal Gregório
- Instituto de Pesquisas Biomédicas do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - José Eduardo Ferreira Manso
- Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
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Benmokhtar S, Laraqui A, Hilali F, Bajjou T, El Zaitouni S, Jafari M, Baba W, Elannaz H, Lahlou IA, Hafsa C, Oukabli M, Mahfoud T, Tanz R, Ichou M, Ennibi K, Dakka N, Sekhsokh Y. RAS/RAF/MAPK Pathway Mutations as Predictive Biomarkers in Middle Eastern Colorectal Cancer: A Systematic Review. Clin Med Insights Oncol 2024; 18:11795549241255651. [PMID: 38798959 PMCID: PMC11128178 DOI: 10.1177/11795549241255651] [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: 10/05/2023] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Background This review article aims to investigate the prevalence and spectrum of rat sarcoma (RAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations, and their connection with geographical location, clinicopathological features, and other relevant factors in colorectal cancer (CRC) patients in the Middle East. Methods A systematic literature review, employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, was conducted to investigate the association between the frequency of relevant mutations and the descriptive clinicopathological characteristics of CRC patients. Multiple electronic databases, including PubMed, Science Direct, Web of Science, Scopus, and Google Scholar, were searched to analyze the relevant literature. Results A total of 19 eligible studies comprising 2960 patients with CRC were included in this review. A comprehensive analysis of the collected literature data as well as descriptive and methodological insights is provided. Men were predominant in reviewed studies for the region, accounting for 58.6%. Overall, RAS mutation prevalence was 38.1%. Kirsten RAS Viral Oncogene Homolog (KRAS) mutations were the most common, accounting for 37.1% of cases and distributed among different exons, with the G12D mutation being the most frequent in exon 2 (23.2%) followed by G12V (13.7%), G13D (10.1%), G12C (5.1%), G12A (5.04%), and G12S (3.6%). Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutations were identified in 3.3% of tumor samples, with the most common mutation site located in exons 2, 3, and 4, and codon 61 being the most common location for the region. The total mutation frequency in the BRAF gene was 2.6%, with the V600E mutation being the most common. Conclusion The distribution patterns of RAS and BRAF mutations among CRC patients exhibit notable variations across diverse ethnic groups. Our study sheds light on this phenomenon by demonstrating a higher prevalence of KRAS mutations in CRC patients from the Middle East, as compared with those from other regions. The identification of these mutations and geographical differences is important for personalized treatment planning and could potentially aid in the development of novel targeted therapies. The distinct distribution patterns of RAS and BRAF mutations among CRC patients across different ethnic groups, as well as the regional variability in mutation prevalence, highlight the need for further research in this area.
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Affiliation(s)
- Soukaina Benmokhtar
- Royal School of Military Health Service, Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious, and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Abdelilah Laraqui
- Royal School of Military Health Service, Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious, and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Farida Hilali
- Laboratory of Research and Biosafety P3, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Tahar Bajjou
- Laboratory of Research and Biosafety P3, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Sara El Zaitouni
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Meryem Jafari
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Walid Baba
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Hicham Elannaz
- Royal School of Military Health Service, Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious, and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Idriss Amine Lahlou
- Royal School of Military Health Service, Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious, and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Chahdi Hafsa
- Department of Medical Oncology, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Mohamed Oukabli
- Department of Pathology, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Tarik Mahfoud
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Rachid Tanz
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Mohamed Ichou
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Khaled Ennibi
- Royal School of Military Health Service, Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious, and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Nadia Dakka
- Laboratory of Biology of Human Pathologies and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Yassine Sekhsokh
- Laboratory of Research and Biosafety P3, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
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Lawler T, Parlato L, Warren Andersen S. The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1349572. [PMID: 38737895 PMCID: PMC11082351 DOI: 10.3389/fonc.2024.1349572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes. Methods We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC. Results In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent. Discussion A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.
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Affiliation(s)
- Thomas Lawler
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Shaneda Warren Andersen
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
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Santos FA, Reis RM, Barroti LC, Pereira AAL, Matsushita MM, de Carvalho AC, Datorre JG, Berardinelli GN, Araujo RLC. Overall Survival, BRAF, RAS, and MSI Status in Patients Who Underwent Cetuximab After Refractory Chemotherapy for Metastatic Colorectal Cancer. J Gastrointest Cancer 2024; 55:344-354. [PMID: 37608030 DOI: 10.1007/s12029-023-00964-x] [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] [Accepted: 08/12/2023] [Indexed: 08/24/2023]
Abstract
PURPOSE Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. METHODS A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. RESULTS The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). CONCLUSION Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis.
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Affiliation(s)
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
- Life and Health Sciences Research Institute (ICVS), School Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal
| | - Lucas C Barroti
- Department of Dermatology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
| | - Allan A L Pereira
- Clinical Oncology Department, Hospital Sirio Libanes de Brasilia-DF, Sao Paulo, Brazil
| | | | | | | | | | - Raphael L C Araujo
- Department of Surgery, Digestive Surgery Service, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
- Instituto de Ensino e Pesquisa, Barretos Cancer Hospital, Sao Paulo, Brazil.
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10
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Lawler T, Parlato L, Warren Andersen S. Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control 2024; 35:223-239. [PMID: 37688643 PMCID: PMC11090693 DOI: 10.1007/s10552-023-01783-y] [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: 03/21/2023] [Accepted: 08/21/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin-Madison, Suite 1007B, WARF, 610 Walnut Street, Madison, WI, 53726, USA.
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11
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Singh G, Thakur N, Kumar U. RAS: Circuitry and therapeutic targeting. Cell Signal 2023; 101:110505. [PMID: 36341985 DOI: 10.1016/j.cellsig.2022.110505] [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: 08/05/2022] [Revised: 10/05/2022] [Accepted: 10/21/2022] [Indexed: 11/26/2022]
Abstract
Cancer has affected the lives of millions worldwide and is truly regarded as a devastating disease process. Despite advanced understanding of the genomic underpinning of cancer development and progression, therapeutic challenges are still persistent. Among all the human cancers, around 33% are attributed to mutations in RAS oncogene, a crucial component of the signaling pathways. With time, our understanding of RAS circuitry has improved and now the fact that it activates several downstream effectors, depending on the type and grades of cancer has been established. The circuitry is controlled via post-transcriptional mechanisms and frequent distortions in these mechanisms lead to important metabolic as well as immunological states that favor cancer cells' growth, survival, plasticity and metastasis. Therefore, understanding RAS circuitry can help researchers/clinicians to develop novel and potent therapeutics that, in turn, can save the lives of patients suffering from RAS-mutant cancers. There are many challenges presented by resistance and the potential strategies with a particular focus on novel combinations for overcoming these, that could move beyond transitory responses in the direction of treatment. Here in this review, we will look at how understanding the circuitry of RAS can be put to use in making strategies for developing therapeutics against RAS- driven malignancies.
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Affiliation(s)
- Gagandeep Singh
- Department of Biosciences (UIBT), Chandigarh University, NH-05, Ludhiana - Chandigarh State Hwy, Sahibzada Ajit Singh Nagar, Punjab 140413, India
| | - Neelam Thakur
- Department of Biosciences (UIBT), Chandigarh University, NH-05, Ludhiana - Chandigarh State Hwy, Sahibzada Ajit Singh Nagar, Punjab 140413, India; Department of Zoology, Sardar Patel University, Vallabh Government College Campus, Paddal, Kartarpur, Mandi, Himachal Pradesh 175001, India.
| | - Umesh Kumar
- School of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), Adhyatmik Nagar, NH09, Ghaziabad, Uttar Pradesh 201015, India.
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12
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Purwanto I, Leo B, Purwanto Utomo B, Sofii I, Kus Dwianingsih E, Ratnasari N. Rapid Malignant Transformation of Tubulovillous Adenoma, Initially Presenting as McKittrick-Wheelock Syndrome: A Case Report. Case Rep Oncol 2023; 16:818-826. [PMID: 37900797 PMCID: PMC10601724 DOI: 10.1159/000531992] [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: 06/02/2023] [Accepted: 07/07/2023] [Indexed: 10/31/2023] Open
Abstract
Most cases of colorectal cancer develop from adenomatous polyps, slowly progressing within an average period of 8-10 years. McKittrick-Wheelock syndrome (MKWS) is a rare manifestation of tubulovillous adenoma. It generally presents as hypersecretory diarrhea with severe electrolyte and fluid depletion. Roughly, 5% of the published cases have reported malignant histopathology associated with MKWS, with little to no data regarding the malignant transformation process of those patients. Our patient was a 53-year-old Asian woman suffering from chronic secretory diarrhea, resulting in severe volume, electrolyte depletion, and prerenal azotemia, consistent for MKWS. Her symptoms initially improved with sulfasalazine but eventually worsened. She demonstrated signs of systemic (elevated leukocyte, CRP, and LDH) and local inflammation (dense lymphocyte infiltration in colorectal tissue) throughout the course of her disease. Serial pathological results showed rapid neoplastic progression of adenomatous polyp to adenocarcinoma within 1 year period. Surgical resection resulted in complete symptom resolution. Molecular examination showed a favorable profile of exon 4 Kirsten rat sarcoma viral oncogene homolog mutation, normal NRAS, BRAF, CDX2, and CK20 expressions. Her molecular pattern did not reflect the profile of an aggressive disease, suggesting the possibility of oncogenic processes outside the major pathways of adenoma to carcinoma progression. Chronic inflammation is a well-established risk factor for colorectal cancer, and prostaglandin E2 (PGE2) has been observed as one of the key regulators of tumor initiation and growth. PGE2 is also responsible for hypersecretory diarrhea associated with MKWS.
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Affiliation(s)
- Ibnu Purwanto
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
| | - Benedreky Leo
- Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
| | - Bambang Purwanto Utomo
- Department of Radiology, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
| | - Imam Sofii
- Department of Surgery, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
| | - Ery Kus Dwianingsih
- Department of Pathological Anatomy, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
| | - Neneng Ratnasari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia
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Lavacchi D, Fancelli S, Roviello G, Castiglione F, Caliman E, Rossi G, Venturini J, Pellegrini E, Brugia M, Vannini A, Bartoli C, Cianchi F, Pillozzi S, Antonuzzo L. Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer. Front Oncol 2022; 12:1055019. [PMID: 36523988 PMCID: PMC9745189 DOI: 10.3389/fonc.2022.1055019] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/16/2022] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs. METHODS Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA. RESULTS Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031). CONCLUSIONS Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.
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Affiliation(s)
- Daniele Lavacchi
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Sara Fancelli
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Francesca Castiglione
- Pathologic Histology and Molecular diagnostic Unit, Careggi University Hospital, Florence, Italy
| | - Enrico Caliman
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gemma Rossi
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Jacopo Venturini
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Elisa Pellegrini
- Medical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Marco Brugia
- Medical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Agnese Vannini
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Caterina Bartoli
- Pathologic Histology and Molecular diagnostic Unit, Careggi University Hospital, Florence, Italy
| | - Fabio Cianchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Medical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Medical Oncology Unit, Careggi University Hospital, Florence, Italy
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14
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Kim TW, Hwang SW, Kim KO, Cha JM, Joo YE, Cho YS. The Prognostic Utilities of DNA Mismatch Repair Status and KRAS and BRAF Mutation in Korean Colorectal Cancer Patients: The KASID Multicenter Study. Oncology 2022; 101:49-58. [PMID: 36191562 PMCID: PMC9872844 DOI: 10.1159/000527285] [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: 07/25/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023]
Abstract
INTRODUCTION KRAS, BRAF, and DNA mismatch repair (MMR) mutations aid clinical decision-making for colorectal cancer (CRC) patients. To ensure accurate predictions, the prognostic utilities of these biomarkers and their combinations must be individualized for patients with various TNM stages. METHODS Here, we retrospectively analyzed the clinicopathological features of 904 Korean CRC patients who underwent CRC surgery in three teaching hospitals from 2011 to 2013; we also assessed the prognostic utilities of KRAS, BRAF, and MMR mutations in these patients. RESULTS The overall frequencies of KRAS and BRAF mutations were 35.8% and 3.2%, respectively. Sixty-nine patients (7.6%) lacking expression of ≥1 MMR protein were considered MMR protein deficient (MMR-D); the remaining patients were considered MMR protein intact. KRAS mutations constituted an independent risk factor for shorter overall survival (OS) in TNM stage I-IV and stage III patients. BRAF mutations were associated with shorter OS in TNM stage I-IV patients. MMR-D status was strongly positive prognostic in TNM stage I-II patients. DISCUSSION/CONCLUSION To our knowledge, this is the first multicenter study to explore the prognostic utilities of KRAS, BRAF, and MMR statuses in Korean CRC patients. Various combinations of KRAS, BRAF, and DNA MMR mutations serve as genetic signatures that affect tumor behavior; they are prognostic in CRC patients.
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Affiliation(s)
- Tae-Woo Kim
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soon Woo Hwang
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyeong Ok Kim
- Division of Gastroenterology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jae Myung Cha
- Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Young-Eun Joo
- Division of Gastroenterology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Young-Seok Cho
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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15
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Ognerubov NA, Ezhova EN. Somatic mutations in colorectal cancer: regional experience. CONSILIUM MEDICUM 2022. [DOI: 10.26442/20751753.2022.5.201796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Introduction. Colorectal cancer is one of the most common malignant neoplasms in economically developed countries, ranking 3rd and 2nd in the structure of morbidity and mortality, respectively. Current knowledge about the molecular features of colorectal cancer is necessary to implement the principle of personalized therapy.
Aim. To study regional features of tumor genomic landscape in colorectal cancer.
Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage IIV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females.
Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%).
Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.
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Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin 2022; 72:372-401. [PMID: 35472088 DOI: 10.3322/caac.21728] [Citation(s) in RCA: 279] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.
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Affiliation(s)
- Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Davide Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- Division of Medical Oncology, IRCCS Foundation Home for the Relief of Suffering, San Giovanni Rotondo, Italy
| | - Giulia Martini
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Stefania Napolitano
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus, Barcelona, Spain
- Institute of Oncology, University of Vic/Central University of Catalonia, Barcelona, Spain
- Oncology Institute of Barcelona-Quironsalud, Biomedical Research Center in Cancer, Barcelona, Spain
| | - Andres Cervantes
- Medical Oncology Department, Instituto de Investigación Sanitaria Valencia Biomedical Research Institute, University of Valencia, Valencia, Spain
- Carlos III Institute of Health, Biomedical Research Center in Cancer, Madrid, Spain
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17
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Lazar I, Fabre B, Feng Y, Khateb A, Frit P, Kashina A, Zhang T, Avitan-Hersh E, Kim H, Brown K, Topisirovic I, Ronai ZA. Arginyl-tRNA-protein transferase 1 (ATE1) promotes melanoma cell growth and migration. FEBS Lett 2022; 596:1468-1480. [PMID: 35561126 PMCID: PMC10118390 DOI: 10.1002/1873-3468.14376] [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: 08/08/2021] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 11/10/2022]
Abstract
Arginyl-tRNA-protein transferase 1 (ATE1) catalyses N-terminal protein arginylation, a post-translational modification implicated in cell migration, invasion and the cellular stress response. Herein, we report that ATE1 is overexpressed in NRAS-mutant melanomas, while it is downregulated in BRAF-mutant melanomas. ATE1 expression was higher in metastatic tumours, compared with primary tumours. Consistent with these findings, ATE1 depletion reduced melanoma cell viability, migration and colony formation. Reduced ATE1 expression also affected cell responses to mTOR and MEK inhibitors and to serum deprivation. Among putative ATE1 substrates is the tumour suppressor AXIN1, pointing to the possibility that ATE1 may fine-tune AXIN1 function in melanoma. Our findings highlight an unexpected role for ATE1 in melanoma cell aggressiveness and suggest that ATE1 constitutes a potential new therapeutic target.
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Affiliation(s)
- Ikrame Lazar
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.,Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.,MCD, Centre de Biologie Intégrative (CBI), CNRS, UT3, Université de Toulouse, France
| | - Bertrand Fabre
- Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.,Laboratoire de Recherche en Sciences Végétales, UMR5546, UT3, INP, CNRS, Université de Toulouse, Auzeville-Tolosane, France
| | - Yongmei Feng
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Ali Khateb
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.,Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Philippe Frit
- Institut de Pharmacologie et de Biologie Structurale (IPBS), UMR 5089, CNRS, UT3, Université de Toulouse, France
| | - Anna Kashina
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Emily Avitan-Hersh
- Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Hyungsoo Kim
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Kevin Brown
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Ivan Topisirovic
- Gerald Bronfman Department of Oncology, Departments of Experimental Medicine and Biochemistry, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Ze'ev A Ronai
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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Kumar S, Mishra S. MALAT1 as master regulator of biomarkers predictive of pan-cancer multi-drug resistance in the context of recalcitrant NRAS signaling pathway identified using systems-oriented approach. Sci Rep 2022; 12:7540. [PMID: 35534592 PMCID: PMC9085754 DOI: 10.1038/s41598-022-11214-8] [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: 01/19/2022] [Accepted: 04/18/2022] [Indexed: 11/25/2022] Open
Abstract
NRAS, a protein mutated in several cancer types, is involved in key drug resistance mechanisms and is an intractable target. The development of drug resistance is one of the major impediments in targeted therapy. Currently, gene expression data is used as the most predictive molecular profile in pan-cancer drug sensitivity and resistance studies. However, the common regulatory mechanisms that drive drug sensitivity/resistance across cancer types are as yet, not fully understood. We focused on GDSC data on NRAS-mutant pan-cancer cell lines, to pinpoint key signaling targets in direct or indirect associations with NRAS, in order to identify other druggable targets involved in drug resistance. Large-scale gene expression, comparative gene co-expression and protein–protein interaction network analyses were performed on selected drugs inducing drug sensitivity/resistance. We validated our data from cell lines with those obtained from primary tissues from TCGA. From our big data studies validated with independent datasets, protein-coding hub genes FN1, CD44, TIMP1, SNAI2, and SPARC were found significantly enriched in signal transduction, proteolysis, cell adhesion and proteoglycans pathways in cancer as well as the PI3K/Akt-signaling pathway. Further studies of the regulation of these hub/driver genes by lncRNAs revealed several lncRNAs as prominent regulators, with MALAT1 as a possible master regulator. Transcription factor EGR1 may control the transcription rate of MALAT1 transcript. Synergizing these studies, we zeroed in on a pan-cancer regulatory axis comprising EGR1-MALAT1-driver coding genes playing a role. These identified gene regulators are bound to provide new paradigms in pan-cancer targeted therapy, a foundation for precision medicine, through the targeting of these key driver genes in the improvement of multi-drug sensitivity or resistance.
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Affiliation(s)
- Santosh Kumar
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India
| | - Seema Mishra
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India.
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Uchida S, Kojima T, Sugino T. Frequency and Clinicopathological Characteristics of Patients With KRAS/BRAF Double-Mutant Colorectal Cancer: An In Silico Study. Pathol Oncol Res 2022; 28:1610206. [PMID: 35280113 PMCID: PMC8908457 DOI: 10.3389/pore.2022.1610206] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/26/2022] [Indexed: 11/16/2022]
Abstract
KRAS and BRAF mutations are currently thought to be mutually exclusive as their co-occurrence is extremely rare. Therefore, clinicopathological and molecular characteristics of colorectal carcinoma with KRAS/BRAF double mutations are unclear. We aimed to investigate the frequency and clinicopathological characteristics of double-mutant colorectal carcinoma and its differences from KRAS/BRAF single-mutant colorectal carcinoma using bioinformatics tools. We estimated the KRAS/BRAF double mutation frequency in the whole exon and coding sequences via bioinformatic analyses of three datasets from cBioPortal. We compared the clinicopathological characteristics, microsatellite instability status, BRAF classification, and tumor mutation burden of patients harboring the double mutants with those of patients harboring KRAS or BRAF single mutations. We integrated three large datasets and found that the frequency of the KRAS/BRAF double mutation in the dataset was 1.2% (29/2347). The double mutation occurred more frequently in males, with a slightly higher occurrence in the right side of the colon. Sex, histological type, histological grade, microsatellite instability, and tumor mutation burden of the patients harboring KRAS-mutant, BRAF-mutant, and double-mutant colorectal carcinoma varied significantly. The frequency of double-mutant colorectal carcinoma was 60 times higher than that previously reported. Significantly fewer double-mutant colorectal carcinoma cases were classified as BRAF class 1 and more were classified as unknown. Our findings indicate that the biological characteristics of double-mutant tumors are different from those of single-mutant tumors.
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Affiliation(s)
- Shiro Uchida
- Division of Diagnostic Pathology, Kikuna Memorial Hospital, Yokohama, Japan.,Pathology Division, Shizuoka Cancer Center, Shizuoka, Japan.,Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takaaki Kojima
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
| | - Takashi Sugino
- Pathology Division, Shizuoka Cancer Center, Shizuoka, Japan
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20
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The application of radiomics in predicting gene mutations in cancer. Eur Radiol 2022; 32:4014-4024. [DOI: 10.1007/s00330-021-08520-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022]
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21
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Wang Y, Ma LY, Yin XP, Gao BL. Radiomics and Radiogenomics in Evaluation of Colorectal Cancer Liver Metastasis. Front Oncol 2022; 11:689509. [PMID: 35070948 PMCID: PMC8776634 DOI: 10.3389/fonc.2021.689509] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is one common digestive malignancy, and the most common approach of blood metastasis of colorectal cancer is through the portal vein system to the liver. Early detection and treatment of liver metastasis is the key to improving the prognosis of the patients. Radiomics and radiogenomics use non-invasive methods to evaluate the biological properties of tumors by deeply mining the texture features of images and quantifying the heterogeneity of metastatic tumors. Radiomics and radiogenomics have been applied widely in the detection, treatment, and prognostic evaluation of colorectal cancer liver metastases. Based on the imaging features of the liver, this paper reviews the current application of radiomics and radiogenomics in the diagnosis, treatment, monitor of disease progression, and prognosis of patients with colorectal cancer liver metastases.
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Affiliation(s)
| | | | - Xiao-Ping Yin
- CT-MRI Room, Affiliated Hospital of Hebei University, Baoding, China
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22
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Bożyk A, Krawczyk P, Reszka K, Krukowska K, Kolak A, Mańdziuk S, Wojas-Krawczyk K, Ramlau R, Milanowski J. Correlation between KRAS, NRAS and BRAF mutations and tumor localizations in patients with primary and metastatic colorectal cancer. Arch Med Sci 2022; 18:1221-1230. [PMID: 36160343 PMCID: PMC9479594 DOI: 10.5114/aoms/109170] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 05/06/2019] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Detection of abnormalities in the KRAS, NRAS and BRAF genes is extremely important for proper qualification of colorectal cancer (CRC) patients for therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibodies. However, data about prevalence of mutations in these genes, in different localizations of CRC tumors, are limited. MATERIAL AND METHODS We examined the frequency of mutations in the KRAS, NRAS and BRAF genes in 500 Caucasian CRC patients (200 women and 300 men, median age 66 years). DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) tissues using a Qiagen QIAamp DNA FFPE-kit. Analysis of mutations was carried out using the KRAS/BRAF, NRAS and BRAF Mutation Analysis Kit for Real-Time PCR (EntroGen) with the Cobas 480 real-time PCR apparatus (Roche Diagnostics). RESULTS KRAS mutations were detected in 190 (38%) patients, NRAS mutations in 20 (4%) patients, and BRAF mutations in 24 (4.8%) patients. There were no associations between age of CRC patients and frequency of KRAS, NRAS and BRAF gene mutations. These mutations were significantly more often diagnosed in women (55.5%) than in men (41%, p < 0.005). Tumors of the rectum and sigmoideum were the most often observed in both groups of CRC patients - with and without KRAS, NRAS and BRAF gene mutations. However, transverse colon, ascending colon and cecum cancers were the most often affected by mutations. CONCLUSIONS Our study showed that the occurrence of mutations in the KRAS, NRAS and BRAF genes is not accidental and depends on the location of CRC tumors.
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Affiliation(s)
- Aleksandra Bożyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | | | - Kinga Krukowska
- Institute of Genetics and Immunology GENIM LLC, Lublin, Poland
| | - Agnieszka Kolak
- Department of Oncology and Chemotherapy, Medical University of Lublin, Lublin, Poland
| | - Sławomir Mańdziuk
- Department of Oncology and Chemotherapy, Medical University of Lublin, Lublin, Poland
| | - Kamila Wojas-Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Rodryg Ramlau
- Department of Oncology, Medical University of Poznan, Poznan, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
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23
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Motta R, Cabezas-Camarero S, Torres-Mattos C, Riquelme A, Calle A, Montenegro P, Sotelo MJ. Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives. J Clin Transl Res 2021; 7:771-785. [PMID: 34988329 PMCID: PMC8710355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/12/2021] [Accepted: 11/12/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Colorectal cancer is one of the most frequent neoplasms worldwide, and the majority of patients are diagnosed in advanced stages. Metastatic colorectal cancer (mCRC) harbors several mutations with different prognostic and predictive values; KRAS, NRAS, and BRAF mutations are the best known. Indeed, RAS and BRAF molecular status are associated with a different response to monoclonal antibodies (Anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor agents), which are usually added to chemotherapy in first-line, and thus allow to select the optimal therapy for patients with mCRC. Furthermore, sidedness is an important predictive and prognostic factor in mCRC, which is explained by the different molecular profile of left and right-sided tumors. Recently, microsatellite instability-high has emerged as a predictive factor of response and survival from immune checkpoint inhibitors in mCRC. Finally, several other alterations have been described in lower frequencies, such as human epidermal growth factor receptor-2 overexpression/amplification, PIK3CA pathway alterations, phosphatase and tension homolog loss, and hepatocyte growth factor/mesenchymal-epithelial transition factor pathway dysregulation, with several targeted therapies already demonstrating activity or being tested in currently ongoing clinical trials. AIM To review the importance of studying the predictive and prognostic roles of the molecular profile of mCRC, the changes occurred in recent years and how they would potentially change in the near future, to guide physicians in treatment decisions. RELEVANCE FOR PATIENTS Today, several different therapeutic options can be offered to patients in the first-line setting of mCRC. Therapies at present approved or under investigation in clinical trials will be thoroughly reviewed, with special emphasis on the molecular rationale behind them. Understanding the molecular status, resistance mechanisms and potential new druggable targets may allow physicians to choose the best therapeutic option in the first-line mCRC.
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Affiliation(s)
- Rodrigo Motta
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Santiago Cabezas-Camarero
- Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain
| | - Cesar Torres-Mattos
- Department of Medical Oncology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru
- Oncological Research Unit, Clínica San Gabriel, Lima, Peru
| | - Alejandro Riquelme
- Department of Medical Oncology, Hospital Universitario Infanta Cristina, Madrid, Spain
| | - Ana Calle
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Department of Medical Oncology, Hospital María Auxiliadora, Lima, Peru
| | - Paola Montenegro
- Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
- Auna-OncoSalud Network, Lima, Peru
| | - Miguel J. Sotelo
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Oncological Research Unit, Clínica San Gabriel, Lima, Peru
- Department of Medical Oncology, Hospital María Auxiliadora, Lima, Peru
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24
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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25
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da Cunha IW, de Almeida Coudry R, de Macedo MP, de Assis EACP, Stefani S, Soares FA. A call to action: molecular pathology in Brazil. SURGICAL AND EXPERIMENTAL PATHOLOGY 2021. [DOI: 10.1186/s42047-021-00096-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Adoption of molecular pathology in Brazil is currently very limited. Of note, there are no programs for training new molecular pathologists in the country; thus, documents compiling nationally applicable information on molecular pathology are few.
Methods
A selected panel of Brazilian experts in fields related to molecular pathology were provided with a series of relevant questions to address prior to the multi-day conference. Within this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion until a consensus was achieved.
Results
The panel proposes specific and realistic recommendations for implementing molecular pathology in cancer care in Brazil. In creating these recommendations, the authors strived to address all barriers to the widespread use and impediments to access mentioned previously within this manuscript.
Conclusion
This manuscript provides a review of molecular pathology principles as well as the current state of molecular pathology in Brazil. Additionally, the panel proposes practical and actionable recommendations for the implementation of molecular pathology throughout the country in order to increase awareness of the importance molecular pathology in Brazil.
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26
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Alharbi A, Bin Dokhi H, Almuhaini G, Alomran F, Masuadi E, Alomran N. Prevalence of colorectal cancer biomarkers and their impact on clinical outcomes in Riyadh, Saudi Arabia. PLoS One 2021; 16:e0249590. [PMID: 33979337 PMCID: PMC8116043 DOI: 10.1371/journal.pone.0249590] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives KRAS, NRAS, and BRAF mutations are commonly present in colorectal cancer (CRC). We estimated the frequency of KRAS, NRAS, and BRAF mutations and assessed their impact on survival and other clinical variables among Saudi patients. Design Retrospective cohort study design. Settings Oncology department of a tertiary hospital in Riyadh, Saudi Arabia. We gathered information from 2016 to 2018. Participants Cohort of 248 CRC patients to assess the demographic data, pathological tumour features, response to treatment modalities, disease progression, and metastasis. Statistical analysis used Correlation analysis using the chi-square test. Survival analysis using a Kaplan Meier method. Cox regression analysis to calculate the hazard ratios. Results Demographic data revealed that 84% of patients were diagnosed with CRC above the age of 50 years. Only 27% of patients presented with distant metastasis. KRAS mutations were the most prevalent (49.6%), followed by NRAS mutations (2%) and BRAF mutations (0.4%). Wild type tumours were found among 44.4% of patients. KRAS mutation showed no significant correlation with the site, type, pathological grade, and stage of the tumour. The mean survival time was shorter among patients with KRAS mutations than among patients with wild type KRAS tumours (54.46 vs. 58.02 months). Adjusted analysis showed that the survival time was significantly affected by patients’ age at diagnosis (P = 0.04). Male patients had an increased risk of mortality by 77% (hazard ratio: 1.77). Conclusions Saudi CRC patients had a high frequency of KRAS mutations and a low frequency of BRAF mutations. The KRAS mutation status did not affect the patients’ survival.
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Affiliation(s)
- Amjad Alharbi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Haifa Bin Dokhi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- * E-mail:
| | - Ghadir Almuhaini
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- College of Sciences and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Futoon Alomran
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Emad Masuadi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Nouf Alomran
- College of Medicine, Alfarabi Colleges, Riyadh, Saudi Arabia
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27
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Fiala O, Sorejs O, Hosek P, Liska V, Vycital O, Bruha J, Kucera R, Topolcan O, Finek J, Maceckova D, Pitule P. Association of miR-125b, miR-17 and let-7c Dysregulations With Response to Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With Metastatic Colorectal Cancer. Cancer Genomics Proteomics 2021; 17:605-613. [PMID: 32859639 DOI: 10.21873/cgp.20217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/21/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM MicroRNAs (miRs) play an important role in the regulation of cancer-related processes and are promising candidates for cancer biomarkers. The aim of the study was to evaluate the association of response to anti-EGFR monoclonal antibodies (mAbs) with selected miR expression profiles, including miR-125b, let-7c, miR-99a, miR-17, miR-143 and miR-145 in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS This retrospective study included 46 patients with mCRC harbouring wild-type RAS gene treated with cetuximab or panitumumab combined with chemotherapy in first- or second-line therapy. The miR expression was assessed using qRT-PCR. RESULTS Down-regulation of miR-125b and let-7c and up-regulation of miR-17 were found in the tumour tissue (p=0.0226, p=0.0040, p<0.0001). Objective response rate (ORR) was associated with up-regulation of miR-125b (p=0.0005). Disease control rate (DCR) was associated with up-regulation of miR-125b and let-7c (p=0.0383 and p=0.0255) and down-regulation of miR-17 (p=0.0464). MiR-125b showed correlation with progression-free and overall survival (p=0.055 and p=0.006). CONCLUSION The results show that up-regulation of miR-125b is associated with higher ORR and DCR and longer survival; let-7c up-regulation and miR-17 down-regulation are associated with higher DCR in mCRC patients treated with anti-EGFR mAbs.
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Affiliation(s)
- Ondrej Fiala
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic .,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Sorejs
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic.,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Petr Hosek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Vaclav Liska
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Vycital
- Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jan Bruha
- Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Radek Kucera
- Department of Immunochemistry Diagnostics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Topolcan
- Department of Immunochemistry Diagnostics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jindrich Finek
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Diana Maceckova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Pitule
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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Discovering the Mutational Profile of Early Colorectal Lesions: A Translational Impact. Cancers (Basel) 2021; 13:cancers13092081. [PMID: 33923068 PMCID: PMC8123354 DOI: 10.3390/cancers13092081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common malignancies worldwide. Next-generation sequencing technologies have identified new candidate genes and deepened the knowledge of the molecular mechanisms underlying the progression of colonic adenomas towards CRC. The main genetic, epigenetic, and molecular alterations driving the onset and progression of CRC in both hereditary and sporadic settings have also been investigated. The evaluation of the CRC risk based on the molecular characterization of early pre-cancerous lesions may contribute to the development of targeted preventive strategies development, help define specific risk profiles, and identify patients who will benefit from targeted endoscopic surveillance. Abstract Colorectal cancer (CRC) develops through a multi-step process characterized by the acquisition of multiple somatic mutations in oncogenes and tumor-suppressor genes, epigenetic alterations and genomic instability. These events lead to the progression from precancerous lesions to advanced carcinomas. This process requires several years in a sporadic setting, while occurring at an early age and or faster in patients affected by hereditary CRC-predisposing syndromes. Since advanced CRC is largely untreatable or unresponsive to standard or targeted therapies, the endoscopic treatment of colonic lesions remains the most efficient CRC-preventive strategy. In this review, we discuss recent studies that have assessed the genetic alterations in early colorectal lesions in both hereditary and sporadic settings. Establishing the genetic profile of early colorectal lesions is a critical goal in the development of risk-based preventive strategies.
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Chung C. Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation. J Oncol Pharm Pract 2021; 28:850-869. [PMID: 33832365 DOI: 10.1177/10781552211005525] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [NTRK] fusion genes, and human epidermal growth factor receptor type II [HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.
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Affiliation(s)
- Clement Chung
- 23530Houston Methodist West Hospital, Houston, TX, USA
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30
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Prejac J, Kekez D, Belev B, Prejac M, Pleština S. Frequency of Body Weight Loss is an Independent Prognostic Factor of First-Line Treatment Outcomes in Metastatic Colorectal Cancer. Nutr Cancer 2021; 74:520-526. [PMID: 33739208 DOI: 10.1080/01635581.2021.1900300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
One of the main features of wasting in cancer is an involuntary weight loss which is most pronounced in gastrointestinal tract tumors and leads to worse clinical outcomes. The aim of this study is to analyze the frequency of body weight loss (FBWL) as an additional prognostic factor in the treatment of patients with metastatic colorectal cancer (mCRC).In this observational, single-center study, data were retrieved for 236 patients treated for mCRC. FBWL was defined as a percent of change in weight divided by weeks of therapy. Patients were stratified into two groups according to the median of FBWL which equaled to the loss of 0.05%/week. Patients who lost >0.05%/week (N = 116) had shorter progression-free survival (PFS) in the first-line treatment, then the ones who lost <0.05%/week (N = 120); 28.3 vs 46.3 weeks, respectively. Cox regression model showed that FBWL and sidedness were significant predictors of PFS, while age, sex and ECOG were not. Significantly more patients with stable weight were also eligible for second-line treatment. In conclusion, stabilization of body weight is important and independent predictor of longer PFS in first-line therapy of patients with mCRC.
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Affiliation(s)
- Juraj Prejac
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.,School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Domina Kekez
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Borislav Belev
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.,School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Prejac
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Stjepko Pleština
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.,School of Medicine, University of Zagreb, Zagreb, Croatia
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31
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Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept. Clin Transl Oncol 2021; 23:1520-1528. [PMID: 33630242 PMCID: PMC8238745 DOI: 10.1007/s12094-021-02568-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/02/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.
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32
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Ounissi D, Weslati M, Boughriba R, Hazgui M, Bouraoui S. Clinicopathological characteristics and mutational profile of KRAS and NRAS in Tunisian patients with sporadic colorectal cancer. Turk J Med Sci 2021; 51:148-158. [PMID: 32892548 PMCID: PMC7991861 DOI: 10.3906/sag-2003-42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Background/aim Colorectal cancer (CRC) is a major public health problem worldwide and in Tunisia due to its increasing rate of incidence.
KRAS
and
NRAS
mutations have become a pivotal part of CRC diagnosis, given their association to treatment resistance with antiepidermal growth factor receptor (EGFR) monoclonal antibodies. In this study, we aimed to screen for mutations in
KRAS
and
NRAS
genes in Tunisian patients with CRC and explore their correlations with clinicopathological features. Materials and methods AmoyDx
KRAS
and
NRAS
mutation real-time PCR kits were used to screen for mutations in
KRAS
(exon 2) and
NRAS
(exons 2, 3, and 4) in 96 CRC tumors. Results KRAS
exon 2 mutations were found in 41.7% (40/96) of the patients. Codon 12’s most abundant mutations were G12D and G12V, followed by G12A, while G13D is the predominant mutation in codon 13.
KRAS
exon 2 mutations were associated with older patients (P = 0.029), left-sided tumors (P = 0.037), and greater differentiation (P = 0.044). The prevalence rate of
NRAS
mutations was 7.3%, mostly in exon 2. These mutations were associated with early stages of the disease (P = 0.039) and the absence of lymph node metastasis (P = 0.045). Conclusion It can be inferred from this study that Tunisian CRC patients have a similar frequency of
KRAS
and
NRAS
mutations compared to those observed in other populations. Consequently, screening for
KRAS
and
NRAS
mutations is crucial for the orientation of therapies and the selection of appropriate candidates, while also helping to avoid unnecessary toxicity and increased costs for patients.
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Affiliation(s)
- Donia Ounissi
- Laboratory of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Marwa Weslati
- Laboratory of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Rahma Boughriba
- Laboratory of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Meriam Hazgui
- Laboratory of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Saadia Bouraoui
- Laboratory of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia,Department of Pathology and Cytology, Mongi Slim Hospital, La Marsa, Tunisia
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33
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Jia B, Liang F. Joint estimation of multiple mixed graphical models for pan-cancer network analysis. Stat (Int Stat Inst) 2020; 9:e271. [PMID: 33223572 PMCID: PMC7676750 DOI: 10.1002/sta4.271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/17/2020] [Indexed: 02/01/2023]
Abstract
Graphical models have been used in many scientific fields for exploration of conditional independence relationships for a large set of random variables. Although a variety of methods have been proposed in the literature for estimating graphical models with different types of data, none of them is applicable for jointly estimating multiple mixed graphical models. To tackle this problem, we propose a joint mixed learning method. The proposed method is very flexible, which works for various mixed types of data, such as those mixed with Gaussian, multinomial, and Poisson, and also allows people to incorporate domain knowledge into network construction by restricting some links to be included in or excluded from the networks. As an application, the proposed method is applied to pan-cancer network analysis for six types of cancer with data from The Cancer Genome Atlas. To our knowledge, this is the first work for joint estimation of multiple mixed graphical models.
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Affiliation(s)
- Bochao Jia
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46225, USA
| | - Faming Liang
- Department of Statistics, Purdue University, West Lafayette, 47907, IN, USA
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34
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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35
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Sammarco G, Gallo G, Vescio G, Picciariello A, De Paola G, Trompetto M, Currò G, Ammendola M. Mast Cells, microRNAs and Others: The Role of Translational Research on Colorectal Cancer in the Forthcoming Era of Precision Medicine. J Clin Med 2020; 9:2852. [PMID: 32899322 PMCID: PMC7564551 DOI: 10.3390/jcm9092852] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer. In fact, tumorigenesis is extremely complex, with many immunologic and non-immunologic factors present in the tumor microenvironment that can influence tumorigenesis. In the last few years, a role for mast cells (MCs), microRNAs (miRNAs), Kirsten rat sarcoma (KRAS) and v-raf murine sarcoma viral oncogene homologue B (BRAF) in cancer development and progression has been suggested, and numerous efforts have been made to thoroughly assess their correlation with CRC to improve patient survival and quality of life. The identification of easily measurable, non-invasive and cost-effective biomarkers, the so-called "ideal biomarkers", for CRC screening and treatment remains a high priority. The aim of this review is to discuss the emerging role of mast cells (MCs), microRNAs (miRNAs), KRAS and BRAF as diagnostic and prognostic biomarkers for CRC, evaluating their influence as potential therapy targets in the forthcoming era of precision medicine.
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Affiliation(s)
- Giuseppe Sammarco
- Department of Health Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.S.); (G.C.); (M.A.)
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.V.); (G.D.P.)
| | - Giuseppina Vescio
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.V.); (G.D.P.)
| | - Arcangelo Picciariello
- Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Piazza G Cesare, 11, 70124 Bari, Italy;
| | - Gilda De Paola
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.V.); (G.D.P.)
| | - Mario Trompetto
- Department of Colorectal Surgery, S. Rita Clinic, 13100 Vercelli, Italy;
| | - Giuseppe Currò
- Department of Health Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.S.); (G.C.); (M.A.)
| | - Michele Ammendola
- Department of Health Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (G.S.); (G.C.); (M.A.)
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36
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NRAS mutant E132K identified in young-onset sporadic colorectal cancer and the canonical mutants G12D and Q61K affect distinct oncogenic phenotypes. Sci Rep 2020; 10:11028. [PMID: 32620824 PMCID: PMC7334206 DOI: 10.1038/s41598-020-67796-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/14/2020] [Indexed: 02/07/2023] Open
Abstract
Recent data show a global increase in colorectal cancer (CRC) cases among younger demographics, which portends poorer prognosis. The cause of rising incidence is uncertain, and its mutational landscape remains largely unexplored, including those in genes of the epidermal growth factor receptor pathway. Among these are NRAS mutants where there is paucity of functional studies compared to KRAS. Here, the novel NRAS mutant E132K, identified in three tumor samples from Filipino young-onset, sporadic colorectal cancer patients, was investigated for its effects on different cancer hallmarks, alongside the NRAS canonical mutants G12D and Q61K which are yet poorly characterized in the context of CRC. The novel NRAS mutant E132K and the canonical G12D and Q61K mutants show resistance to apoptosis, cytoskeletal reorganization, and loss of adhesion. In contrast to activating KRAS mutations, including the analogous KRAS G12D and Q61K mutations, all three NRAS mutants have no apparent effect on cell proliferation and motility. The results highlight the need to characterize isoform- and mutation-specific oncogenic phenotypes which can have repercussions in disease management and choice of therapeutic intervention. Further analyses of young-onset versus late-onset CRC datasets are necessary to qualify NRAS E132K as a biomarker for the young-onset subtype.
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37
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Eshraghi A, Esfandbod M, SafaeiNodehi SR, Shahi F, Eshraghi A. The predictive value of KRAS and NRAS mutations in metastatic colorectal cancer. Med J Islam Repub Iran 2020; 34:39. [PMID: 32617278 PMCID: PMC7320980 DOI: 10.34171/mjiri.34.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Indexed: 11/14/2022] Open
Affiliation(s)
- Abbas Eshraghi
- 1Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Esfandbod
- 1Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran,Corresponding author: Dr Mohsen Esfandbod,
| | | | - Farhad Shahi
- 1Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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38
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Song Y, Wang L, Ran W, Li G, Xiao Y, Wang X, Zhang L, Xing X. Effect of Tumor Location on Clinicopathological and Molecular Markers in Colorectal Cancer in Eastern China Patients: An Analysis of 2,356 Cases. Front Genet 2020; 11:96. [PMID: 32161617 PMCID: PMC7052354 DOI: 10.3389/fgene.2020.00096] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/28/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) has become a major health concern in China due to its increasing incidence and mortality. This study aimed to clarify the relationship between tumor locations and the clinicopathological molecular marker features in eastern China CRC patients. We continuously collected data on 2,356 CRC patients who underwent surgical resection from January 2017 to April 2019. Right-sided colorectal cancer (RCC), was located from the cecum to the transverse colon and left-side colorectal cancer (LCRC) was located from the splenic flexure to the rectum. The clinicopathological indices (including age, sex, pTNM stage, mucinous production, and distant metastasis) and frequency of molecular markers such as KRAS, NRAS, BRAF, and microsatellite instability (MSI) were statistically analyzed between the RCC and LCRC groups. The associations between clinicopathological characters and molecular markers were also investigated. LCRC and RCC proportions in eastern China CRC patients were 81.75% and 18.25%, respectively. RCC (vs. LCRC) was more frequently observed with higher frequencies of MSI-high (MSI-H) and BRAF mutations in female and younger patients, and was closely associated with metastasis, poor differentiation, and mucinous tumors. Tumor location also showed significant differences in bowel wall infiltration degree and pTNM stage. Mutation rates of KRAS, NRAS, MSI, and BRAF were 40.15%, 3.85%, 6.31%, and 2.30%, respectively. Patients with a KRAS mutation tended to be female, had mucinous, perineural invasive, and polypoid tumor. Those with NRAS mutation tended to develop well-differentiated ulcerative tumors. The BRAF mutation was more relevant with lymph node involvement, deeper infiltration of the bowel wall, mucinous, poorly-differentiated tumor with thrombus, and perineural invasion. Furthermore, MSI-H was more commonly found in younger patients with deeper bowel wall infiltration and a poorly-differentiated polypoid tumor, whereas MSS patients tended to develop lymph node involvement, and a mucinous and perineural invasive tumor. In our study, we found that LCRC and RCC showed different features on the clinicopathological and molecular markers in eastern China CRC patients. Since our data differ from those of Western countries and other regions in China, further studies are required to clarify the regional differences of the clinicopathological and molecular markers in CRC patients.
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Affiliation(s)
- Yaolin Song
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Wang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenwen Ran
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guangqi Li
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yujing Xiao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaonan Wang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoming Xing
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
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39
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Lee SH, Yoo J, Song YS, Lim CH, Kim TM. Mutation Analysis of Colorectal and Gastric Carcinomas Originating from Adenomas: Insights into Genomic Evolution Associated with Malignant Progression. Cancers (Basel) 2020; 12:cancers12020325. [PMID: 32023847 PMCID: PMC7072232 DOI: 10.3390/cancers12020325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/26/2020] [Accepted: 01/27/2020] [Indexed: 12/30/2022] Open
Abstract
Small malignant tumor foci arising from benign lesions are rare but offer a unique opportunity to investigate the genomic evolution that occurs during malignant transformation. In this study, we analyzed 11 colorectal and 10 gastric adenoma–carcinoma pairs, each of which represented malignant tumors (carcinomas) embedded in benign lesions (adenomas) found in the same patient. Whole-exome sequencing revealed that mutation abundance was variable across different cases, but comparable between adenoma–carcinoma pairs. When mutations were classified as adenoma-specific, carcinoma-specific, or common, adenoma-specific mutations were more enriched with subclonal mutations than were carcinoma-specific mutations, indicative of a perturbation in mutational subclonal architecture (such as selective sweep) during malignant transformation. Among the recurrent mutations in colorectal cancers, APC and KRAS mutations were common between adenomas and carcinomas, indicative of their early occurrence during genomic evolution. TP53 mutations were often observed as adenoma-specific and therefore likely not associated with the emergence of malignant clones. Clonality-based enrichment analysis revealed that subclonal mutations of extracellular matrix genes in adenomas are more likely to be clonal in carcinomas, indicating potential roles for these genes in malignant transformation. Compared with colorectal cancers, gastric cancers showed more lesion-specific mutations than common mutations and higher levels of discordance in copy number profiles between matched adenomas and carcinomas, which may explain the elevated evolutionary dynamics and heterogeneity of gastric cancers compared to colorectal cancers. Taken together, this study demonstrates that co-existing benign and malignant lesions enable the evolution-based categorization of genomic alterations that may reveal clinically important biomarkers in colorectal and gastric cancers.
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Affiliation(s)
- Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul 06591, Korea;
| | - Jinseon Yoo
- Department of Medical Informatics, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul 06591, Korea;
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul 06591, Korea
| | - Young Soo Song
- Department of Pathology, College of Medicine, Konyang University, 158 Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea;
| | - Chul-Hyun Lim
- Division of Gastroenterology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 1021, Tongil-ro, Eunpyeong-gu, Seoul 03312, Korea
- Correspondence: (C.-H.L.); (T.-M.K.); Tel.: +82-2-2030-4316 (C.-H.L.); +82-2-2258-7483 (T.-M.K.)
| | - Tae-Min Kim
- Department of Medical Informatics, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul 06591, Korea;
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul 06591, Korea
- Correspondence: (C.-H.L.); (T.-M.K.); Tel.: +82-2-2030-4316 (C.-H.L.); +82-2-2258-7483 (T.-M.K.)
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40
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Post JB, Roodhart JML, Snippert HJG. Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants. Trends Cancer 2020; 6:111-129. [PMID: 32061302 DOI: 10.1016/j.trecan.2019.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/27/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
RAS and BRAF proteins are frequently mutated in colorectal cancer (CRC) and have been associated with therapy resistance in metastatic CRC patients. RAS isoforms are considered to act as redundant entities in physiological and pathological settings. However, there is compelling evidence that mutant variants of RAS and BRAF have different oncogenic potentials and therapeutic outcomes. In this review we describe similarities and differences between various RAS and BRAF oncogenes in CRC development, histology, and therapy resistance. In addition, we discuss the potential of patient-derived tumor organoids for personalized therapy, as well as CRC modeling using genome editing in preclinical model systems to study similarities and discrepancies between the effects of oncogenic MAPK pathway mutations on tumor growth and drug response.
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Affiliation(s)
- Jasmin B Post
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Jeanine M L Roodhart
- Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Hugo J G Snippert
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands.
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41
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Hara Y, Minami Y, Yoshimoto S, Hayashi N, Yamasaki A, Ueda S, Masuko K, Masuko T. Anti-tumor effects of an antagonistic mAb against the ASCT2 amino acid transporter on KRAS-mutated human colorectal cancer cells. Cancer Med 2020; 9:302-312. [PMID: 31709772 PMCID: PMC6943164 DOI: 10.1002/cam4.2689] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 10/01/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
Abstract
KRAS mutations are detected in numerous human cancers, but there are few effective drugs for KRAS-mutated cancers. Transporters for amino acids and glucose are highly expressed on cancer cells, possibly to maintain rapid cell growth and metabolism. Alanine-serine-cysteine transporter 2 (ASCT2) is a primary transporter for glutamine in cancer cells. In this study, we developed a novel monoclonal antibody (mAb) recognizing the extracellular domain of human ASCT2, and investigated whether ASCT2 can be a therapeutic target for KRAS-mutated cancers. Rats were immunized with RH7777 rat hepatoma cells expressing human ASCT2 fused to green fluorescent protein (GFP). Splenocytes from the immunized rats were fused with P3X63Ag8.653 mouse myeloma cells, and selected and cloned hybridoma cells secreting Ab3-8 mAb were established. This mAb reacted with RH7777 transfectants expressing ASCT2-GFP proteins in a GFP intensity-dependent manner. Ab3-8 reacted with various human cancer cells, but not with non-cancer breast epithelial cells or ASCT2-knocked out HEK293 and SW1116 cells. In SW1116 and HCT116 human colon cancer cells with KRAS mutations, treatment with Ab3-8 reduced intracellular glutamine transport, phosphorylation of AKT and ERK, and inhibited in vivo tumor growth of these cells in athymic mice. Inhibition of in vivo tumor growth by Ab3-8 was not observed in HT29 colon and HeLa uterus cancer cells with wild-type KRAS. These results suggest that ASCT2 is an excellent therapeutic target for KRAS-mutated cancers.
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Affiliation(s)
- Yuta Hara
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Yushi Minami
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Soshi Yoshimoto
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Natsumi Hayashi
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Akitaka Yamasaki
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Shiho Ueda
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Kazue Masuko
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
| | - Takashi Masuko
- Cell Biology LaboratorySchool of PharmacyKindai UniversityHigashi‐OsakaOsakaJapan
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42
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Bardia A, Gounder M, Rodon J, Janku F, Lolkema MP, Stephenson JJ, Bedard PL, Schuler M, Sessa C, LoRusso P, Thomas M, Maacke H, Evans H, Sun Y, Tan DS. Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. Oncologist 2020; 25:e160-e169. [PMID: 31395751 PMCID: PMC6964137 DOI: 10.1634/theoncologist.2019-0297] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/18/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. MATERIALS AND METHODS Eighty-nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0-2. Binimetinib and buparlisib combinations were explored in patients with KRAS-, NRAS-, or BRAF-mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)-mutant, advanced non-small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS- or BRAF-mutant ovarian cancer; or advanced non-small cell lung cancer with KRAS mutation. RESULTS At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF-mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. CONCLUSION Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose-limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. IMPLICATIONS FOR PRACTICE Because dysregulation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single-agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.
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Affiliation(s)
- Aditya Bardia
- Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center; Harvard Medical SchoolBostonMassachusettsUSA
| | - Mrinal Gounder
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Jordi Rodon
- Medical Oncology Department, Vall D'Hebron Institute of Oncology, VHIOBarcelonaSpain
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Martijn P. Lolkema
- Department of Medical Oncology, University Medical Center UtrechtUtrechtThe Netherlands
| | - Joe J. Stephenson
- Department of Medical Oncology, GHS Cancer InstituteGreenvilleSouth CarolinaUSA
| | - Philippe L. Bedard
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of TorontoTorontoOntarioCanada
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Duisburg‐Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital EssenEssenGermany
| | - Cristiana Sessa
- Department of Medical Oncology, Oncology Institute of Southern SwitzerlandBellinzonaSwitzerland
| | - Patricia LoRusso
- Department of Medical Oncology, Yale Cancer CenterNew HavenConnecticutUSA
| | - Michael Thomas
- Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC‐H), Member of the German Center for Lung Research (DZL)HeidelbergGermany
| | | | | | | | - Daniel S.W. Tan
- Department of Medical Oncology, National Cancer Centre SingaporeSingapore
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Awidi M, Ababneh N, Shomaf M, Al Fararjeh F, Owaidi L, AlKhatib M, Al Tarawneh B, Awidi A. KRAS and NRAS mutational gene profile of metastatic colorectal cancer patients in Jordan. PLoS One 2019; 14:e0226473. [PMID: 31881025 PMCID: PMC6934288 DOI: 10.1371/journal.pone.0226473] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND A constitutively active RAS protein in the absence of stimulation of the epidermal growth factor receptor (EGFR) is the result of mutations in KRAS and NRAS genes. Mutations in the KRAS exon 2 and outside exon 2 have been found to predict the resistance to anti-EGFR monoclonal therapy. A substantial proportion of metastatic colorectal cancer cases (mCRC) exhibit RAS mutations outside KRAS exon 2, particularly in KRAS exon 3 and 4 and NRAS exons 2 and 3. No data about RAS mutations outside KRAS exon 2 are available for Jordanian patients with mCRC. We aim to study the molecular spectrum, frequency, and distribution pattern of KRAS and NRAS mutations in Jordanian patients with mCRC. METHODS A cohort of 190 Jordanian metastatic colorectal cancer patients were enrolled in the trial. We detected mutations in exon 2 of the KRAS and NRAS gene as well as mutations outside of exon 2 using the StripAssay technique. The KRAS StripAssay covered 29 mutations and 22 NRAS mutations. RESULTS Mutations were observed in 92 (48.42%) cases, and KRAS exon 2 mutations accounted for 76 cases (83.69%). KRAS G12D was the most common mutation, occurring in 18 cases, followed by KRAS G12A in 16 cases, and G12T in 13 cases. Mutations outside of KRAS exon 2 represented 16.3% of the mutated cases. Among those, 6 cases (6.48%) carried mutations in NRAS exon 2 and 3, and 10 cases (10.87%) in KRAS exon 3 and 4. CONCLUSION The frequency of NRAS and KRAS mutations outside of exon 2 appears to be higher in Jordanian patients in comparison with patients from western countries. KRAS mutations outside of exon 2 should be tested routinely to identify patients who should not be treated with anti-EGFR antibodies.
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Affiliation(s)
- Muhammad Awidi
- Beth Israel Lahey Health-Lahey Hospital and Medical Center, Burlington, Massachusetts, United States of America
| | - Nidaa Ababneh
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Maha Shomaf
- Department of Pathology and Microbiology and Forensic Medicine, The University of Jordan, Amman, Jordan
| | - Feras Al Fararjeh
- Department of Medicine, The University of Jordan, School of Medicine, Amman, Jordan
| | - Laila Owaidi
- Hemostasis and Thrombosis Laboratory, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mohammad AlKhatib
- Hemostasis and Thrombosis Laboratory, School of Medicine, The University of Jordan, Amman, Jordan
| | - Buthaina Al Tarawneh
- Hemostasis and Thrombosis Laboratory, School of Medicine, The University of Jordan, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- Department of Hematology and Oncology, Jordan University Hospital, Amman, Jordan
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Giopanou I, Pintzas A. RAS and BRAF in the foreground for non-small cell lung cancer and colorectal cancer: Similarities and main differences for prognosis and therapies. Crit Rev Oncol Hematol 2019; 146:102859. [PMID: 31927392 DOI: 10.1016/j.critrevonc.2019.102859] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/16/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023] Open
Abstract
Lung and colorectal cancer are included in the most tremendously threatening diseases in terms of incidence and death. Although they are located in completely different organs and differ in various characteristics they do share some common features, especially regarding their molecular mutational profile. Among several commonly mutated genes KRAS and BRAF are spotted to be highly associated with patient's poor disease outcome and resistance to targeted therapies mostly in liaison with other mutant activated genes. Many studies have shed light in these mechanisms for disease progression and numerous preclinical models, clinical trials and meta-analysis reports investigate the impact of specific treatments or combination of therapies. The present review is an effort to compare the mutational imprint of these genes between the two diseases and their impact in prognosis, current therapy, mechanisms of therapy resistance and future therapeutic plans and provide a spherical perspective regarding the systemic molecular profile of cancer.
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Affiliation(s)
- Ioanna Giopanou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece.
| | - Alexandros Pintzas
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece.
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Hoo WPY, Siak PY, In LLA. Overview of Current Immunotherapies Targeting Mutated KRAS Cancers. Curr Top Med Chem 2019; 19:2158-2175. [PMID: 31483231 DOI: 10.2174/1568026619666190904163524] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023]
Abstract
The occurrence of somatic substitution mutations of the KRAS proto-oncogene is highly prevalent in certain cancer types, which often leads to constant activation of proliferative pathways and subsequent neoplastic transformation. It is often seen as a gateway mutation in carcinogenesis and has been commonly deemed as a predictive biomarker for poor prognosis and relapse when conventional chemotherapeutics are employed. Additionally, its mutational status also renders EGFR targeted therapies ineffective owing to its downstream location. Efforts to discover new approaches targeting this menacing culprit have been ongoing for years without much success, and with incidences of KRAS positive cancer patients being on the rise, researchers are now turning towards immunotherapies as the way forward. In this scoping review, recent immunotherapeutic developments and advances in both preclinical and clinical studies targeting K-ras directly or indirectly via its downstream signal transduction machinery will be discussed. Additionally, some of the challenges and limitations of various K-ras targeting immunotherapeutic approaches such as vaccines, adoptive T cell therapies, and checkpoint inhibitors against KRAS positive cancers will be deliberated.
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Affiliation(s)
- Winfrey Pui Yee Hoo
- Department of Biotechnology, Faculty of Applied Sciences, UCSI University, 56000, Kuala Lumpur, Malaysia
| | - Pui Yan Siak
- Department of Biotechnology, Faculty of Applied Sciences, UCSI University, 56000, Kuala Lumpur, Malaysia
| | - Lionel L A In
- Department of Biotechnology, Faculty of Applied Sciences, UCSI University, 56000, Kuala Lumpur, Malaysia
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Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell Lines. Cells 2019; 8:cells8080878. [PMID: 31409052 PMCID: PMC6721647 DOI: 10.3390/cells8080878] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/31/2019] [Accepted: 08/10/2019] [Indexed: 12/21/2022] Open
Abstract
The targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in the treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in a limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by KRASG12D mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. Through integrated analyses of differential gene expression with TCGA and CCLE public database, we identified TNS4, overexpressed in CRC patients and KRAS mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of TNS4 expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore, TNS4 expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a MEK1/2 inhibitor, suppressed oncogenic activity of CRC cells, and this effect is more profound in combination with cetuximab. Altogether, we propose that TNS4 plays a crucial role in CRC tumorigenesis, and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations.
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Korphaisarn K, Pongpaibul A, Roothumnong E, Pongsuktavorn K, Thamlikitkul L, Anekpuritanang T, Poungvarin N, Thongnoppakhun W, Pithukpakorn M. High Frequency of KRAS Codon 146 and FBXW7 Mutations in Thai Patients with Stage II-III Colon Cancer. Asian Pac J Cancer Prev 2019; 20:2319-2326. [PMID: 31450901 PMCID: PMC6852819 DOI: 10.31557/apjcp.2019.20.8.2319] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Indexed: 12/24/2022] Open
Abstract
Background: KRAS, NRAS, and BRAF gene mutations are the most clinically relevant and frequently reported in
colorectal cancer (CRC). Although data on these genes are frequently reported in several counties, data specific to these
genes among Thai population are scarce. The aim of this study was to investigate and identify molecular alterations
associated with colon cancer in Thai population, and to determine the impact of these genetic aberrations on clinical
outcome. Methods: DNA from 108 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically
confirmed adenocarcinoma of stage II-III colon cancer between 2010 and 2012 at Siriraj Hospital (Bangkok, Thailand)
were extracted. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine
Solid Tumor DNA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results: A total of 22 somatic gene
mutations were detected. The mutation frequency observed in KRAS, NRAS, BRAF, PIK3CA, and FBXW7 mutations
was 47.2%, 1.9%, 1.9%, 12%, and 14.8%, respectively. KRAS mutation codon 12, 13, 59, 61, 117, and 146 mutations
were identified in 29.6%, 8.3%, 1.8%, 0.9%, 0.0%, and 8.3%, respectively. KRAS Exon 4 had better DFS compared
with Exon 2 and 3. Conclusions: This study is the first to comprehensively report hotspot mutations using NGS in Thai
colon cancer patients. The most commonly identified gene mutation frequencies among Thai patients (KRAS, NRAS,
BRAF, TP53, and PIK3CA) were similar to the gene mutation frequencies reported in Western population, except for
subgroup of KRAS codon 146 and FBXW7 mutations that had a slightly higher frequency.
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Affiliation(s)
- Krittiya Korphaisarn
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. ,Siriraj Center of Research Excellence in Precision Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ananya Pongpaibul
- Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ekkapong Roothumnong
- Siriraj Center of Research Excellence in Precision Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics Research and Laboratory, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Khontawan Pongsuktavorn
- Siriraj Center of Research Excellence in Precision Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics Research and Laboratory, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Lucksamon Thamlikitkul
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Tauangtham Anekpuritanang
- Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wanna Thongnoppakhun
- Siriraj Center of Research Excellence in Precision Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics Research and Laboratory, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Manop Pithukpakorn
- Siriraj Center of Research Excellence in Precision Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Division of Medical Genetics Research and Laboratory, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Bodalal Z, Trebeschi S, Nguyen-Kim TDL, Schats W, Beets-Tan R. Radiogenomics: bridging imaging and genomics. Abdom Radiol (NY) 2019; 44:1960-1984. [PMID: 31049614 DOI: 10.1007/s00261-019-02028-w] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
From diagnostics to prognosis to response prediction, new applications for radiomics are rapidly being developed. One of the fastest evolving branches involves linking imaging phenotypes to the tumor genetic profile, a field commonly referred to as "radiogenomics." In this review, a general outline of radiogenomic literature concerning prominent mutations across different tumor sites will be provided. The field of radiogenomics originates from image processing techniques developed decades ago; however, many technical and clinical challenges still need to be addressed. Nevertheless, increasingly accurate and robust radiogenomic models are being presented and the future appears to be bright.
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Integrated molecular and clinical staging defines the spectrum of metastatic cancer. Nat Rev Clin Oncol 2019; 16:581-588. [DOI: 10.1038/s41571-019-0220-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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50
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Zhang Y, Zhang Z, Wang D, Xu J, Li Y, Wang H, Li J, Mo S, Zhang Y, Lin Y, Fan X, Li E, Huang J, Fan H, Yi Y. Multidimensional Integration Analysis of Autophagy-related Modules in Colorectal Cancer. LETT ORG CHEM 2019; 16:340-346. [DOI: 10.2174/1570178615666180914113224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/30/2018] [Accepted: 09/05/2018] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive tract occurring in the colon, which mainly divided into adenocarcinoma, mucinous adenocarcinoma, and undifferentiated carcinoma. However, autophagy is related to the occurrence and development of various kinds of human diseases such as cancer. There is little research on the relationship between CRC and autophagy. Hence, we performed multidimensional integration analysis to systematically explore potential relationship between autophagy and CRC. Based on gene expression datasets of colon adenocarcinoma (COAD) and protein-protein interactions (PPIs), we first identified 12 autophagy-related modules in COAD using WGCNA. Then, 9 module pairs which with significantly crosstalk were deciphered, a total of 6 functional modules. Autophagy-related genes in these modules were closely related with CRC, emphasizing that the important role of autophagy-related genes in CRC, including PPP2CA and EIF4E, etc. In addition to, by integrating transcription factor (TF)-target and RNA-associated interactions, a regulation network was constructed, in which 42 TFs (including SMAD3 and TP53, etc.) and 20 miRNAs (including miR-20 and miR-30a, etc.) were identified as pivot regulators. Pivot TFs were mainly involved in cell cycle, cell proliferation and pathways in cancer. And pivot miRNAs were demonstrated associated with CRC. It suggests that these pivot regulators might be have an effect on the development of CRC by regulating autophagy. In a word, our results suggested that multidimensional integration strategy provides a novel approach to discover potential relationships between autophagy and CRC, and further improves our understanding of autophagy and tumor in human.
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Affiliation(s)
- Yang Zhang
- Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Zheng Zhang
- Department of Physical Education, Nanjing Audit University, Nanjing, China
| | - Dong Wang
- Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Jianzhen Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area and Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Yanhui Li
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University Health Science Center, Beijing, China
| | - Hong Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jin Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Shaowen Mo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yuncong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yunqing Lin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiuzhao Fan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Enmin Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area and Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Jian Huang
- Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Huihui Fan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Ying Yi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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