Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer
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Purpose Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression. Materials and Methods Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed. Results As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoaR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families. Conclusion The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.
Abstract
Purpose Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression. Materials and Methods Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed. Results As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoaR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families. Conclusion The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.
참고문헌 (39)
- Ferlay J, "Cancer incidence and mortality worldwide : sources, methods and major patterns in GLOBOCAN 2012", Int J Cancer, 136, pp.E359~E386 (2015)
- Moller H, "Working group report on schistosomes, liver flukes and Helicobacter pylori", Int J Cancer, 60, pp.587~589 (1995)
- Neugut AI, "Epidemiology of gastric cancer", Semin Oncol, 23, pp.281~291 (1996)
- Genta RM, "Acid suppression and gastric atrophy : sifting fact from fiction", Gut, 43(Suppl 1), pp.S35~S38 (1998)
- World Cancer Research Fund, American Institute for Cancer Research, "Food, nutrition, physical activity, and the prevention of cancer: a global perspective" (2007), World Cancer Research Fund, American Institute for Cancer Research
- Ladeiras-Lopes R, "Smoking and gastric cancer : systematic review and meta-analysis of cohort studies", Cancer Causes Control, 19, pp.689~701 (2008)
- Matsukura N, "Simultaneous gastric cancer in monozygotic twins", Cancer, 62, pp.2430~2435 (1988)
- Kinugasa S, "Simultaneous early gastric cancer in identical twins : report of a case", Surg Today, 26, pp.189~191 (1996)
- Shah SC, "Population-based analysis of differences in gastric cancer incidence among races and ethnicities in individuals age 50 years and older", Gastroenterology, 159, pp.1705~1714 (2020)
- van der Post RS, "Hereditary diffuse gastric cancer : updated clinical guidelines with an emphasis on germline CDH1 mutation carriers", J Med Genet, 52, pp.361~374 (2015)
- Guilford P, "E-cadherin germline mutations in familial gastric cancer", Nature, 392, pp.402~405 (1998)
- Grunwald GB, "The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules", Curr Opin Cell Biol, 5, pp.797~805 (1993)
- Shiozaki H, "E-cadherin mediated adhesion system in cancer cells", Cancer, 77, pp.1605~1613 (1996)
- Majewski IJ, "An alpha-E-catenin(CTNNA1)mutation in hereditary diffuse gastric cancer", J Pathol, 229, pp.621~629 (2013)
- Rimm DL, "Alpha 1(E)-catenin is an actin-binding and-bundling protein mediating the attachment of F-actin to the membrane adhesion complex", Proc Natl Acad Sci U S A, 92, pp.8813~8817 (1995)
- Lien WH, "alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway", Science, 311, pp.1609~1612 (2006)
- Jose L, "Encyclopedia of signaling molecules", pp.4681~4691 (2018), Springer
- Oliveira C, "Familial gastric cancer : genetic susceptibility, pathology, and implications for management", Lancet Oncol, 16, pp.e60~e70 (2015)
- Luo X, "Optimising clinical care through CDH1-specific germline variant curation : improvement of clinical assertions and updated curation guidelines", J Med Genet, 60, pp.568~575 (2023)
- de Assumpcao PB, "Incidence of hereditary gastric cancer may be much higher than reported", Cancers(Basel), 14, pp.6125~ (2022)
- Amano M, "Rho-kinase", ROCK : a key regulator of the cytoskeleton and cell polarity, 2010, pp.67, 545~554
- Sadok A, "Rho GTPases : masters of cell migration", Small GTPases, 5, pp.e29710~ (2014)
- Shi J, "Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment", Cell Death Dis, 4, pp.e483~ (2013)
- Li Y, "Regulation and mechanism of YAP", TAZ in the mechanical microenvironment of stem cells(Review), 2021, pp.24, 506~
- Almodovar-Garcia K, "ANKRD1 acts as a transcriptional repressor of MMP13 via the AP-1 site", Mol Cell Biol, 34, pp.1500~1511 (2014)
- Samaras SE, "Global deletion of Ankrd1 results in a wound-healing phenotype associated with dermal fibroblast dysfunction", Am J Pathol, 185, pp.96~109 (2015)
- Jimenez AP, "The tumor suppressor RASSF1A induces the YAP1 target gene ANKRD1 that is epigenetically inactivated in human cancers and inhibits tumor growth", Oncotarget, 8, pp.88437~88452 (2017)
- Saab S, "The potential role of YAP in Axl-mediated resistance to EGFR tyrosine kinase inhibitors", Am J Cancer Res, 9, pp.2719~2729 (2019)
- Xu MZ, "AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma", Oncogene, 30, pp.1229~1240 (2011)
- He L, "Implications of the receptor tyrosine kinase Axl in gastric cancer progression", Onco Targets Ther, 13, pp.5901~5911 (2020)
- Hanahan D, "Hallmarks of cancer : the next generation", Cell, 144, pp.646~674 (2011)
- Kakiuchi M, "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma", Nat Genet, 46, pp.583~587 (2014)
- Nam S, "RHOA in gastric cancer : functional roles and therapeutic potential", Front Genet, 10, pp.438~ (2019)
- Dvorsky R, "Structural insights into the interaction of ROCKI with the switch regions of RhoA", J Biol Chem, 279, pp.7098~7104 (2004)
- Wang K, "Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer", Nat Genet, 46, pp.573~582 (2014)
- Cho SY, "Sporadic early-onset diffuse gastric cancers have high frequency of somatic CDH1 alterations, but low frequency of somatic RHOA mutations compared with late-onset cancers", Gastroenterology, 153, pp.536~549 (2017)
- Manso R, "The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature", Blood, 123, pp.2893~2894 (2014)
- Chang HR, "Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer", Oncotarget, 7, pp.81435~81451 (2016)
- Yoon C, "Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells", Clin Cancer Res, 22, pp.971~983 (2016)