Gastric Cancer in the Era of Precision Medicine
2017; Elsevier BV; Volume: 3; Issue: 3 Linguagem: Inglês
10.1016/j.jcmgh.2017.02.003
ISSN2352-345X
Autores Tópico(s)Genetic factors in colorectal cancer
ResumoGastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine. Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine. SummaryThe following pages provide a summary of current knowledge regarding the genomics of gastric cancer (GC), with a particular emphasis on how new genomic knowledge informs precision medicine and personalized therapies. The following pages provide a summary of current knowledge regarding the genomics of gastric cancer (GC), with a particular emphasis on how new genomic knowledge informs precision medicine and personalized therapies. Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer death in developed countries, with 984,000 new cases and 841,000 deaths occurring globally in 2013.1Fitzmaurice C. Dicker D. Pain A. et al.The global burden of cancer 2013.JAMA Oncol. 2015; 1: 505-527Crossref PubMed Google Scholar The incidence and mortality of GC are declining, in part because of improved Helicobacter pylori eradication and cancer screening. However, adenocarcinoma of the gastric cardia is increasing in North America and Europe,2Torre L.A. Bray F. Siegel R.L. et al.Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Crossref PubMed Scopus (7404) Google Scholar, 3Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2016.CA Cancer J Clin. 2016; 66: 7-30Crossref PubMed Scopus (6195) Google Scholar and the incidence of non-cardia GC among whites aged 25–39 years has increased 1.67-fold in the United States during the past 2 decades.4Anderson W.F. Camargo M.C. Fraumeni J.F. et al.Age-specific trends in incidence of noncardia gastric cancer in US adults.JAMA. 2010; 303: 1723-1728Crossref PubMed Scopus (176) Google Scholar Moreover, most GC cases are diagnosed at advanced stages, with consequent poor outcome; treatment is mostly restricted to cytotoxic chemotherapy. Thus, there is an urgent need to improve our understanding of the pathogenesis of GC and to identify more effective, less toxic therapeutic strategies. GC is multifactorial, with complex host genetic and environmental factors contributing to its development. GC is also highly heterogeneous; it is customarily divided into 2 main histologic subtypes, intestinal and diffuse, which are based on the Lauren classification.5Lauren P. The two histological main types of gastric carcinoma: diffuse and so called intestinal-type carcinoma.Acta Pathol Microbiol Scand. 1965; 64: 31-49Crossref PubMed Google Scholar However, the use of anti–human epidermal growth factor receptor-2 monoclonal antibody, trastuzumab, and anti–vascular endothelial growth factor receptor-2 monoclonal antibody, ramucirumab, has shifted the previous histopathologic paradigm to incorporate new genetic and molecular features.6Bang Y.J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (2762) Google Scholar, 7Fuchs C.S. Tomasek J. Yong C.J. et al.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet. 2014; 383: 31-39Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar Recently, remarkable advances in next-generation sequencing (NGS) technologies have defined the genomic landscape of GC8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar, 10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar; studies of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)11Song J.H. Meltzer S.J. MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers.Gastroenterology. 2012; 143 (e2): 35-47Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 12Fang X.Y. Pan H.F. Leng R.X. et al.Long noncoding RNAs: novel insights into gastric cancer.Cancer Lett. 2015; 356: 357-366Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar as well as novel preclinical models (such as patient-derived tumor xenografts [PDX] and patient-derived organoids) have largely filled the gap between cancer genetics and phenotype.13McCracken K.W. Catá E.M. Crawford C.M. et al.Modelling human development and disease in pluripotent stem-cell-derived gastric organoids.Nature. 2014; 516: 400-404Crossref PubMed Scopus (188) Google Scholar, 14Sachs N. Clevers H. Organoid cultures for the analysis of cancer phenotypes.Curr Opin Genet Dev. 2014; 24: 68-73Crossref PubMed Scopus (75) Google Scholar, 15Merker S.R. Weitz J. Stange D.E. Gastrointestinal organoids: how they gut it out.Dev Biol. 2016; 420: 239-250Crossref PubMed Scopus (7) Google Scholar, 16Hidalgo M. Amant F. Biankin A.V. et al.Patient-derived xenograft models: an emerging platform for translational cancer research.Cancer Discov. 2014; 4: 998-1013Crossref PubMed Scopus (269) Google Scholar, 17McCracken K.W. Aihara E. Martin B. et al.Wnt/β-catenin promotes gastric fundus specification in mice and humans.Nature. 2017; 541: 182-187Crossref PubMed Google Scholar These advances have made it possible to integrate traditional, genome-based and phenotype-based diagnostic and therapeutic methods with application to individual GC patients in the era of precision medicine. Among clinical risk factors for GC, which include smoking, high-salt diet, high intake of meats, and bile reflux, infection with H pylori is a leading factor, especially in distal GC.18Correa P. Houghton J. Carcinogenesis of Helicobacter pylori.Gastroenterology. 2007; 133: 659-672Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 19Correa P. Helicobacter pylori and gastric carcinogenesis.Am J Surg Pathol. 1995; 19: S37-S43Crossref PubMed Google Scholar, 20Bouvard V. Baan R. Straif K. et al.A review of human carcinogens: part B—biological agents.Lancet Oncol. 2009; 10: 321-322Abstract Full Text Full Text PDF PubMed Google Scholar, 21Moss S.F. The clinical evidence linking Helicobacter pylori to gastric cancer.Cell Mol Gastroenterol Hepatol. 2017; 3: 183-191Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar On the basis of improved estimates from prospective studies, 89% of new non-cardia GC cases are attributable to H pylori worldwide.22Plummer M. Franceschi S. Vignat J. et al.Global burden of gastric cancer attributable to Helicobacter pylori.Int J Cancer. 2015; 136: 487-490Crossref PubMed Scopus (117) Google Scholar H pylori–mediated gastric carcinogenesis involves several mechanisms: cytotoxin-associated gene A, vacuolating cytotoxin A–induced chronic inflammation, oxidative damage, genomic instability, and epigenetic changes in gastric epithelial cells.18Correa P. Houghton J. Carcinogenesis of Helicobacter pylori.Gastroenterology. 2007; 133: 659-672Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 23Hatakeyama M. Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis.Cell Host Microbe. 2014; 15: 306-316Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 24Wadhwa R. Song S. Lee J.S. et al.Gastric cancer: molecular and clinical dimensions.Nat Rev Clin Oncol. 2013; 10: 643-655Crossref PubMed Scopus (146) Google Scholar, 25Graham D.Y. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits.Gastroenterology. 2015; 148: 719-731.e3Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 26Hamilton J.P. Meltzer S.J. A review of the genomics of gastric cancer.Clin Gastroenterol Hepatol. 2006; 4: 416-425Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Interestingly, an inverse relation between H pylori infection and the risk of proximal GC has been observed in Western countries.27Chow W.H. Blaser M.J. Blot W.J. et al.An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma.Cancer Res. 1998; 58: 588-590PubMed Google Scholar Epstein-Barr virus (EBV) occurs in 2%–20% of GC, with a worldwide average of 10%.28Chen J.N. He D. Tang F. et al.Epstein-Barr virus-associated gastric carcinoma: a newly defined entity.J Clin Gastroenterol. 2012; 46: 262-271Crossref PubMed Scopus (0) Google Scholar In EBV-associated GC, latent membrane protein 2A activates DNA methyltransferase 1 by inducing phosphorylation of STAT3, thereby causing CpG island hypermethylation of the PTEN promoter.29Hino R. Uozaki H. Murakami N. et al.Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma.Cancer Res. 2009; 69: 2766-2774Crossref PubMed Scopus (171) Google Scholar Specific EBV transcripts, including latent genes and viral miRNAs, also have oncogenic properties such as increased cell proliferation and motility, impairment of apoptosis, and increased chemoresistance.30Shinozaki-Ushiku A. Kunita A. Fukayama M. Update on Epstein-Barr virus and gastric cancer (review).Int J Oncol. 2015; 46: 1421-1434Crossref PubMed Scopus (51) Google Scholar Hereditary cancer syndromes linked to 1%–3% of GC consist of 3 principal syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal GC.31Oliveira C. Pinheiro H. Figueiredo J. et al.Familial gastric cancer: genetic susceptibility, pathology, and implications for management.Lancet Oncol. 2015; 16: e60-e70Abstract Full Text Full Text PDF PubMed Google Scholar Germline mutations in CDH1, CTNNA1, and other tumor suppressor genes, including BRCA2, STK11, and SDHB, have been identified in HDGC.32Hansford S. Kaurah P. Li-Chang H. et al.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol. 2015; 1: 23-32Crossref PubMed Google Scholar CDH1 mutations are prognostic genetic markers in HDGC. GAPPS is characterized by autosomal dominant transmission of fundic gland polyposis restricted to the proximal stomach, without evidence of colorectal or duodenal polyposis or other hereditary gastrointestinal cancer syndromes.33Worthley D. Phillips K. Wayte N. et al.Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.Gut. 2012; 61: 774-779Crossref PubMed Scopus (62) Google Scholar GC is also increased in other heritable syndromes, such as Li-Fraumeni syndrome with germline mutation of TP53, Peutz-Jeghers syndrome with frameshift mutation in STK11, hereditary nonpolyposis colorectal cancer with germline DNA mismatch repair gene mutation, and familial adenomatous polyposis with germline APC mutation.31Oliveira C. Pinheiro H. Figueiredo J. et al.Familial gastric cancer: genetic susceptibility, pathology, and implications for management.Lancet Oncol. 2015; 16: e60-e70Abstract Full Text Full Text PDF PubMed Google Scholar, 34McLean M.H. El-Omar E.M. Genetics of gastric cancer.Nat Rev Gastroenterol Hepatol. 2014; 11: 664-674Crossref PubMed Scopus (121) Google Scholar GC has long been categorized by using histomorphologic classification systems. According to the Lauren classification, GCs are divided into 2 main subtypes, intestinal and diffuse.5Lauren P. The two histological main types of gastric carcinoma: diffuse and so called intestinal-type carcinoma.Acta Pathol Microbiol Scand. 1965; 64: 31-49Crossref PubMed Google Scholar However, these histologic classifications are not sufficient to reflect the molecular and genetic characteristics of GC or to develop personalized treatment strategies in the era of precision medicine. Recently, advances in genomic technology and high-throughput analysis have helped reveal the molecular genetic landscape of GC (Figure 1). Several molecular classification systems have been proposed, and distinct molecular subtypes have been identified.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar, 10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar, 35Kakiuchi M. Nishizawa T. Ueda H. et al.Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.Nat Genet. 2014; 46: 583-587Crossref PubMed Scopus (151) Google Scholar, 36Wong S.S. Kim K.M. Ting J.C. et al.Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing.Nat Commun. 2014; 5: 5477Crossref PubMed Google Scholar, 37Chen K. Yang D. Li X. et al.Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.Proc Natl Acad Sci U S A. 2015; 112: 1107-1112Crossref PubMed Scopus (43) Google Scholar In 2014, a landmark study by The Cancer Genome Atlas (TCGA) proposed 4 subtypes: (1) EBV-positive (8.8%), (2) microsatellite unstable/instability (MSI, 21.7%), (3) genomically stable (19.7%), and (4) chromosomally unstable/chromosomal instability (CIN, 49.8%).8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar Most EBV-positive tumors occurred in male patients and in the gastric fundus or body, displaying extreme DNA hypermethylation and amplification of JAK2 and PD-L1/2, with 80% harboring non-silent PIK3CA mutations. All EBV-positive GCs displayed CDKN2A promoter hypermethylation, while lacking the MLH1 hypermethylation characteristic of the MSI-associated CpG island methylator phenotype (CIMP).8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 38Geddert H. Zur Hausen A. Gabbert H.E. et al.EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1.Anal Cell Pathol (Amst). 2010; 33: 143-149Crossref PubMed Google Scholar Strong interleukin-12–mediated signaling signatures suggested a robust immune cell presence in this subtype. In contrast, MSI-subtype tumors tended to occur in female patients, diagnosed at advanced ages, and characterized by elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins. The genomically stable subtype lacked numerous molecular alterations, correlated well with the Lauren diffuse histologic variant, but harbored mutations of RHOA or fusions involving RHO-family guanosine triphosphatase (GTPase)–activating proteins. The active GTP-bound form of RHOA activates STAT3 to promote tumorigenesis.39Yu H. Jove R. The STATs of cancer: new molecular targets come of age.Nat Rev Cancer. 2004; 4: 97-105Crossref PubMed Google Scholar Finally, CIN subtype tumors were frequent at the gastroesophageal junction/cardia, correlated well with the Lauren intestinal histologic variant, showed marked aneuploidy, and harbored focal amplifications of receptor tyrosine kinases (RTKs), in addition to recurrent TP53 mutations and RTK-RAS activation.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar In 2015, the Asian Cancer Research Group proposed a new classification system associated with distinct genomic alterations, disease progression, and prognosis across multiple GC cohorts.9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar On the basis of whole-genome sequencing, gene expression profiling, genome-wide copy number microarrays, and targeted gene sequencing, 4 molecular subtypes were identified: (1) MSI, (2) microsatellite stable with epithelial-to-mesenchymal transition features (MSS/EMT), (3) MSS/TP53 mutant (MSS/TP53+), and (4) MSS/TP53 wild-type (MSS/TP53–).9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar One strong point of this study was the availability of long-term follow-up data, enabling association of this molecular classification with clinical outcome. The postoperative surveillance program for recurrence in the Asian Cancer Research Group study consisted of performing follow-up exams every 6 months until 5 years after the date of surgery.9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar MSI tumors were hypermutated, intestinal, usually antral, and diagnosed at clinical stage I/II. MSI tumors had the best prognosis; their recurrence rate after surgical resection of primary GC was the lowest among all 4 subtypes (22%). MSS/TP53+ tumors were linked to EBV infection and had the next best prognosis, followed by MSS/TP53- tumors. MSS/EMT tumors occurred at a younger age, mostly diagnosed at clinical stage III/IV, and were the Lauren diffuse histologic type. The MSS/EMT subtype had the worst prognosis and the highest recurrence rate (63%), with recurrences located mostly in the peritoneal cavity.9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar Continuing to refine molecular classification, regular mutated (2.4 mutations/megabase; range, 0–8.3) and hypermutated (20.5 mutations/megabase; range, 9.6–200.2) GC types were identified in another recent study.10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar The regular mutated type was further subclassified into 2 subgroups, C1 and C2. The first subgroup, C1, was enriched in mutations of TP53, XIRP2, and APC and was associated with a significantly better prognostic outcome, whereas C2 was overrepresented by mutations in ARID1A, CDH1, PIK3CA, ERBB2, and RHOA. Furthermore, consistent with the Asian Cancer Research Group study, this research team observed that CDH1 mutations were associated with a worse outcome in diffuse-type GC, independent of disease stage.10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar Because ARID1A is frequently mutated in both EBV and MSI subtypes, its mutation alone is not likely to constitute an alternative GC pathway. The mutational landscape of GC has been deciphered by using large-scale analyses of data from genomic, expressional, and mutational profiling studies, especially potential clinically relevant driver mutations (Figure 2). Approximately 16.4% of GC cases exhibit hyperdense mutation frequencies.10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar Genomic instability, and thus mutability, endows cells with genetic alterations, which in turn aid tumorigenesis and tumor progression.40Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (18169) Google Scholar As the guardian of the genome, TP53 plays a central role in maintenance of genome integrity.41Lane D.P. Cancer: p53, guardian of the genome.Nature. 1992; 358: 15-16Crossref PubMed Scopus (0) Google Scholar TP53 mutations allow the accumulation of genetic alterations, leading to genomic instability. As the most frequently mutated gene, TP53 mutations occurred in about 50% of GC and 71% of CIN subtype tumors, on the basis of TCGA data.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar BRCA2 is also involved in maintaining genomic integrity. BRCA2 mutations were identified in 8% of the Tianjin (northern Chinese) cohort, validated in the TCGA cohort, and associated with significantly better survival.37Chen K. Yang D. Li X. et al.Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.Proc Natl Acad Sci U S A. 2015; 112: 1107-1112Crossref PubMed Scopus (43) Google Scholar Recurrent somatic mutations in cell adhesion genes (eg, CDH1, CTNNA2, CTNNB1, and FAT4) and chromatin remodeling genes (eg, ARID1A, MLL, and MLL3) have been identified as the most commonly perturbed pathways in GC.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 9Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (208) Google Scholar, 10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar, 42Zang Z.J. Cutcutache I. Poon S.L. et al.Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes.Nat Genet. 2012; 44: 570-574Crossref PubMed Scopus (337) Google Scholar, 43Wang K. Kan J. Yuen S.T. et al.Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.Nat Genet. 2011; 43: 1219-1223Crossref PubMed Scopus (364) Google Scholar, 44Wang K. Yuen S.T. Xu J. et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014; 46: 573-582Crossref PubMed Scopus (312) Google Scholar Among mutated genes in GC exomes, cell adhesion was the most significantly enriched biological process, consistent with a marked tendency of GC toward loss of cell-cell adhesion.42Zang Z.J. Cutcutache I. Poon S.L. et al.Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes.Nat Genet. 2012; 44: 570-574Crossref PubMed Scopus (337) Google Scholar, 43Wang K. Kan J. Yuen S.T. et al.Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.Nat Genet. 2011; 43: 1219-1223Crossref PubMed Scopus (364) Google Scholar CDH1 mutations occurred in 11.6% of regular mutated GC and constituted a significant negative prognostic factor in diffuse-type GC, because they were associated with shortened patient survival independent of TNM staging.10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar Nineteen percent to 40% of HDGC families have germline CDH1 mutations.32Hansford S. Kaurah P. Li-Chang H. et al.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol. 2015; 1: 23-32Crossref PubMed Google Scholar CTNNA2, encoding a component of cell adhesion complexes, was mutated in 6.4% of MSS-subtype GCs,44Wang K. Yuen S.T. Xu J. et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014; 46: 573-582Crossref PubMed Scopus (312) Google Scholar whereas CTNNB1 was mutated in 3.1% of regular mutated GCs.10Li X. Wu W.K. Xing R. et al.Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability.Cancer Res. 2016; 76: 1724-1732Crossref PubMed Scopus (50) Google Scholar Additional CTNNA2 and CTNNB1 functions include regulation of β-catenin signaling during early embryonic development.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 44Wang K. Yuen S.T. Xu J. et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014; 46: 573-582Crossref PubMed Scopus (312) Google Scholar ARID1A encodes a member of the SWI-SNF protein complex, which represses gene activity via chromatin remodeling. An interesting finding was the inverse relationship between ARID1A and TP53; TP53 mutations were uncommon in both MSI and EBV subtypes, which possessed frequent ARID1A mutations (83% and 73%, respectively).43Wang K. Kan J. Yuen S.T. et al.Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.Nat Genet. 2011; 43: 1219-1223Crossref PubMed Scopus (364) Google Scholar Moreover, ARID1A mutations were associated with better prognosis in a stage-independent manner. Thus, independent of TP53, mutation of ARID1A, encoding a chromatin-remodeling enzyme, may constitute an alternative GC developmental pathway, with distinct clinical behavior.42Zang Z.J. Cutcutache I. Poon S.L. et al.Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes.Nat Genet. 2012; 44: 570-574Crossref PubMed Scopus (337) Google Scholar, 43Wang K. Kan J. Yuen S.T. et al.Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.Nat Genet. 2011; 43: 1219-1223Crossref PubMed Scopus (364) Google Scholar RHOA, belonging to the Rho GTP family, mediates anoikis, focal adhesions, and cell adherens junctions.35Kakiuchi M. Nishizawa T. Ueda H. et al.Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.Nat Genet. 2014; 46: 583-587Crossref PubMed Scopus (151) Google Scholar, 44Wang K. Yuen S.T. Xu J. et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014; 46: 573-582Crossref PubMed Scopus (312) Google Scholar Residues Arg5, Tyr42, Gly17, and Leu57 are RHOA mutational hotspots.8The Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (1036) Google Scholar, 35Kakiuchi M. Nishizawa T. Ueda H. et al.Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.Nat Genet. 2014; 46: 583-587Crossref PubMed Scopus (151) Google Scholar, 44Wang K. Yuen S.T. Xu J. et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014; 46: 573-582Crossref PubMed Scopus (312) Google Scholar RHOA mutation, specifically in the diffuse-
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