Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

Cristescu, Rǎzvan; Lee, Jeeyun; Nebozhyn, Michael; Kim, Kyoung‐Mee; Ting, Jason C.; Wong, Suei Nee; Liu, Jiangang; Yue, Yong; Wang, Jian; Yu, Kun; Ye, Xiang S.; Do, In‐Gu; Liu, Shawn; Gong, Lara; Fu, Jake; Jin, Jiamin; Choi, Min Gew; Sohn, Tae Sung; Lee, Woo Jung; Bae, Jae Moon; Park, Se Hoon; Sohn, Insuk; Jung, Sin‐Ho; Tan, Patrick; Chen, Ronghua; Hardwick, James S.; Kang, Won Ki; Ayers, Mark; Dai, Hongyue; Reinhard, Christoph; Loboda, Andrey; Aggarwal, Amit

doi:10.1038/nm.3850

Cited by 1,734 publications

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“…3 Thus, after a decade of repeated failures of most targeted agents, except HER2, in showing survival benefits in gastric cancer, these positive trial results have opened a new era for exploring targeted agents for the treatment of gastric cancer. 4,5 Fibroblast growth factor receptors (FGFRs) are transmembrane tyrosine kinase receptors, and binding of ligands to FGFRs leads to activation of the downstream PI3K-AKT and MAPK-ERK pathways. 6 Dysregulation of the FGFR2 signaling pathway because of accumulation of epigenetic modifications and genetic alterations is associated with the development and progression of various cancers.…”

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confidence: 99%

“…11 In previous studies, the frequency of FGFR2 amplification varied from 3 to 9% depending on the testing methods. 4,5,[12][13][14][15][16][17][18] The prevalence rates also varied between countries-7% in the United Kingdom, 5% in China, and 4% in Korea-using the same FISH test analyzed in one core laboratory. 18 Nevertheless, the frequency of FGFR2 overexpression detection by immunohistochemistry ranged from 31% up to 51%-which were considerably higher than the incidence of FGFR2 amplifica tions.…”

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FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

et al. 2016

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FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoformspecific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r = 0.79) and FISH (r = 1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; Po0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P = 0.01) and higher N stage (P = 0.006). FGFR2b overexpression with H-score ≥ 150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P = 0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors. Gastric cancer is the second most common cause of cancer-related deaths worldwide, and the prognosis of advanced gastric cancer is still poor. 1 Several large-scaled clinical trials have failed to demonstrate survival benefits of targeted therapeutic agents in patients with metastatic gastric cancer. Nevertheless, the REGARD trial demonstrated significantly longer progression-free survival of gastric cancer patients treated with ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2, compared with that of patients in the placebo group. 2 This was the first trial to demonstrate a meaningful benefit for a monotherapy in metastatic gastric cancer. The RAINBOW trial, which compared the efficacy of paclitaxel with or without ramucirumab in second-line chemotherapy, showed prolonged

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FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

et al. 2016

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“…Similarly, no statistical significance was observed when the TLS gene signature was evaluated in an independent Asian Cancer Research Group (ACRG) cohort of GC patients (GEO accession GSE62254; Supporting Information Fig. S7) 34. Thus, mirroring the temporal development of TLSs in established disease in the gp130 F/F GC model, TLSs and an associated 3‐gene signature were also observed in human GC, albeit without prognostic value.…”

Section: Resultsmentioning

confidence: 98%

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

Hill

Gao

et al. 2018

Intl Journal of Cancer

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Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130 F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130 F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.

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“…Gastric cancer driver genes were obtained from 3 sources: (1) 16 gastric cancer‐related driver genes from Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census(v78)31; (2) 175 driver genes of gastric cancer from the Integrative Onco Genomics (IntOGen) database32; (3) 108 significantly mutated genes (SMGs) and 26 somatic copy number alteration genes from previously published Whole Genome Sequencing (WGS) or Whole Exome Sequencing (WES) articles 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22…”

Section: Methodsmentioning

confidence: 99%

“…These studies have identified many driver genes, whose mutations confer selective growth advantage to tumor 11. Some of these driver genes are previously known cancer genes (eg, TP53 , ARID1A, and CDH1 ), while the others are new‐found significantly mutated genes in gastric cancer (eg, MUC6 , CTNNA2 , GLI3, and RNF43 ) 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. Moreover, the copy number changes and characteristic mutational signatures also play important roles in gastric cancer development 4, 16, 17, 18, 19…”

Section: Introductionmentioning

confidence: 99%

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

et al. 2018

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Genome‐wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common‐enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12‐0.55, P = 3.93 × 10−4). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.

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Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

Cited by 1,734 publications

References 46 publications

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

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