The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with the worst prognosis and few treatment options. Here we present a dataset from 84 DGC patients, composed of a proteome of 11,340 gene products and mutation information of 274 cancer driver genes covering paired tumor and nearby tissue. DGC can be classified into three subtypes (PX1–3) based on the altered proteome alone. PX1 and PX2 exhibit dysregulation in the cell cycle and PX2 features an additional EMT process; PX3 is enriched in immune response proteins, has the worst survival, and is insensitive to chemotherapy. Data analysis revealed four major vulnerabilities in DGC that may be targeted for treatment, and allowed the nomination of potential immunotherapy targets for DGC patients, particularly for those in PX3. This dataset provides a rich resource for information and knowledge mining toward altered signaling pathways in DGC and demonstrates the benefit of proteomic analysis in cancer molecular subtyping.

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Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATPcompetitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1-3, in patients with FGFR2-amplified gastric cancer.Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI 50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572-83. Ó2013 AACR.

Neoadjuvant chemotherapy is a common treatment for patients with gastric cancer. Although its benefits have been demonstrated, neoadjuvant chemotherapy is underutilized in gastric cancer management, because of the lack of biomarkers for patient selection and a limited understanding of resistance mechanisms. Here, we performed whole-genome, whole-exome, and RNA sequencing on 84 clinical samples (including matched pre- and posttreatment tumors) from 35 patients whose responses to neoadjuvant chemotherapy were rigorously defined. We observed increased microsatellite instability and mutation burden in nonresponse tumors. Through comparisons of response versus nonresponse tumors and pre- versus posttreatment samples, we found that C10orf71 mutations were associated with treatment resistance, which was supported by drug response data and potentially through inhibition of cell cycle, and that MYC amplification correlated with treatment sensitivity, whereas MDM2 amplification showed the opposite pattern. Neoadjuvant chemotherapy also reshapes tumor-immune signaling and microenvironment. Our study provides a critical basis for developing precision neoadjuvant regimens.

Purpose Metastasis is the leading cause of death for gastric carcinoma (GC). An epigenetic biomarker panel for predicting GC metastasis could have significant clinical impact on the care of GC patients. The main purpose of this study is to characterize the methylation differences between GCs with and without metastasis. Experimental Design Genome-wide DNA methylation profiles between 4 metastatic and 4 non-metastatic GCs and their surgical margins (SM) were analyzed using methylated-CpG island amplification with microarray. The methylation states of 73 candidate genes were further analyzed in GC patients in a discovery cohort (n=108) using DHPLC, bisulfite-sequencing, and MethyLight. The predictive values of potential metastasis-methylation biomarkers were validated in GC patient cohorts in China (n=330), Japan (n=129), and Korea (n=153). Results The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. Significant differential methylation was validated in the CGIs of 15 genes (Ps<0.05) and confirmed using bisulfite-sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Methylation changes of GFRA1, SRF and ZNF382 resulted in up- or down-regulation of their transcription. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations was consistently and coordinately associated with GC metastasis and the patients’ overall survival throughout discovery and validation cohorts in China, Japan and Korea. Conclusion Methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of GC metastasis.

BackgroundThis study assessed the postoperative morbidity and mortality occurring in the first 30 days after radical gastrectomy by comparing gastric cancer patients who did or did not receive the FOLFOX7 regimen of neoadjuvant chemotherapy.MethodsWe completed a retrospective analysis of 377 patients after their radical gastrectomies were performed in our department between 2005 and 2009. Two groups of patients were studied: the SURG group received surgical treatment immediately after diagnosis; the NACT underwent surgery after 2-6 cycles of neoadjuvant chemotherapy.ResultsThere were 267 patients in the SURG group and 110 patients in the NACT group. The NACT group had more proximal tumours (P = 0.000), more total/proximal gastrectomies (P = 0.000) and longer operative time (P = 0.005) than the SURG group. Morbidity was 10.0% in the NACT patients and 17.2% in the SURG patients (P = 0.075). There were two cases of postoperative death, both in the SURG group (P = 1.000). No changes in complications or mortality rate were observed between the SURG and NACT groups.ConclusionThe FOLFOX7 neoadjuvant chemotherapy is not associated with increased postoperative morbidity, indicating that the FOLFOX7 neoadjuvant chemotherapy is a safe choice for the treatment of local advanced gastric cancer.

BackgroundWe investigated the superiority of the 8th edition of the tumor-node-metastasis (TNM) system for patients in China with gastric cancer.MethodsThe survival outcomes of 1663 patients with gastric cancer undergoing radical resection were analyzed.ResultsIn the 8th edition system, homogeneous 5-year survival rates among different pathological TNM (pTNM) categories belonging to the same stage were observed. However, in the 7th edition system, the differences of 5-year survival rate among pTNM categories belonging to the same stage were observed in stages IIB (P = 0.010), IIIB (P = 0.004), and IIIC (P < 0.001). For patients in the pT1-3 (P < 0.001) and pT4a (P < 0.001) categories, there were significant differences in survival between patients in the pN3a and pN3b categories. Furthermore, partial cases (pT4bN0M0/T4aN2M0) of stage IIIB were downstaged to stage IIIA in the 8th edition system, and the 5-year survival rate of these patients was significantly better than that of patients in stage IIIB in the 8th edition system. Similarly, the 5-year survival rate of patients in p4bN2M0/T4aN3aM0 downstaged from stage IIIC to IIIB was significantly better than that of patients in stage IIIC. Compared with the 7th edition system, the 8th edition system had a higher likelihood ratio and linear trend chi-squared score and a smaller Akaike information criteria value.ConclusionsThe 8th edition system is superior to the 7th edition system in terms of homogeneity, discriminatory ability, and monotonicity of gradients for Chinese patients with gastric cancer.

BackgroundNeoadjuvant chemotherapy before radical gastrectomy is preferred for locally advanced gastric cancer. To avoid the problematic use of pTNM for patients after neoadjuvant chemotherapy, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) gastric cancer TNM staging system (8th edition) added ypTNM for the first time. But patients achieving pathological complete response were not covered by the new ypTNM staging system. To investigate whether pathological complete response is associated with better outcome in gastric cancer, as was reported in rectal, breast and bladder cancer.MethodsWe systematically searched the databases of PubMed, EMBASE, Web of Science and Cochrane Collaboration’s Central register of controlled trials from January 1988 to April 2015 for publications which reported outcomes of patients with and without pathological complete response (pCR) (pT0N0M0) to investigate whether pCR after neoadjuvant chemotherapy in gastric or gastroesophageal junction (GEJ) treated with radical surgery is associated with better survival. The primary outcome was overall survival (OS). The secondary outcome was disease-free survival (DFS). Both were measured with a relative risk (RR). A meta-analysis was performed using the fixed effects model. Forest plots and the Q test was used to evaluate overall heterogeneity for OS and DFS.ResultsA total of seven trials, 1143 patients were included and analyzed after neoadjuvant chemotherapy and radical surgery with no other preoperative treatment. The average rate of pCR was 6.74% (range: 3%-15%). The RR of patients who achieved pCR in the primary tumor and lymph nodes is 0.5 (95% confidence interval [CI], 0.25–0.98; p = 0.04), 0.34 (95% CI, 0.21–0.55; p<0.0001) and 0.44 (95% CI, 0.30–0.63; p<0.0001) for one-year-OS, three-year-OS and five-year-OS, respectively. The summary RR for three-year-DFS was 0.43 (95% CI, 0.25–0.72; p = 0.002).ConclusionPatients with resectable gastric or GEJ cancer who achieved pCR after neoadjuvant chemotherapy can gain a better outcome than patients without pCR.