Genomic profiling using a 435-gene panel provides a vision for precision medicine in Japanese gastric cancer.

Abstract

e15592 Background: Molecular heterogeneity represents a significant hurdle in realizing precision medicine for gastric cancer (GC). Large-scale whole exome sequencing projects have identified distinct molecular subtypes to help define the heterogeneity of GC. However, it remains unclear whether the targeted gene panel-based sequencing can provide optimum targeted therapies and clinical utility in GC. The aim of this study is to generate comprehensive genomic profiling data and classify Japanese GC into actionable clusters associated with targeted therapies. Methods: FFPE tumor tissues were obtained from surgical or biopsy specimens of 207 Japanese patients with GC. Extracted DNA was subjected to genomic sequencing for 435 cancer related genes including 69 druggable genes with FDA approved targeted therapies. Somatic mutations, copy number alterations (SCNA), microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection were evaluated using sequencing data. Results: Genomic sequencing identified at least one alteration of 435 genes in 194 pts (94%), and that of 69 druggable genes in 141 pts (68%). The most frequently altered druggable gene was ERBB2 (14%), following BRCA2 (11%) and ATM (10%). We successfully classified 207 tumors into four molecular subtypes, similar to the previously report; EBV (4%), MSI (8%), chromosomal instability (58%) and genomically stable subtype (30%). Frequent alterations of druggable genes ( > 5%) were widely observed through these subtypes. To discover the novel classifications associated with targeted therapies, we classified 207 tumors using mutation rate and hierarchical clustering. We identified a hypermutated group (n = 32), and a remaining non-hypermutated group (n = 175) which were sub-divided into six clusters including five actionable ones; ERBB2 (n = 25), CDKN2A and CDKN2B (n = 10), KRAS (n = 10), BRCA2 (n = 9) and ATM cluster (n = 12). Interestingly, we experienced a case of unresectable GC with a remarkable response for anti-HER2 therapy in the ERBB2 cluster. Conclusions: Genomic sequencing using a 435-gene panel has the potential to provide the information of optimum targeted therapies for upcoming precision medicine in Japanese GC.