Actionable gene-based classification toward precision medicine in gastric cancer

Abstract

BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users.

Radiomics in esophageal and gastric cancer

“…Recent genomic analyses have highlighted the genetic heterogeneity present in esophageal, esophago-gastric [10], and gastric cancer [11,12] as an underlying cause for the differences in outcome and heterogeneity of response to therapy. Quality of life also remains poor for many patients post-surgery, taking up to 3 years to return to pre-therapy levels in patients undergoing esophageal resection [13].…”

Next generation sequencing‐based gene panel tests for the management of solid tumors

“…Indeed, we found that 7 of 53 (13%) Japanese TNBC patients had possible germline BRCA1/2 alterations by additional bioinformatic analysis of solid tumor sequencing. Comprehensive genomic analysis utilizing gene panel tests revealed the frequency of BRCA1 and BRCA2 alterations to be 3.9% and 10.6% in Japanese gastric cancers, respectively . Among them, we confirmed 3 patients with germline mutations and a family history, which indicates that BRCA1/2 germline mutations can be a cause of gastric cancer in Japan .…”

“…Among them, we found 11 patients with MSI, and 2 patients with polymerase ε mutation, which is another cause of hypermutation . We also identified 32 out of 207 (15.5%) Japanese gastric cancer patients as having hypermutated tumors, which were observed to be not only an MSI subtype, but also Epstein‐Barr virus infection, which is detectable by integrative genomic analysis that makes use of NGS technologies, chromosomal instability, and genomically stable subtypes of TCGA . In contrast, MSI is merely observed in breast cancer.…”

Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type

“…However, TMIT IV and TMIT I, the CD8 High groups, were enriched with mutations of BRCA2 and FLT4. BRCA2 is well‐known for its role in the repair of double stranded DNA breaks via homologous recombination (HR), and is also one of the actionable genes in GCs; defective BRCA2 implies a favorable response to platinum‐based chemotherapy and poly(ADP‐ribose) polymerase inhibitors . The association between BRCA2 mutation and TMIT I/IV, the highly inflamed TME groups, suggests that these subgroups of GC would be the good candidates for such treatment strategies.…”