Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability

Gastric cancer is not a single disease and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as molecular classifiers or prognostic markers of disease outcome have yet to be established. In this study, we integrated somatic mutational profiles and clinicopathological information from 544 gastric cancer patients by previous genomics studies to identify significantly mutated genes with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hyper-mutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hyper-mutated, gastric cancers where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, AKAP6) and 12 recurrent mutated genes exhibited high mutation prevalence (≥ 3.0%) and an unexpectedly higher incidence of nonsynonymous mutations. We also identified two molecular subtypes of regular-mutated gastric cancer that were associated with distinct prognostic outcomes, independently of disease staging, as confirmed in a distinct patient cohort by targeted capture sequencing. Lastly, in diffuse-type gastric cancer, CDH1 mutation was found to be associated with shortened patient survival, independently of disease staging. Overall, our work identified previously unreported significantly mutated genes and a mutation signature predictive of patient survival in newly classified subtypes of gastric cancer, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/1SfqZof
via IFTTT