Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability

Abstract

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 has yet to be established. In this study, we integrated somatic mutational profiles and clinicopathologic information from 544 gastric cancer patients from previous genomic studies to identify significantly mutated genes (SMG) with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hypermutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hypermutated, gastric cancers, where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, and 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. Finally, 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 SMGs 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.

Molecular predictive markers in tumors of the gastrointestinal tract

“…Genetic and epigenetic alterations play important role in GCs therefore, targeted therapy based on the biology of the individual patient could improve treatment outcome[17-19]. …”

Comparison between two amplicon-based sequencing panels of different scales in the detection of somatic mutations associated with gastric cancer

“…In this study, we were unable to identify any mutations in seven patients using the Selective hotspot Panel, compared with only one using the Comprehensive Panel (Table 3). A recent study reported newly identified SMGs including NRG1 , ERBB4 , XIRP2 , NBEA , COL14A1 , CNBD1 , ITGAV , and AKAP6 [32, 33] that should be included in the mutational spectrum analyzed in all patients with gastric cancer. Second, from a cost perspective, covering more SMGs is beneficial, as shown by the comparable library preparation and sequencing running costs between the two panels used in this study.…”

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

“…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…”

“…DNA mismatch repair (MMR) genes were collected from 2 resources: identified MMR genes in a reported study and the genes in KEGG mismatch repair pathway 21. As a result, a total of 26 MMR genes were included in our analysis (Table S1).…”

“…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…”