Whole-genome sequencing and comprehensive molecular profiling of gastric cancer

Abstract

Gastric cancer is characterised by marked histological and molecular heterogeneity linked to different aetiological factors and pathways of cancer development. Our prior exome sequencing study on gastric cancer revealed pathway-specific driver mutations, with frequent ARID1A inactivation in more than 70% of cancers in the MSI and EBV subgroups, and around 11% in the remaining microsatellite stable subgroup. A follow-up study utilizing whole genome sequencing and comprehensive genomic profiling of a large cohort revealed the complex interaction of genetic and epigenetic changes that are specific for each molecular subgroup. These include extensive genomic wide hypermethylation and ARID1A mutation in EBV-associated gastric cancer; extensive mutation, hypermethylation and demethylation in MSI gastric cancer; extensive demethylation and chromosomal instability with oncogenic amplification in intestinal type gastric cancer; chromosomal stability, hypermethylation and RHOA mutation in diffuse type gastric cancer. We discovered many novel gastric driver genes being mutated (e.g. MUC6, RNF43, GLI3, RHOA), amplified or deleted, as well as de-regulated by hypermethylation or demethylation. This study offered us a unique opportunity to observe the diversity and range of genomic perturbations starting from the earliest stage of carcinogenesis. Overall, our study reveals the complex molecular portrait of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.