Whole-genome sequencing and comprehensive molecular profiling of gastric cancer

Abstract

Recent advances in next generation sequencing and molecular profiling has enabled the rapid generation of large datasets in cancer genomics that may provide novel insights into the process of carcinogenesis. We performed whole-genome sequencing and comprehensive genome-wide assessment of DNA copy number, gene expression and methylation using array-based technology in a large cohort of gastric cancers. We found accumulation of a substantial number of somatic mutations in the cancer genome starting from the earliest stage of carcinogenesis. The number of mutations increased with increasing age of cancer onset. The somatic mutations were not evenly distributed across the genome, with mutation density being higher in intergenic regions, regions of closed chromatin, in genes with low expression levels, and in transcribed regions distant from transcriptional-start sites. Knowledge of such information is important in distinguishing cancer driver genes from background passenger mutations. We also observed unique mutational signatures linked to clinical or molecular subgroups of gastric cancer, each with differing distribution in the cancer genome. We found molecular subtype-specific patterns of genetic and epigenetic perturbations, many of them converging to target the same key cancer driver genes or pathways. Our study identified many novel driver genes, deregulated by various genomic perturbations, that participate in key signaling pathways which are targets of emerging therapy. Overall, our study illustrates a multi-dimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer, and provides a roadmap to facilitate genome-guided patient stratification and personalized therapy.