Abstract
BackgroundGastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability.ResultsIntegrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer - against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer.ConclusionsThese results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.
Highlights
IntroductionTo explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability
Gastric cancer is the second highest cause of global cancer mortality
Note that we identified more than five times the number of somatic variants uncovered in earlier sequencing studies [6,7] that were restricted to exomes (5,588 single nucleotide variation (SNV) and 2,347 indels identified from 37 exomes), highlighting the statistical advantage of whole-genome analysis for studying mutational signatures
Summary
To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. We sought to explore the combination of these datasets for de novo assembly of cancer and normal genomes and to comprehensively catalogue a range of (point mutations to megabase-sized) somatic alterations in the tumor. We used this catalogue to characterize the impact of mutational processes on genes and used a screening approach to validate recurrently mutated genes in subtypes of GC defined by specific mutational processes
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