Abstract
BackgroundGastric cancer is the fourth most common cancer and the second leading cause of cancer death worldwide. In order to understand the genetic background, we sequenced the whole exome and the whole genome of one microsatellite stable as well as one microsatellite unstable tumor and the matched healthy tissue on two different NGS platforms. We here aimed to provide a comparative approach for individual clinical tumor sequencing and annotation using different sequencing technologies and mutation calling algorithms.ResultsWe applied a population-based whole genome resource as a novel pathway-based filter for interpretation of genomic alterations from single nucleotide variations (SNV), indels, and large structural variations. In addition to a comparison with tumor genome database resources and a filtering approach using data from the 1000 Genomes Project, we performed pyrosequencing analysis and immunohistochemistry in a large cohort of 428 independent gastric cancer cases.ConclusionWe here provide an example comparing the usefulness and potential pitfalls of different technologies for a clinical interpretation of genomic sequence data of individual gastric cancer samples. Using different filtering approaches, we identified a multitude of novel potentially damaging mutations and could show a validated association between a mutation in GNAS and gastric cancer.
Highlights
Gastric cancer is the fourth most common cancer and the second leading cause of cancer death worldwide
Our results are in line with these recent findings and present a benchmark strategy of individual tumor genome analysis combining both, Whole exome sequencing (WES) and Whole genome sequencing (WGS) information with two different next generation sequencing (NGS) platforms, used population-based whole genome resources as a novel pathway-based filter, and integrated single nucleotide variations (SNV) as well as structural variant analyses
Using this comprehensive strategy we identified a multitude of novel somatic potentially damaging mutations and show that Microsatellite stable (MSS) and Microsatellite instable (MSI) gastric cancer (GC) have markedly different numbers of somatic and germline mutations, which is in line with observations made by Wang et al [28]
Summary
Gastric cancer is the fourth most common cancer and the second leading cause of cancer death worldwide. In order to understand the genetic background, we sequenced the whole exome and the whole genome of one microsatellite stable as well as one microsatellite unstable tumor and the matched healthy tissue on two different NGS platforms. We employed several scoring systems in parallel including a new exonic conservation score (ECS) and revealed pathways with an unexpectedly high number of deleterious polymorphisms and somatic mutations. Using this comprehensive strategy we were able to identify a multitude of novel potentially damaging mutations, which were partially validated in an independent cohort of 482 GC patients
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