Immune pathway activation in gastric cancers with LINE-1 retrotransposon overexpression and homologous recombination deficiency.

Abstract

There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.