Apr 25, 2020

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

BioRxiv : the Preprint Server for Biology
s. kumarMasood A. Shammas

Abstract

Identification of genes driving genomic evolution can provide novel targets for cancer treatment and prevention. Here we show identification of a genomic instability gene signature, using an integrated genomics approach. Elevated expression of this signature correlated with poor survival in esophageal adenocarcinoma (EAC) as well as three other human cancers. Knockout and overexpression screens confirmed the relevance of this signature to genomic instability. Indepth evaluation of TTK (a kinase), TPX2 (spindle assembly factor) and RAD54B (recombination protein) further confirmed their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrated that DNA damage and homologous recombination were common mechanisms of genomic instability induced by these genes. Consistently, a TTK inhibitor impaired EAC cell growth in vivo, and increased chemotherapy-induced cytotoxicity while inhibiting genomic instability in surviving cells. Thus inhibitors of TTK and other genes identified in this study have potential to inhibit/delay genomic evolution and tumor growth. Such inhibitors also have potential to increase chemotherapy-induced cytotoxicity while reducing ...Continue Reading

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Mentioned in this Paper

Biological Markers
Genome-Wide Association Study
Laboratory Procedures
Genome
Aggregation
Dysequilibrium Syndrome
Research Personnel
Genetic Association Studies
Genomics
Prospective Cohort Study

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