PT  - JOURNAL ARTICLE
AU  - Subodh Kumar
AU  - Leutz Buon
AU  - Srikanth Talluri
AU  - Marco Roncador
AU  - Chengcheng Liao
AU  - Jiangning Zhao
AU  - Jialan Shi
AU  - Chandraditya Chakraborty
AU  - Gabriel B. Gonzalez
AU  - Yu-Tzu Tai
AU  - Rao Prabhala
AU  - Mehmet K. Samur
AU  - Nikhil C. Munshi
AU  - Masood A. Shammas
TI  - Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma
AID  - 10.1101/2020.04.23.058230
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.23.058230
4099  - http://biorxiv.org/content/early/2020/04/25/2020.04.23.058230.short
4100  - http://biorxiv.org/content/early/2020/04/25/2020.04.23.058230.full
AB  - 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 its harmful genomic impact in EAC and possibly other cancers.Competing Interest StatementThe authors have declared no competing interest.