RT Journal Article
SR Electronic
T1 Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.23.058230
DO 10.1101/2020.04.23.058230
A1 Subodh Kumar
A1 Leutz Buon
A1 Srikanth Talluri
A1 Marco Roncador
A1 Chengcheng Liao
A1 Jiangning Zhao
A1 Jialan Shi
A1 Chandraditya Chakraborty
A1 Gabriel B. Gonzalez
A1 Yu-Tzu Tai
A1 Rao Prabhala
A1 Mehmet K. Samur
A1 Nikhil C. Munshi
A1 Masood A. Shammas
YR 2020
UL http://biorxiv.org/content/early/2020/04/25/2020.04.23.058230.abstract
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.