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

Autor:	Kumar S; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA., Buon L; Dana Farber Cancer Institute, Boston, MA, USA., Talluri S; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA., Roncador M; Dana Farber Cancer Institute, Boston, MA, USA., Liao C; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA., Zhao J; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA., Shi J; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Chakraborty C; Dana Farber Cancer Institute, Boston, MA, USA., Gonzalez G; Veterans Administration Healthcare System, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Tai YT; Dana Farber Cancer Institute, Boston, MA, USA., Prabhala R; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Samur MK; Dana Farber Cancer Institute, Boston, MA, USA., Munshi NC; Dana Farber Cancer Institute, Boston, MA, USA.; Veterans Administration Healthcare System, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Shammas MA; Dana Farber Cancer Institute, Boston, MA, USA. Masood_Shammas@DFCI.Harvard.edu.; Veterans Administration Healthcare System, Boston, MA, USA. Masood_Shammas@DFCI.Harvard.edu.
Jazyk:	angličtina
Zdroj:	Communications biology [Commun Biol] 2021 May 24; Vol. 4 (1), pp. 617. Date of Electronic Publication: 2021 May 24.
DOI:	10.1038/s42003-021-02125-x
Abstrakt:	Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (TTK, TPX2 and RAD54B) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.
Databáze:	MEDLINE
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