The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations.
Cancer Cell Jun 29 [Epub ahead of print]
CA034196, CA190121, Andrea Branch and David Elliman Cancer Study Fund, Scott R. MacKenzie Foundation
The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ∼11 kb TDs feature loss of TP53 and BRCA1. TDPs with ∼231 kb and ∼1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.
Menghi, Francesca; Barthel, Floris P; Yadav, Vinod; Tang, Ming; Ji, Bo; Tang, Zhonghui; Carter, Gregory W.; Ruan, Yijun; Scully, Ralph; Verhaak, Roel G W; Jonkers, Jos; and Liu, Edison T, "The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations." (2018). Faculty Research Ahead of Print. 92.