Title

The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations.

Document Type

Article

Publication Date

8-13-2018

JAX Source

Cancer Cell 2018 Aug 13; 34(2):197-210.e5

PMID

30017478

DOI

https://doi.org/10.1016/j.ccell.2018.06.008

Grant

CA034196, CA190121, Andrea Branch and David Elliman Cancer Study Fund, Scott R. MacKenzie Foundation

Abstract

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.

Comments

WGS library preparation, sequencing and analysis were performed by JAX Cancer Center Shared Resources (Genomic Technology and the Computational Sciences) at The Jackson Laboratory.

Share

COinS