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
Volume
34
Issue
2
First Page
197
Last Page
210
ISSN
1878-3686
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.
Recommended Citation
Menghi F,
Barthel F,
Yadav V,
Tang M,
Ji B,
Tang Z,
Carter GW,
Ruan Y,
Scully R,
Verhaak R,
Jonkers J,
Liu E.
The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations. Cancer Cell 2018 Aug 13; 34(2):197-210.e5
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.