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

Francesca Menghi, The Jackson Laboratory
Floris P Barthel, The Jackson Laboratory
Vinod Yadav, The Jackson Laboratory
Ming Tang
Bo Ji, The Jackson Laboratory
Zhonghui Tang, The Jackson Laboratory
Gregory W. Carter, The Jackson Laboratory
Yijun Ruan, The Jackson Laboratory
Ralph Scully
Roel G W Verhaak, The Jackson Laboratory
Jos Jonkers
Edison T Liu, The Jackson Laboratory

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


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.