The Tandem Duplicator Phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations

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. TDPs with prominent ~11 Kb TDs feature the conjoint loss of TP53 and BRCA1. TDPs with ~231 Kb and ~1.7 Mb TDs associate with CCNE1 pathway activation or CDK12 disruptions, in conjunction with TP53 mutations. We prove the driver role of TP53 and BRCA1 abrogation for TDP induction by generating short-span TDP mammary tumors in genetically modified mouse models harboring deleterious mutations in only these two genes. Lastly, heterogeneous combinations of mutations mediated by TDs are selected for and contribute to the oncogenic burden of TDP tumors.