The tandem duplicator phenotype as a distinct genomic configuration in cancer

Significance In this study, we provide the first detailed molecular characterization, to our knowledge, of a distinct cancer genomic configuration, the tandem duplicator phenotype (TDP), that is significantly enriched in the molecularly related triple-negative breast, serous ovarian, and endometrial carcinomas. We show here that TDP represents an oncogenic configuration featuring ( i ) genome-wide disruption of cancer genes, ( ii ) loss of cell cycle control and DNA damage repair, and ( iii ) increased sensitivity to cisplatin chemotherapy both in vitro and in vivo. Therefore, the TDP is a systems strategy to achieve a protumorigenic genomic configuration by altering a large number of oncogenes and tumor suppressors. The TDP arises in a molecular context of joint genomic instability and replicative drive, and is consequently associated with enhanced sensitivity to cisplatin.