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

Abstract

SUMMARYThe 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.

Patterns of somatic structural variation in human cancer genomes

“…6a). However, as previously reported 6,29 , individual patients tend to have a simpler-usually unimodal-distribution of deletions or tandem duplications (Extended Data Fig. 6b), which implies that the complexity seen in a given tumour type results from combining samples with different profiles.…”

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

“…Recent findings show that many cancers with disrupted CDK12 catalytic activity have a unique, CDK12‐inactivation‐specific genome instability phenotype: tandem duplications . There are several possible scenarios for their genesis; nevertheless, we favor the concept that they arise due to disrupted expression of both core DNA replication and HR genes upon inhibition of CDK12.…”

“…CDK12 is frequently mutated in cancer. Inactivation of CDK12 kinase activity was recently associated with unique genome instability phenotypes in ovarian, breast, and prostate cancers . They consist of large (up to 2–10 Mb in size) tandem duplications, which are completely different from other genome alteration patterns, including those observed in BRCA1 ‐ and other HR‐inactivated tumors.…”

“…They consist of large (up to 2–10 Mb in size) tandem duplications, which are completely different from other genome alteration patterns, including those observed in BRCA1 ‐ and other HR‐inactivated tumors. Furthermore, they are characterized by an increased sensitivity to cisplatin and thus represent potential biomarker for treatment response . Although inactivation of CDK12 kinase activity clearly leads to HR defects and sensitivity to PARP inhibitors in cells , the discovery of the CDK12 inactivation‐specific tandem duplication phenotype indicated a distinct function of CDK12 in maintenance of genome stability.…”

“…Although inactivation of CDK12 kinase activity clearly leads to HR defects and sensitivity to PARP inhibitors in cells , the discovery of the CDK12 inactivation‐specific tandem duplication phenotype indicated a distinct function of CDK12 in maintenance of genome stability. The size and distribution of the tandem duplications suggested that DNA replication stress‐mediated defect(s) are a possible driving force for their formation .…”