The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations
A partir de données issues des projets "The Cancer Genome Atlas", "International Cancer Genome Consortium" et "Catalogue Of Somatic Mutations In Cancer", puis menée à l'aide de modèles murins de cancer du sein, cette étude montre notamment que l'absence d'expression des gènes p53 et BRCA1 favorise l'induction d'un phénotype de duplication en tandem dans les tumeurs mammaires
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.