title: Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications.
abstract: CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal (∼0.3 and ∼3 Mb) size distribution and overlapping microhomology at the breakpoints. This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis. Cancer Res; 76(7); 1882-91. ©2016 AACR.
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France. tatiana.popova@curie.fr.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Manié
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. PSL Research University, Paris, France. INSERM U900, Paris, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Boeva
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Battistella
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. PSL Research University, Paris, France. EA4340-BCOH, Versailles Saint-Quentin-en-Yvelines University, Guyancourt, France. Institut Curie, Département de Biopathologie, Paris, France. Institut Curie, Département de Recherche Translationnelle, Paris, France.
authors.forename: Oumou
authors.initials: O
authors.lastname: Goundiam
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Smith
authors.affiliation: Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Mueller
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Raynal
authors.affiliation: PSL Research University, Paris, France. Institut Curie, Département de Biopathologie, Paris, France. Institut Curie, Centre de Ressources Biologiques, Paris, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: PSL Research University, Paris, France. EA4340-BCOH, Versailles Saint-Quentin-en-Yvelines University, Guyancourt, France. Institut Curie, Département de Biopathologie, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France.
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
mesh_terms: D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D020080:Tandem Repeat Sequences / Q000235:genetics*
chemical_list: C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases