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Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern

Tatiana Popova1, Elodie Manié2, Valentina Boeva3

  • 1Institut Curie, Centre de Recherche, Paris, France. INSERM U830, Paris, France. PSL Research University, Paris, France. tatiana.popova@curie.fr.

Cancer Research
|January 21, 2016
PubMed

Insights

CDK12 gene loss in ovarian cancer causes unique genomic instability, characterized by tandem duplications. This CDK12 TD-plus phenotype offers new insights into genome maintenance and cancer development.

Area of Science:

  • Genomic instability
  • Cancer genomics
  • DNA repair mechanisms

Background:

  • Cyclin-dependent kinase 12 (CDK12) mutations are common in serous ovarian carcinoma.
  • CDK12 downregulation impairs DNA damage repair gene expression, leading to sensitivity to DNA-damaging agents and PARP inhibitors.

Purpose of the Study:

  • Investigate the genomic landscape associated with CDK12 inactivation in serous ovarian carcinoma.
  • Characterize the specific genomic instability pattern linked to CDK12 loss.
  • Explore the occurrence of this phenotype in other cancer types.

Main Methods:

  • Genomic profiling of serous ovarian carcinoma patients with CDK12 inactivation.
  • Analysis of tandem duplication size distribution and breakpoint characteristics.
  • Comparative analysis across The Cancer Genome Atlas and in-house cohorts.
  • Examination of prostate cancer cohorts for CDK12 mutations and the TD-plus phenotype.

Main Results:

  • CDK12 loss is consistently associated with a distinct genomic instability pattern: hundreds of tandem duplications (TDs) up to 10 Mb.
  • These TDs exhibit a bimodal size distribution (∼0.3 and ∼3 Mb) with overlapping microhomology at breakpoints, termed the CDK12 TD-plus phenotype.
  • The CDK12 TD-plus phenotype involves >10% genomic content gain and occurs in 3-4% of serous ovarian carcinoma patients.
  • CDK12-inactivating mutations and the TD-plus phenotype were also identified in prostate cancers.

Conclusions:

  • CDK12 inactivation drives a unique form of genomic instability (TD-plus phenotype) in ovarian and prostate cancers.
  • This finding enhances understanding of CDK12's role in genome maintenance and oncogenesis.
  • The CDK12 TD-plus phenotype represents a distinct genomic alteration pattern relevant to cancer research.

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