The DNA Cytosine Deaminase APOBEC3B is a Molecular Determinant of Platinum Responsiveness in Clear Cell Ovarian Cancer

Clin Cancer Res. 2020 Jul 1;26(13):3397-3407. doi: 10.1158/1078-0432.CCR-19-2786. Epub 2020 Feb 14.


Purpose: Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention.

Experimental designs: APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages.

Results: One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues.

Conclusions: These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Mice
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Platinum / pharmacology*
  • Prognosis
  • Synthetic Lethal Mutations / drug effects
  • Synthetic Lethal Mutations / genetics
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Minor Histocompatibility Antigens
  • Platinum
  • APOBEC3B protein, human
  • Cytidine Deaminase