The DNA cytosine deaminase APOBEC3B is a molecular determinant of platinum responsiveness in clear cell ovarian cancer

Artur A. Serebrenik, Prokopios P. Argyris, Matthew C. Jarvis, William L. Brown, Martina Bazzaro, Rachel I. Vogel, Britt K. Erickson, Sun Hee Lee, Krista M. Goergen, Matthew J. Maurer, Ethan P. Heinzen, Ann L. Oberg, Yajue Huang, Xiaonan Hou, S. John Weroha, Scott H. Kaufmann, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 ¼ 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n ¼ 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 ¼ 0.026) and moderately with overall survival (P ¼ 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 APOBEC3Binduced 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.

Original languageEnglish (US)
Pages (from-to)3397-3407
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number13
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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