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 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 DESIGN: APOBEC3 expression was analyzed by immunohistochemistry and RT-qPCR in a pilot set of CCOC specimens (n=9 tumors). The immunohistochemistry 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 (PDX) 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 DNA damage caused APOBEC3B 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 : an official journal of the American Association for Cancer Research
Volume26
Issue number13
Early online dateFeb 14 2020
DOIs
StatePublished - Jul 1 2020

Bibliographical note

Publisher Copyright:
©2020 American Association for Cancer Research.

PubMed: MeSH publication types

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

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