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

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

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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)
JournalClinical cancer research : an official journal of the American Association for Cancer Research
DOIs
StateE-pub ahead of print - Feb 14 2020
Externally publishedYes

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Copyright ©2020, American Association for Cancer Research.

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