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

Autor:	Serebrenik AA; Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota.; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota.; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Argyris PP; Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota.; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota.; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Division of Oral and Maxillofacial Pathology, School of Dentistry, University of Minnesota, Minneapolis, Minnesota., Jarvis MC; Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota.; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota.; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Brown WL; Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota.; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota.; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Bazzaro M; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Vogel RI; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Erickson BK; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Lee SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Goergen KM; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Maurer MJ; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Heinzen EP; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Oberg AL; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Huang Y; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Hou X; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Weroha SJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Harris RS; Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota. rsh@umn.edu.; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota.; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Jul 01; Vol. 26 (13), pp. 3397-3407. Date of Electronic Publication: 2020 Feb 14.
DOI:	10.1158/1078-0432.CCR-19-2786
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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