Rachel I. Vogel

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

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 = 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.

The intersection of sexual orientation with race and ethnicity in cervical cancer screening

BackgroundCervical cancer screening is recommended for those with a cervix who are 21 to 65 years old, with specific timelines being dependent on individual risk. This study compared rates of ever undergoing Papanicolaou (Pap) testing at the intersection of self‐reported sexual minority (SM) status and race/ethnicity.MethodsData from the National Health Interview Survey (2015 and 2018) were used to examine cervical cancer screening disparities. Natal females without a history of hysterectomy who were 21 to 65 years old and had reported their sexual orientation and Pap testing history were included. Demographic and health characteristics were summarized with descriptive statistics. To adjust for differences in confounding variables between groups, propensity score–based inverse probability of treatment weighting (IPTW) was performed. IPTW‐adjusted multivariable logistic regression models estimated odds of ever undergoing a Pap test by sexual orientation alone and with race/ethnicity (non‐Hispanic White, non‐Hispanic Black, and Hispanic).ResultsSM persons (n = 877) had significantly reduced odds of ever undergoing Pap testing (odds ratio, 0.54; 95% confidence interval, 0.42‐0.70) in comparison with heterosexual persons (n = 17,760). When the intersection of sexual orientation and race/ethnicity was considered, non‐Hispanic White SM participants and Hispanic SM participants had reduced odds of ever undergoing Pap testing in comparison with non‐Hispanic White heterosexual participants. No significant differences were observed between non‐Hispanic White heterosexual participants and participants of non‐Hispanic Black SM or Hispanic heterosexual identities.ConclusionsSM participants were significantly less likely to have ever undergone a Pap test in comparison with heterosexual participants, with Hispanic SM participants having the lowest uptake. Future studies should further examine the roles of systemic discrimination and other key drivers of these disparities.