Investigator
Emory University
Regular Physical Inactivity and Ovarian Cancer Risk in the Ovarian Cancer in Women of African Ancestry Consortium
Abstract Background: Regular physical inactivity may increase ovarian cancer risk, but few studies have investigated whether this association is similar among Black and White women. Methods: In a pooled nested case–control study within the Ovarian Cancer in Women of African Ancestry consortium, logistic regression models evaluated regular recreational physical inactivity with risk of epithelial ovarian cancer among Black (223 cases; 1,472 controls) and White women (985 cases; 6,212 controls) enrolled in four cohort studies. Models were further stratified by histologic type. Results: Regular physical inactivity was not associated with the risk of overall ovarian cancer among Black [OR = 1.16; 95% confidence interval (CI), 0.83–1.61] or White women (OR = 1.03; 95% CI, 0.87–1.23). We did not detect associations according to histologic type. Conclusions: Physical inactivity was not associated with ovarian cancer among Black or White women in a consortium of cohort studies. Impact: These results are counter to case–control-based studies and emphasize the complexity of investigating physical activity prospectively.
An Analytic Pipeline to Obtain Reliable Genetic Ancestry Estimates from Tumor-Derived RNA Sequencing Data
Abstract Background: Germline genetics may influence tumor molecular characteristics and ultimately cancer survival. Studies of tumor characteristics, including our epithelial ovarian cancer (EOC) studies of Black women in the United States, may have RNA sequencing (RNA-seq) data from archival tumor tissue but lack germline DNA for at least some individuals. Incomplete germline DNA measurements impede analyses of important measures such as global genetic ancestry, often used in downstream analyses, by reducing sample sizes. Methods: The study population consists of 184 women who participated in two population-based studies of EOC with both germline and formalin-fixed, paraffin-embedded (FFPE) tumor samples and an additional 58 women diagnosed with EOC from the same two studies with only FFPE tumor tissue. We used tumor RNA-seq data to calculate proportions of African, European, and Asian genetic ancestry using a pipeline built on the packages SeqKit, HISAT2, SAMtools, BCFtools, PLINK, and ADMIXTURE. Women from the 1000 Genomes Project were used as the reference populations, and germline genetic ancestry estimates from blood or saliva were used as the baseline comparison. We evaluated multiple quality control strategies to improve genetic ancestry estimation. Results: Correlations between tumor RNA-seq–derived estimates of genetic ancestry from our pipeline and germline-derived African and European genetic ancestry ranged between 0.76 and 0.94. Conclusions: RNA-seq data from archival FFPE tumor tissue can be confidently and efficiently used to approximate global genetic ancestry in an admixed population when germline DNA is unavailable. Impact: This approach supports analyses of genetic ancestry and cancer when germline samples are not available.
Neighborhood disorder and ovarian cancer survival in Black women
Abstract Ovarian cancer (OC) is the fifth leading cause of cancer mortality among women in the US. Black women experience significantly lower OC survival than White women. Evidence suggests that this disparity is not solely the result of barriers to healthcare access but may also be impacted by other factors, including neighborhood social characteristics. To investigate this further, this study developed an approach for remotely estimating the degree of physical disorder (PD) in neighborhoods using structured audits of Google Street View imagery for participants in the AACES, a multi-site population-based study of Black women newly diagnosed with OC. We then assessed whether neighborhood disadvantage (ND) and PD were associated with overall survival. We fit Weibull accelerated failure time models to assess the association of both PD and ND with survival among 471 Black women with OC (n = 317 deaths). Both PD (event time ratio (ETR), 0.99; 95% CI, 0.98, 1.00) and Area Deprivation Index (ETR: 0.96, 95% CI: 0.94, 1.00) were associated with shorter survival. The results suggest that both physical and social neighborhood characteristics may impact survival in woman with OC, but further research is warranted.
Comorbid conditions and survival among Black women with ovarian cancer
AbstractBackgroundBlack women with epithelial ovarian cancer (EOC) have worse survival and a higher burden of comorbid conditions compared with other racial groups. This study examines the association of comorbid conditions and medication use for these conditions with survival among Black women with EOC.MethodsIn a prospective study of 592 Black women with EOC, the Charlson comorbidity index (CCI) based on self‐reported data, three cardiometabolic comorbidities (type 2 diabetes, hypertension, and hyperlipidemia), and medication use for each cardiometabolic comorbidity were evaluated. Cox proportional hazards regression models were used to examine the association of comorbid conditions and related medication use with all‐cause mortality while adjusting for relevant covariates overall and by histotype (high‐grade serous [HGS]/carcinosarcoma vs. non‐HGS/carcinosarcoma) and stage (I/II vs. III/IV).ResultsA CCI of ≥2 was observed in 42% of the cohort, and 21%, 67%, and 34% of women had a history of type 2 diabetes, hypertension, and hyperlipidemia, respectively. After adjusting for prognostic factors, a CCI ≥2 (vs. 0; hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.04–1.71) and type 2 diabetes (HR, 1.42; 95% CI, 1.10–1.84) were associated with an increased risk of mortality. The increased risk of mortality for type 2 diabetes was present specifically among women with HGS/carcinosarcoma (HR, 1.47; 95% CI, 1.10–1.97) and among women with stage III/IV disease (HR, 1.47; 95% CI, 1.10–1.98). The authors did not find evidence that hypertension, hyperlipidemia, or medication use for the cardiometabolic comorbidities meaningfully impacted survival.ConclusionComorbid conditions, especially type 2 diabetes, had a significant adverse impact on survival among Black women with EOC.
Molecular Subtypes of High-Grade Serous Ovarian Cancer across Racial Groups and Gene Expression Platforms
Abstract Background: High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by self-identified race may contribute to poorer HGSC survival among Black versus White individuals. Methods: We included newly generated RNA sequencing data from Black and White individuals and array-based genotyping data from four existing studies of White and Japanese individuals. We used K-means clustering, a method with no predefined number of clusters or dataset-specific features, to assign subtypes. Cluster- and dataset-specific gene expression patterns were summarized by moderated t-scores. We compared cluster-specific gene expression patterns across datasets by calculating the correlation between the summarized vectors of moderated t-scores. After mapping to The Cancer Genome Atlas–derived HGSC subtypes, we used Cox proportional hazards models to estimate subtype-specific survival by dataset. Results: Cluster-specific gene expression was similar across gene expression platforms and racial groups. Comparing the Black population with the White and Japanese populations, the immunoreactive subtype was more common (39% vs. 23%–28%) and the differentiated subtype was less common (7% vs. 22%–31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA sequencing data; compared with mesenchymal cases, the risk of death was similar for proliferative and differentiated cases and suggestively lower for immunoreactive cases [Black population HR = 0.79 (0.55, 1.13); White population HR = 0.86 (0.62, 1.19)]. Conclusions: Although the prevalence of HGSC subtypes varied by race, subtype-specific survival was similar. Impact: HGSC subtypes can be consistently assigned across platforms and self-identified racial groups.
Psychosocial factors associated with genetic testing status among African American women with ovarian cancer: Results from the African American Cancer Epidemiology Study
BackgroundRacial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can influence the uptake of genetic testing among AA women is needed.MethodsData came from 270 AA women diagnosed with ovarian cancer and participating in a population‐based, case‐control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake.ResultsOne‐third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio [OR] for $25,000‐$74,999, 2.04; 95% confidence interval [CI], 1.06‐3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92‐5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14‐0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses.ConclusionsConsistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.
Race Differences in the Associations between Menstrual Cycle Characteristics and Epithelial Ovarian Cancer
Abstract Background: Menstrual cycle characteristics—including age at menarche and cycle length— have been associated with ovarian cancer risk in White women. However, the associations between menstrual cycle characteristics and ovarian cancer risk among Black women have been sparsely studied. Methods: Using the Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium that includes 1,024 Black and 2,910 White women diagnosed with epithelial ovarian cancer (EOC) and 2,325 Black and 7,549 White matched controls, we investigated associations between menstrual cycle characteristics (age at menarche, age at menstrual regularity, cycle length, and ever missing three periods) and EOC risk by race and menopausal status. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: Black women were more likely to be <11 years at menarche than White women (controls: 9.9% vs. 6.0%). Compared with ≥15 years at menarche, <11 years was associated with increased EOC risk for White (OR = 1.25; 95% CI, 0.99–1.57) but not Black women (OR = 1.10; 95% CI, 0.80–1.55). Among White women only, the association was greater for premenopausal (OR = 2.20; 95% CI, 1.31–3.68) than postmenopausal women (OR = 1.06; 95% CI, 0.82–1.38). Irregular cycle length was inversely associated with risk for White (OR = 0.78; 95% CI, 0.62–0.99) but not Black women (OR = 1.06; 95% CI, 0.68–1.66). Conclusions: Earlier age at menarche and cycle irregularity are associated with increased EOC risk for White but not Black women. Impact: Associations between menstrual cycle characteristics and EOC risk were not uniform by race.
Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race
Abstract Background: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race. Methods: HRD features were identified using matched tumor–normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race. Results: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43–1.09; White HR = 0.38; 95% CI, 0.14–1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%). Conclusions: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals. Impact: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.
Genomic Characterization of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features in Black Individuals
Abstract Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole-exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared with historic data from The Cancer Genome Atlas (TCGA). Despite technical differences (e.g., formalin-fixed vs. fresh-frozen tissue), the distribution of mutations and their variant classifications for major HGSC genes were nearly identical across study populations. However, de novo significantly mutated gene analysis identified genes not previously reported in TCGA analysis, including the oncogene KRAS and the potential tumor suppressor OBSCN. The prevalence of the homologous recombination deficiency signature was higher among Black individuals with the immunoreactive gene expression subtype compared with the mesenchymal and proliferative subtypes. These findings were confirmed by comparing the data from Black patients with those from 123 White patients with identical tissue collection and processing. Overall, this study suggests that, although most features of HGSC tumor phenotypes are similar in Black and White populations, there may be clinically relevant differences. If validated, these phenotypes may be important for clinical decision-making and would have been missed by characterizing tumors from White individuals only. Significance: Elucidation of the somatic mutational landscape of high-grade serous ovarian carcinoma in Black individuals, who experience poor survival and are underrepresented in research, could inform patient prognosis and enable precision medicine opportunities.
Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
The goal of this sequential study design is to increase genetic testing in those meeting national clinical guidelines. The main question it aims to answer is: which intervention is most effective in uptake of genetic testing for the target population? Participants will receive genetic testing and counseling that may initiate life-saving screenings.
