Joellen M. Schildkraut

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.

Mapping Inherited Genetic Variation with Opposite Effects on Autoimmune Disease and Four Cancer Types Identifies Candidate Drug Targets Associated with the Anti-Tumor Immune Response

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10−8 associated with at least one of the cancer types at p < 10−3 and one of the autoimmune/autoinflammatory diseases at p < 10−3. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman’s ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy.

Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Abstract Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes. Methods: We pooled data from 11 case–control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models. Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only. Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes. Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.

Use of non-prescription analgesic medications and survival among Black women with ovarian cancer

Abstract Background Chronic inflammation and inflammatory-related exposures have been implicated in epithelial ovarian cancer (EOC) prognosis. However, no studies have evaluated whether analgesic medication use impacts survival in Black women with EOC, an understudied population with poor survival. Methods Leveraging data from the African American Cancer Epidemiology Study, we examined the association of pre-diagnostic analgesic medication use (aspirin, non-aspirin non-steroidal anti-inflammatory drugs [naNSAIDs], and acetaminophen) with survival among self-identified Black women diagnosed with EOC ( N  = 541) using multivariable Cox proportional hazards regression. Stratified analyses were conducted by comorbidities and histotype. Results Acetaminophen use was associated with a higher risk of mortality overall (HR = 1.40; 95% CI = 1.00–1.97) and for frequent and chronic use (≥30 days per month: HR = 1.62; 95% CI = 1.12–2.34; >5 years: HR = 1.57; 95% CI = 1.03–2.39). These associations were more pronounced among women with high-grade serous carcinoma (HGSC)/carcinosarcoma and those with comorbidities. Among women with comorbidities, naNSAID use was associated with a decreased risk of mortality (HR = 0.71; 95% CI = 0.51–0.99), but no association was observed among women without comorbidities (HR = 0.99; 95% CI = 0.56–1.75). No associations with survival were observed for aspirin. Conclusion Chronic use of acetaminophen negatively impacted survival among Black women with EOC, while naNSAID use conferred a survival advantage only among women with comorbidities.

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.

Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium

Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI: 1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI: 0.81-1.78, p The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility

Abstract Background: Predicting protein levels from genotypes for proteome-wide association studies (PWAS) may provide insight into the mechanisms underlying cancer susceptibility. Methods: We performed PWAS of breast, endometrial, ovarian, and prostate cancers and their subtypes in several large European-ancestry discovery consortia (effective sample size: 237,483 cases/317,006 controls) and tested the results for replication in an independent European-ancestry GWAS (31,969 cases/410,350 controls). We performed PWAS using the cancer GWAS summary statistics and two sets of plasma protein prediction models, followed by colocalization analysis. Results: Using Atherosclerosis Risk in Communities (ARIC) models, we identified 93 protein–cancer associations [false discovery rate (FDR) < 0.05]. We then performed a meta-analysis of the discovery and replication PWAS, resulting in 61 significant protein–cancer associations (FDR < 0.05). Ten of 15 protein–cancer pairs that could be tested using Trans-Omics for Precision Medicine (TOPMed) protein prediction models replicated with the same directions of effect in both cancer GWAS (P < 0.05). To further support our results, we applied Bayesian colocalization analysis and found colocalized SNPs for SERPINA3 protein levels and prostate cancer (posterior probability, PP = 0.65) and SNUPN protein levels and breast cancer (PP = 0.62). Conclusions: We used PWAS to identify potential biomarkers of hormone-related cancer risk. SNPs in SERPINA3 and SNUPN did not reach genome-wide significance for cancer in the original GWAS, highlighting the power of PWAS for novel locus discovery, with the added advantage of providing directions of protein effect. Impact: PWAS and colocalization are promising methods to identify potential molecular mechanisms underlying complex traits.

Association of inflammation-related exposures and ovarian cancer survival in a multi-site cohort study of Black women

An association was observed between an inflammation-related risk score (IRRS) and worse overall survival (OS) among a cohort of mostly White women with invasive epithelial ovarian cancer (EOC). Herein, we evaluated the association between the IRRS and OS among Black women with EOC, a population with higher frequencies of pro-inflammatory exposures and worse survival. The analysis included 592 Black women diagnosed with EOC from the African American Cancer Epidemiology Study (AACES). Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of the IRRS and OS, adjusting for relevant covariates. Additional inflammation-related exposures, including the energy-adjusted Dietary Inflammatory Index (E-DII A dose-response trend was observed showing higher IRRS was associated with worse OS (per quartile HR: 1.11, 95% CI: 1.01-1.22). Adding the E-DII to the model attenuated the association of IRRS with OS, and increasing E-DII, indicating a more pro-inflammatory diet, was associated with shorter OS (per quartile HR: 1.12, 95% CI: 1.02-1.24). Scoring high on both indices was associated with shorter OS (HR: 1.54, 95% CI: 1.16-2.06). Higher levels of inflammation-related exposures were associated with decreased EOC OS among Black women.

CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Identification of novel epithelial ovarian cancer loci in women of African ancestry

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome‐wide association study in African ancestry women with 755 EOC cases, including 537 high‐grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10−6), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3′ of UGT2A2) and rs142091544 (5 kb 5′ of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5′ of follistatin [FST]), rs57403204 (81 kb 3′ of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5′ of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3′ of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow‐up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry‐derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

Racial differences in the association of body mass index and ovarian cancer risk in the OCWAA Consortium

Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race. We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models. The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (OR Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

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.

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

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.