African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A.

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function. Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

The Association between Polluted Neighborhoods and TP53-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non-small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations. METHODS: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES. RESULTS: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with "moderate" Environmental Protection Agency-defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with "moderate" versus "good" PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04-1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02-2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES. CONCLUSIONS: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure. IMPACT: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.

A 17-Gene Panel Genomic Prostate Score Has Similar Predictive Accuracy for Adverse Pathology at Radical Prostatectomy in African American and European American Men.

OBJECTIVE: To validate the 17-gene Oncotype DX Genomic Prostate Score (GPS) as a predictor of adverse pathology (AP) in African American (AA) men and to assess the distribution of GPS in AA and European American (EA) men with localized prostate cancer. METHODS: The study populations were derived from 2 multi-institutional observational studies. Between February 2009 and September 2014, AA and EA men who elected immediate radical prostatectomy after a ≥10-core transrectal ultrasound biopsy were included in the study. Logistic regressions, area under the receiver operating characteristics curves (AUC), calibration curves, and predictive values were used to compare the accuracy of GPS. AP was defined as primary Gleason grade 4, presence of any Gleason pattern 5, and/or non-organ-confined disease (≥pT3aN0M0) at radical prostatectomy. RESULTS: Overall, 96 AA and 76 EA men were selected and 46 (26.7%) had AP. GPS result was a significant predictor of AP (odds ratio per 20 GPS units [OR/20 units] in AA: 4.58; 95% confidence interval (CI) 1.8-11.5, P = .001; and EA: 4.88; 95% CI 1.8-13.5, P = .002). On multivariate analysis, there was no significant interaction between GPS and race (P >.10). GPS remained significant in models adjusted for either National Comprehensive Cancer Network (NCCN) risk group or Cancer of the Prostate Risk Assessment (CAPRA) score. In race-stratified models, area under the receiver operating characteristics curves for GPS/20 units was 0.69 for AAs vs 0.74 for EAs (P = .79). The GPS distributions were not statistically different by race (all P >.05). CONCLUSION: In this clinical validation study, the Oncotype DX GPS is an independent predictor of AP at prostatectomy in AA and EA men with similar predictive accuracy and distributions.

Are HIV-infected men vulnerable to prostate cancer treatment disparities?

BACKGROUND: HIV-infected (HIV(+)) men face cancer treatment disparities that impact outcome. Prostate cancer treatment and treatment appropriateness in HIV(+) men are unknown. METHODS: We used electronic chart review to conduct a retrospective cohort study of 43 HIV(+) cases with prostate cancer and 86 age- and race-matched HIV-uninfected (HIV(-)) controls with prostate cancer, ages 40 to 79 years, from 2001 to 2012. We defined treatment appropriateness using National Comprehensive Cancer Network guidelines and the Charlson comorbidity index (CCI) to estimate life expectancy. RESULTS: Median age was 59.5 years at prostate cancer diagnosis. Median CD4(+) T-cell count was 459.5 cells/mm(3), 95.3% received antiretroviral therapy, and 87.1% were virally suppressed. Radical prostatectomy was the primary treatment for 39.5% of HIV(+) and 71.0% of HIV(-) men (P = 0.004). Only 16.3% of HIV(+) versus 57.0% of HIV(-) men received open radical prostatectomy (P < 0.001). HIV(+) men received more radiotherapy (25.6% vs. 16.3%, P = 0.13). HIV was negatively associated with open radical prostatectomy (OR = 0.03, P = 0.007), adjusting for insurance and CCI. No men were undertreated. Fewer HIV(+) men received appropriate treatment (89.2% vs. 100%, P = 0.003), due to four overtreated HIV(+) men. Excluding AIDS from the CCI still resulted in fewer HIV(+) men receiving appropriate treatment (94.6% vs. 100%, P = 0.03). CONCLUSION: Prostate cancer in HIV(+) men is largely appropriately treated. Under- or overtreatment may occur from difficulties in life expectancy estimation. HIV(+) men may receive more radiotherapy and fewer radical prostatectomies, specifically open radical prostatectomies. IMPACT: Research on HIV/AIDS survival indices and etiologies and outcomes of this prostate cancer treatment disparity in HIV(+) men are needed.

Predictors of serum vitamin D levels in African American and European American men in Chicago.

Vitamin D deficiency is epidemiologically linked to prostate, breast, and colon cancer. When compared with European American (EA) men, African American (AA) men have increased risk of prostate cancer, but few studies evaluate vitamin D status in AA men. The authors evaluate the biological and environmental predictors of vitamin D deficiency in AA and EA men in Chicago, Illinois, a low ultraviolet radiation environment. Blood samples were collected from 492 men, aged between 40 and 79 years, from urology clinics at three hospitals in Chicago, along with demographic and medical information, body mass index, and skin melanin content using a portable narrow-band reflectometer. Vitamin D intake and ultraviolet radiation exposure were assessed using validated questionnaires. The results demonstrated that Black race, cold season of blood draw, elevated body mass index, and lack of vitamin D supplementation increase the risk of vitamin D deficiency. Supplementation is a high-impact, modifiable risk factor. Race and sunlight exposure should be taken into account for recommended daily allowances for vitamin D intake.

Race as a social construct in head and neck cancer outcomes.

OBJECTIVE: The authors examined ancestry informative markers (AIMs) to estimate the amount of population admixture and control for this heterogeneity for stage and survival in a primary head and neck squamous cell carcinoma (HNSCC) cohort. STUDY DESIGN: Historical cohort study. SETTING: Integrated health care system. SUBJECTS: The cohort comprised 358 patients with HNSCC who self-reported race as Caucasian American (CA), African American (AA), or other. METHODS: DNA was interrogated for West African (WA) and European genetic background by genotyping AIMs. Associations of race (self-report or WA ancestry) with stage and survival were analyzed using logistic regression and Cox regression modeling. A subgroup analysis for diagnosis (late vs early stage) and survival (time to death) and WA ancestry was performed for self-reported AAs. RESULTS: There were significant associations between stage and self-reported race (P = .04 [univariate]) and with cancer site (oropharynx: P = .014; hypopharynx: P = .026 [multivariate]). For prognosis, there were significant multivariate associations between stage (P = .002), age (>65 years, P < .001), and cancer site (hypopharynx: P < .001; oral cavity: P = .049), but self-reported race was not associated with overall survival. Interestingly, there was no association with degree of WA ancestry and stage or survival. In the subgroup analysis of genetic ancestry among self-reported AAs, cancer site remained an independent risk factor for stage (other site: P = .026) and survival (oropharynx: P = .036). Late stage persisted as an independent variable for poor survival (P = .032). CONCLUSIONS: Stratification within AAs by WA ancestry revealed no correlation with stage or survival, suggesting that HNSCC outcomes with race may be owing to social/behavior factors rather than biological differences.