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African American (AA) prostate cancer associates with vitamin D 3 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) 2 D 3 -regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH) 2 D 3 -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) 2 D 3 -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) 2 D 3 -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., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent., Significance: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483., (©2022 The Authors; Published by the American Association for Cancer Research.)

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 (PM 2.5 ) levels, and neighborhood SES., Results: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with "moderate" Environmental Protection Agency-defined PM 2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with "moderate" versus "good" PM 2.5 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 PM 2.5 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 PM 2.5 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., (©2021 American Association for Cancer Research.)

Background: Given the scarcity of cell lines from underrepresented populations, it is imperative that genetic ancestry for these cell lines is characterized. Consequences of cell line mischaracterization include squandered resources and publication retractions., Methods: We calculated genetic ancestry proportions for 15 cell lines to assess the accuracy of previous race/ethnicity classification and determine previously unknown estimates. DNA was extracted from cell lines and genotyped for ancestry informative markers representing West African (WA), Native American (NA), and European (EUR) ancestry., Results: Of the cell lines tested, all previously classified as White/Caucasian were accurately described with mean EUR ancestry proportions of 97%. Cell lines previously classified as Black/African American were not always accurately described. For instance, the 22Rv1 prostate cancer cell line was recently found to carry mixed genetic ancestry using a much smaller panel of markers. However, our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as African American, was found to carry 92% EUR ancestry. We also determined the MDA-MB-468 breast cancer cell line carries 23% NA ancestry, suggesting possible Afro-Hispanic/Latina ancestry., Conclusions: Our results suggest predominantly EUR ancestry for the White/Caucasian-designated cell lines, yet high variance in ancestry for the Black/African American-designated cell lines. In addition, we revealed an extreme misclassification of the E006AA-hT cell line., Impact: Genetic ancestry estimates offer more sophisticated characterization leading to better contextualization of findings. Ancestry estimates should be provided for all cell lines to avoid erroneous conclusions in disparities literature., (©2019 American Association for Cancer Research.)

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma., Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality., Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles., Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR., (©2016 American Association for Cancer Research.)

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., (©2014 American Association for Cancer Research.)

Background: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer., Methods: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry., Results: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10(-8)). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes., Conclusion: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs., Impact: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs., (©2012 AACR.)

Androgens play an important role in the etiology of prostate cancer. The CYP17 gene encodes the cytochrome P450c17alpha enzyme, which is the rate-limiting enzyme in androgen biosynthesis. A T to C polymorphism in the 5' promoter region has recently been associated with prostate cancer. However, contradictory data exists concerning the risk allele. To investigate further the involvement of the CYP17 variant with prostate cancer, we typed the polymorphism in three different populations and evaluated its association with prostate cancer and clinical presentation in African Americans. We genotyped the CYP17 polymorphism in Nigerian (n = 56), European-American (n = 74), and African-American (n = 111) healthy male volunteers, along with African-American men affected with prostate cancer (n = 71), using pyrosequencing. Genotype and allele frequencies did not differ significantly across the different control populations. African-American men with the CC CYP17 genotype had an increased risk of prostate cancer (odds ratio, 2.8; 95% confidence interval, 1.0-7.4) compared with those with the TT genotype. A similar trend was observed between the homozygous variant genotype in African-American prostate cancer patients and clinical presentation. The CC genotype was significantly associated with higher grade and stage of prostate cancer (odds ratio, 7.1; 95% confidence interval, 1.4-36.1). The risk did not differ significantly by family history or age. Our results suggest that the C allele of the CYP17 polymorphism is significantly associated with increased prostate cancer risk and clinically advanced disease in African Americans.