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Background: B7-H3 (CD276, PD-L3) is an immunomodulatory molecule highly expressed in prostate cancer and belonging to the B7 superfamily that also includes PD-L1 (B7-H1). Immunotherapies (antibodies, antibody-drug conjugates, and CAR-T cells) targeting B7-H3 are currently in clinical trials; thus elucidating the clinical, molecular and tumor immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. Methods: We developed an automated, clinical-grade immunohistochemistry assay to digitally quantify B7-H3 protein expression across two racially diverse cohorts of primary prostate cancer (including one with previously reported transcriptomic data), a set of prostatic neuroendocrine small cell carcinoma, and pre- and post-treatment tumor tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression is significantly lower in self-identified Black patients and inversely correlates with percent African ancestry by ancestry-informative markers. This association with race is independent of the significant association of B7-H3 expression with ERG/ETS and PTEN status. CD276 mRNA level, but not B7-H3 protein expression, is significantly correlated with regulatory (FOXP3+) T-cell density. Finally, androgen receptor activity (AR-A) scores are significantly correlated with CD276 mRNA expression, and neoadjuvant intensive hormonal therapy is associated with a significant decrease in B7-H3 protein expression. Conclusion: These data underscore the importance of studying racially and molecularly diverse prostate cancer cohorts in the era of immunotherapy. Our study is among the first to use genetic ancestry markers to add to emerging evidence that prostate tumors from men of African ancestry may have a distinct immune milieu associated with B7-H3 expression. Citation Format: Adrianna A. Mendes, Jiayun Lu, Harsimar B Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, Karen S. Sfanos, Janielle Maynard, Ashley E. Ross, Steven P. Balk, Mary-Ellen Taplin, Emmanuel S. Antonarakis, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan. Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-100.

African-American (AA) men are more likely to be diagnosed with and to die of prostate cancer than their European-American counterparts. Much of this disparity is due to access to care and social determinants of health; however, there is emerging evidence of molecular differences in prostate tumors arising in patients of different genetic ancestry. We investigated the copy number landscape of 290 grade and race-matched primary prostate tumors through interrogation of Infinium MethylationEPIC Array (Illumina) data derived from primary prostate tumors at radical prostatectomy. Our cohort was composed of 145 self-identified AA patients and 145 self-identified EA surgically-treated patients with accompanying genetic ancestry estimation via SNP array (GSAv3). EPIC array-derived copy number data estimated through the Conumee package on R was significantly correlated with genomic losses and gains identified by exome sequencing of a panel with 100 cancer driver genes. We also observed a significant association between genomic losses of the PTEN gene and PTEN protein loss by immunohistochemistry (P80k coding and non-coding regions from FANTOM CAT. Adjusted LIMMA models with age, Gleason Grade Group, and pre-operative PSA levels showed significant copy number differences by percent African ancestry in chromosomes 6p, 10q, 11p, 12p, and 17p. PTEN losses (as expected) and WT1 gains were more frequent in patients with lower percent African ancestry. Gene expression data from TCGA data showed that WT1 expression was significantly increased for self-identified EA patients. Multivariable Cox regression models adjusted for age, Gleason Grade Group, and pre-operative PSA levels revealed that chromosome 8q gains (including MYC, GRHL2, and FZD6) were significantly associated with biochemical recurrence and metastasis. However, when we stratified the models by self-identified race, only AA tumors showed significant associations with 8q gains and poor outcome. Further in silico and mechanistic validation will be conducted to confirm whether chromosome 8 gains may be a potential biomarker for prostate cancer outcome in AA men. Citation Format: Thiago Vidotto, Eddie Imada, Farzana Faizal, Siqun Zheng, Jianfeng Xu, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan. Copy number landscape of primary African-American and European-American prostate tumors [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-146.

Purpose: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. Experimental Design: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. Results: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. Conclusions: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.

PPP2R2A, a gene mapped to 8p21.2, encodes α isoform of the regulatory B55 subfamily of the protein phosphatase 2 (PP2A). PP2A is one of the four major Ser/Thr phosphatases, and is implicated in the negative control of cell growth and division. Because of its known functions and its location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity were found, we hypothesized that either germline sequence variants or somatic copy number changes in PPP2R2A may increase prostate cancer (PCa) risk. To address this, we first sequenced PPP2R2A in 96 probands of hereditary prostate cancer (HPC) families recruited at John Hopkins Hospital; each family had at least three first-degree relatives affected with prostate cancer. Twenty-five germ-line variants were identified in this analysis, including 15 known SNPs and 10 new sequence variants. Most new sequence variants were rare, except 2 new sequence variants with minor allele frequency (MAF) ≥ 0.05 (−482T/C MAF=0.072 and -78C/G MAF=0.058). Thereafter, it was less likely that these sequence variants of PPP2R2A would be co-segregated with PCa. Second, to see if there are any genetic variants in PPP2R2A associated with sporadic PCa, we analyzed 10 SNPs of 15 known SNPs that span the complete PPP2R2A gene in Cancer Genetic Markers of Susceptibility (CGEMS, 737 cases and 1,105 controls) and in Cancer of the Prostate in Sweden (CAPS, 498 cases and 494 controls) from a Sweden population, as genotypes of these 10 SNPs had already been available in both studies. No consistent significant differences in the allele and genotype frequencies were observed among these sporadic PCa cases and controls. Finally, we examined the deletion status in 141 clinical PCa samples from John Hopkins using Affymetrix 6.0 SNP arrays. With the allele-specific analysis of intensities from all paired tumor and normal tissue samples, it was found that PPP2R2A was commonly (67.1%) deleted in these tumor samples including a homozygous deletion in 3 tumors (2.1%). These results suggest that somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2769. doi:10.1158/1538-7445.AM2011-2769