Finding Genes for Human Prostate Cancer

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Prostate Cancer Studies Prostate Cancer in Men of African Ancestry Although men of African ancestry have a high risk of prostate cancer (PCa), few genes or mutations have been identified that contribute to familial clustering of PCa in this population. This collaboration investigated whether the African ancestry specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (Darst et al., 2020). In men of African ancestry, the relevant variant accounts for 32% of the total familial risk explained by all known PCa risk variants, suggesting that African American men would benefit from guidance about PCA screening and this variant. The PRACTICAL consortium also addressed the issue of risk loci for African American men in their identification of new susceptibility risk loci that inform genetic risk prediction (Conti et al., 2021). The study focused on a multi-ancestry meta-analysis of PCa genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with PCa risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. Prostate Cancer Risk and Prediction In this collaboration the role of DNA methylation in expression quantitative trail loci (eQTL) regulation was investigated (Dai et al., 2020). Specifically, this collaboration identifies and compares eQTLs and CpG methylation quantitative trait loci (meQTLs) among 147 established PCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The study provides a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in tumor development, despite somatic alterations in the tumor genome. Finally, our analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression. In a separate collaboration (Schaid et al., 2020), we sought to understand the role of family history and comparatively more aggressive PCa. A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. Frequencies of genetic variants were compared between cases and controls. Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). This approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefit of sampling patients with a strong family history or aggressive forms of disease. PRACTICAL Consortium Studies We have been long term participants in the PRACTICAL consortium, which has been very prolific in the last two years. Most recently PRACTICAL asked if there is a relationship between marital status and PCa incidence in a pooled study of 12 case control studies (Salmon et al., 2021). Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of PCa, with little difference between low- and high-grade tumors. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumors. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident PCa among widowers, more often characterized by tumors that had spread beyond the prostate at diagnosis. PRACTICAL also published on rare germline variants in ATM, which we show predispose to PCa (Karlsson et al., 2021). We analyzed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. Variant Call Format files were harmonized, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PCa risk and clinical subtypes were estimated. The investigators found that PCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval CI: 2.0-9.5). There was also evidence that PCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).