Findings from a Genetic Sequencing Investigation of Men with Familial and Aggressive Prostate Cancer

Prostate cancer (PCa) is a highly heritable disease with few established nongenetic susceptibility factors, which include age and race/ethnicity. Common genetic variants discovered to date explain approximately 30% of the familial relative risk of this disease [1], suggesting that additional genetic factors are yet to be discovered. Few genomic sequencing studies have been performed in PCa, and this approach could offer a means of discovering novel genetic risk factors.

In this issue of European Urology, Schaid and colleagues [2] report ten novel genes containing variants associated with PCa risk, identified using germline exome sequencing of European ancestry samples from the International Consortium for Prostate Cancer Genetics (ICPCG), initially formed to establish a large sample of hereditary PCa families [3]. This investigation used a two-stage study design: stage 1 consisted of 491 familial PCa cases and 429 controls with whole-exome sequencing, and stage 2 consisted of an independent sample of 2917 unrelated PCa cases, predominantly familial and/or aggressive, and 1899 unrelated controls with targeted exome sequencing of genes identified in stage 1.

Of the ten novel genes, two (PABPC1 and QK1) were identified in gene-based analyses, and both had protective effects against PCa, which may be unexpected given that variants included in gene-based tests were limited to low-frequency variants that are likely to cause protein truncation, nonsynonymous coding variants, and in-frame indels. However, this does not rule out the possibility of their involvement in PCa, and Schaid et al indicate that these genes have reportedly been associated with gastric, esophageal, and colorectal cancer. The eight other novel genes (FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3) were identified in single-variant analyses, each having at least one variant significantly associated with PCa. Although sample size limitations restricted the ability to detect rare variants, the authors report novel associations between common variants (minor allele frequencies ranging from 4% to 10% among controls) and aggressive disease that had not been previously identified in case-control genome-wide association studies. Interestingly, Schaid et al indicate that five of the novel genes have some involvement in various neurological traits, which may be relevant given that PCa growth is stimulated by testosterone, the downstream product of luteinizing hormone–releasing hormone (LHRH) secreted by the hypothalamus. In addition to these ten novel genes, 11 known PCa genes were also identified in this investigation. However, the biological relevance of the ten novel genes should be interpreted with caution until the associations identified are validated in an external sample, especially given the common challenges of replicating genetic findings [4]. One of the strengths of this study is the large number of familial cases included, which enriched the selection of genes and facilitated the identification of the ten novel genes in stage 2. However, all of the novel genes were associated with risk of aggressive PCa and none with risk of familial PCa, despite the larger sample size of the familial (n = 1993) compared to the aggressive (n = 1258) group. While familial and aggressive PCa cases are both likely to enrich a genetic investigation, this study illustrates a potential advantage of focusing on aggressive cases. Family studies successfully led to the identification of the rare HOXB13 risk variant, which accounts for ~5% of hereditary PCa [5,6]; however, beyond HOXB13, it has been challenging to identify genes associated with the familial clustering of PCa.

The cost of whole-exome and whole-genome sequencing is a common limiting factor for the number of samples sequenced in a given cohort. To achieve sufficient power, investigators often aggregate sequence data across studies, combining data generated using different sequencing centers or platforms. To address the batch effects that this introduces, the standard is to jointly call all samples together, which was the approach used by Schaid et al in stage 1, as controls were selected from studies that had existing sequencing data. As the cost of sequencing decreases, data are being cohesively generated with large data sets, such as the Trans-Omics for Precision Medicine (TOPMed) program (www.nhlbiwgs.org; whole-genome sequences for more than 150 000 participants), the UK Biobank (www.ukbiobank.ac.uk; whole-exome sequences for 150 000 participants), and the Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Tumors Markers and Social Stress (RESPOND) study (www.respondstudy.org; whole-exome sequencing for 20 000 men of African ancestry). These initiatives and others will extend investigations of rare variants in PCa and aggressive disease and could potentially serve as a source of external validation for novel findings.

It was recently shown that the risk of breast and ovarian cancer for European ancestry women carrying pathogenic variants in BRCA2, BRCA1, ATM, CHEK2, or PALB2 is modified by polygenic risk scores (PRS), such that carriers with a high PRS had higher odds and absolute risk of breast cancer, while carriers with low PRS had lower odds and absolute risk relative to carriers with average PRS [7,8]. Similar efforts to relate findings from sequencing studies to PCa PRS could refine our ability to accurately predict a man’s risk. In terms of clinical applications, it was recently recommended that men carrying mutations in BRCA2, and potentially BRCA1, HOXB13, ATM, and DNA mismatch repair genes, start PCa screening at age 40 yr for early detection [9]. However, additional research is necessary to evaluate how and when additional genetic factors, such as those found in the current study, should be incorporated into screening, treatment, and disease management. Perhaps the most crucial next step to optimizing the clinical utility of genetics is to increase the diversity in genetic investigations of PCa, particularly increasing the representation of men of African ancestry, who are disproportionately impacted by this disease [10].

The investigation by Schaid and colleagues, designed to identify novel risk variants for familial and aggressive PCa, highlights the challenges in detecting rare variants that contribute to the clustering of PCa in families. While the ten novel genes for aggressive PCa will require external validation in larger studies and other racial/ethnic populations, this study belongs to a new era of PCa research that leverages innovative technologies and statistical tools and is likely to point to novel risk genes and advance our understanding of the biology of PCa susceptibility.