Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Human kallikrein-2 gene and protein expression predicts prostate cancer at repeat biopsy

Abstract Purpose The human kallikrein-2 (hK2) protein and two single nucleotide polymorphism (SNPs) (rs2664155, rs198977) of the gene are associated with prostate cancer risk. We examined whether hK2 protein and gene SNPs predict prostate cancer at the time of repeat biopsy. Methods We prospectively offered a repeat biopsy to men with a negative prostate biopsy performed for a PSA >4.0 ng/mL or abnormal Digital Rectal Exam (DRE) between 2001–2005. We genotyped and measured serum hK2 levels in 941 men who underwent a repeat prostate biopsy. Logistic regression analyses were conducted to determine the significance of KLK2 SNPs and hK2 levels for predicting cancer at repeat biopsy. Results Of the 941 patients, 180 (19.1%) were found to have cancer. The rs198977 SNP was positively associated with cancer at repeat biopsy (OR variant T allele = 1.8, 95% CI: 1.04-3.13, p = 0.049). When combined, the odds ratio for prostate cancer for patients with high hK2 levels and the variant T-allele of rs198977 was 3.77 (95% CI: 1.94-7.32, p < 0.0001), compared to patients with low hK2 levels and the C-allele. The addition of hK2 levels and KLK2 rs198977 to the baseline predictive model did not significantly increase the area under the curve from a baseline model of 0.67 to 0.69 (p = 0.6). Conclusions The KLK2 SNP rs198977 was positively associated with hK2 levels and predicts prostate cancer at the time of repeat prostate biopsy. Further characterization of the KLK2 gene will be needed to determine its clinical utility

Fetal myelomeningocele surgery: Only treating the tip of the iceberg

Objective: Fetal myelomeningocele (fMMC) surgery improves infant outcomes when compared with postnatal surgery. Surgical selection criteria and the option of pregnancy termination, however, limit the number of cases that are eligible for prenatal surgery. We aimed to quantify what proportion of cases could ultimately benefit from fetal therapy. Methods: We retrospectively reviewed all cases of fMMC referred to a large tertiary care center over a 10-year period and assessed their eligibility for fetal surgery, pregnancy termination rates, and actual uptake of the surgery. Results: Of 158 cases, 67 (42%) were ineligible for fetal surgery based on surgical exclusion criteria. Eleven fetuses (7%) had chromosomal anomalies, 10 of which (91%) had other anomalies on ultrasound. Thirty-four patients had a combination of maternal and fetal contraindications. Of the remaining 91 eligible cases (58%), 45 (49%) pregnancies were terminated, leaving only 46 (29% of initial 158 cases) as potential candidates for fetal repair. Actual uptake of fetal surgery was 15% (n = 14 of 91), but this increased after a national program was started. Conclusion: Only a minority of fMMC cases will ultimately undergo fetal surgery. These numbers support the centralization of care in expert centers