Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The Prevalence of Chronic Kidney Disease Requiring Nephrological Referral in Patients with Non-Visible Haematuria

Objective: To quantify the proportion of patients attending for urological investigation of non-visible haematuria who meet criteria for referral to specialist renal services under current UK guidelines. Patients and methods: Data were collected from 377 consecutive patients attending a dedicated non-visible haematuria clinic. Details were recorded for clinic outcomes and indicators of chronic kidney disease (eGFR, dipstick proteinuria, protein:creatinine ratio). The proportion of patients meeting referral criteria was calculated, including the increase in service need and costs. Results: 8.7% of patients had a positive urological diagnosis, with 2.7% having malignancies. 20.7% of patients had CKD stage 3 on the basis of their eGFR readings. 16.7% of patients had dipstick proteinuria, but only 4.4% had a raised protein:creatinine ratio. Overall, up to 22% of patients met current criteria for referral to nephrology, although this varied according to guideline. At this level, it equates to a potential increase of 20–30% in new patient referrals. Conclusion: Features of CKD are common in patients undergoing investigation for non-visible haematuria, with high numbers meeting current UK criteria for referral to nephrology. Appropriate investigation of these risk factors should form an integral part of the haematuria clinic. </jats:sec

Three-Year Outcomes of a Visible Haematuria Clinic—No Initial Role for Urine Cytology?

Objective: To review patients presenting in a specialist macroscopic (visible) haematuria clinic during 2005, incorporating 3 years of follow-up, and to assess the role of urine cytology. Patients and methods: All patients attending the 2005 macroscopic haematuria clinic were identified. All subsequent admissions, pathology and imaging for each patient were captured from the hospital IT system during 3 years of follow-up and reviewed retrospectively. Results: Five hundred and three patients were assessed. No significant abnormalities were diagnosed in 52%, benign disease in 27% and malignant disease in 21% (including 14% urothelial cancer, 3% renal cancer and 4% prostate cancer). All bladder tumours were diagnosed with flexible cystoscopy and the 3 upper-tract urothelial tumours by ultrasound. Overall, cytology had a sensitivity of 66% and specificity 90% but did not diagnose tumours that were not identified with other investigations. Patients with abnormal cytology without apparent cause underwent various investigations including IVU, cystoscopy and biopsy and no tumours were identified. After 3 years no occult diseases became apparent. Conclusions: Half of all those attending with visible haematuria had significant urological diagnoses (21% urological cancer). Urine cytology did not appear to add significant information in the initial assessment of visible haematuria. </jats:sec

Multiple loci on 8q24 associated with prostate cancer susceptibility

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33)