Emma J. Sawyer

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 × 10−8; rs620861: OR = 0.90, P = 4.8 × 10−8). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

PURPOSE To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes. PATIENTS AND METHODS This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1). RESULTS PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup. CONCLUSION Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients

Background:A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ⩽55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival.Methods:To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer.Results:We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ⩽65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group.Conclusion:Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.

Germline BRCA1 mutations increase prostate cancer risk

Background:Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.Methods:We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.Results:We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.ConclusionThis study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population‐based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population‐based family data and established risk variants exist. Genet. Epidemiol. 2011.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease

Background:Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated.Methods:Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified.Results:We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56–2.42).Conclusions:These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.

Dietary fat and early-onset prostate cancer risk

The UK incidence of prostate cancer has been increasing in men aged < 60 years. Migrant studies and global and secular variation in incidence suggest that modifiable factors, including a high-fat diet, may contribute to prostate cancer risk. The aim of the present study was to investigate the role of dietary fat intake and its derivatives on early-onset prostate cancer risk. During 1999-2004, a population-based case-control study with 512 cases and 838 controls was conducted. Cases were diagnosed with prostate cancer when < or = 60 years. Controls were sourced from UK GP practice registers. A self-administered FFQ collected data on typical past diet. A nutritional database was used to calculate daily fat intake. A positive, statistically significant risk estimate for the highest v. lowest quintile of intake of total fat, SFA, MUFA and PUFA was observed when adjusted for confounding variables: OR 2.53 (95 % CI 1.72, 3.74), OR 2.49 (95 % CI 1.69, 3.66), OR 2.69 (95 % CI 1.82, 3.96) and OR 2.34 (95 % CI 1.59, 3.46), respectively, with all P for trend < 0.001. In conclusion, there was a positive statistically significant association between prostate cancer risk and energy-adjusted intake of total fat and fat subtypes. These results potentially identify a modifiable risk factor for early-onset prostate cancer.

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Clinical implications of family history of prostate cancer and genetic risk single nucleotide polymorphism (SNP) profiles in an active surveillance cohort

Family history (FH) is a major risk factor for the development of prostate cancer. The search for genetic variants has led to genome‐wide association studies (GWAS), which have so far reported 47 susceptibility loci that predispose men to prostate cancer. However, the use of genetics or FH status in predicting clinical outcomes after prostate cancer diagnosis remains uncertain. Guidelines currently exist for clinicians and patients summarising evidence relating to the best outcomes of different prostate cancer treatment methods. Genetics and FH could potentially add to this stratification. Our study aimed to ascertain the potential prognostic roles of FH or genetic risk scores in patients managed by active surveillance.