Amanda L. Hall

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

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 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.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis

Background:The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours.Methods:Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan–Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing.Results:Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se.Conclusion:BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive 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.

Hand pattern indicates prostate cancer risk

Background:The ratio of digit lengths is fixed in utero, and may be a proxy indicator for prenatal testosterone levels.Methods:We analysed the right-hand pattern and prostate cancer risk in 1524 prostate cancer cases and 3044 population-based controls.Results:Compared with index finger shorter than ring finger (low 2D : 4D), men with index finger longer than ring finger (high 2D : 4D) showed a negative association, suggesting a protective effect with a 33% risk reduction (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.57–0.80). Risk reduction was even greater (87%) in age group <60 (OR 0.13, 95% CI 0.09–0.21).Conclusion:Pattern of finger lengths may be a simple marker of prostate cancer risk, with length of 2D greater than 4D suggestive of lower risk.

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.

Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population‐based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X‐linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best‐fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11–0.20), with a relative risk for homozygote carriers of 94 (95% CI 46–192), and a polygenic standard deviation of 2.01 (95% CI 1.72–2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non‐additive effects of one or more genes. Genet. Epidemiol. 34:42–50, 2010.

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.