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What's known on the subject? and What does the study add? 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. Objectives To explore the potential prognostic role of family history (FH) of prostate cancer and prostate cancer risk single nucleotide polymorphisms (SNPs) in patients undergoing active surveillance (AS) for prostate cancer. This is the first study to date, which has investigated the potential prognostic role of SNP profiles in an AS cohort Patients and Methods FH data were collected from patients in the Royal Marsden Hospital AS study. In all, 39 prostate cancer-risk SNPs identified from published genome wide association studies (GWAS) were genotyped using the Sequenom Platform and TaqMan™ assays from available DNA. The cumulative genetic-risk scores for each patient were then calculated using the weighted effect estimated from previous GWAS (log-additive model). FH status and the genetic-risk scores were assessed against adverse outcomes in AS, time to treatment and adverse histology on repeat biopsy, using univariable and multivariable Cox regression models to address time to treatment; and binary logistic regression to address biopsy upgrade. Results Of 471 patients, 55 (13.6%) had adverse histology on repeat biopsies and 145 (30.8%) had deferred treatment. On univariate analysis, there was no significant relationship between FH of prostate cancer in any degree of relation, and adverse histology or time to treatment. For risk score analyses, 386 patients' DNA was studied; and there was also no relationship found between the calculated genetic risk scores and adverse histology or time to treatment (P = 0.573 and P = 0.965, respectively). The retrospective study design and the few events were the main limitation of the study. Conclusions There is currently insufficient data to support the use of FH status or prostate cancer SNP profile risk scores as prognostic factors in AS and these should not be used to influence management decisions. As more genetic variants are discovered this may change and should be reassessed in multicentre AS cohorts.

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. Conclusion This 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 (PrCa) is a significant public health problem. In the European Union, approximately 200 000 men are diagnosed annually with the disease. There are 35 515 cases (Cancer Research UK, 2009a) per year in the United Kingdom and 10 239 deaths (Cancer Research UK, 2009b). It is now the commonest male non-cutaneous cancer diagnosed in the United Kingdom; the lifetime risk of being diagnosed with PrCa is 1 in 10 (Cancer Research UK, 2009a). Although the increase in population screening is leading to an increase in diagnosis, many men will not develop aggressive disease. However, it is recognised that some PrCa cases have a particularly poor prognosis. Although there are some histological and stage predictors of prognosis (Kattan and Scardino, 2002), until recently, none of them have been related to inherited factors. Multiple aetiologies have been proposed to contribute to the development of PrCa. There is strong evidence that inherited genetic factors are important and exhibit significant familial aggregation in some men, particularly when affected at a young age (Woolf, 1960; Edwards and Eeles, 2004). There is a recognised association of breast cancer with PrCa in families (Thiessen, 1974; Anderson and Badzioch, 1992; Tulinius et al, 1992). Male relatives in breast cancer families in Iceland have a 2–3-fold risk of PrCa (Sigurdsson et al, 1997). The breast cancer predisposition genes BRCA1 and BRCA2 have been reported to increase the risk of PrCa by three-fold and seven-fold, respectively, in male mutation carriers ascertained through a family history of breast cancer (Ford et al, 1994; Struewing et al, 1997; Breast Cancer Linkage Consortium, 1999). Analyses of PrCa relative risks (RR) in male mutation carriers in breast cancer families from the Breast Cancer Linkage Consortium showed an RR of 4.65 (95% CI: 3.48–6.22) of PrCa in male BRCA2 mutation carriers (the RR is 7.33 below the age of 65 years) and of 1.07 (0.75–1.54) in BRCA1 carriers (with an RR of 1.82 (1.01–3.29) for men under 65 years of age) (Thompson and Easton, 2001, 2002). The estimated cumulative incidence of PrCa by the age of 70 years is 7.5–33%. Recent studies have suggested that the risk of PrCa in BRCA2 mutation carriers may be as high as an RR of 23-fold at age 60 years (Edwards et al, 2003). Studies from Iceland have reported that germline mutations in BRCA2 may be involved not only in susceptibility to PrCa but also in the aggressiveness of the disease (Sigurdsson et al, 1997; Tryggvadottir et al, 2007). However, these individuals all carried a common founder mutation (999del5 in BRCA2). Narod et al (2008) have reported that PrCa survival in BRCA2 mutation carriers is much shorter (median survival from diagnosis was 4 years) when compared with BRCA1 carriers' survival (median survival from diagnosis was 8 years). In PrCa, in which the BRCA2 germline mutation status was unknown, allele loss at the BRCA2 locus has been shown to be a prognostic factor for survival on univariate analysis (Edwards et al, 1998), and loss of the wild-type allele would imply a tumour suppressor mechanism in predisposition to this disease in BRCA2 mutation carriers, but it is not known whether this is a surrogate for high grade or is due to mutation per se (Knudson, 1971; Willems et al, 2008). A BRCA2 genomic screening study has previously been undertaken by ourselves, and six potentially pathogenic germline BRCA2 mutations were found in a set of 263 PrCa patients diagnosed at ⩽55 years (2.3%) (Edwards et al, 2003). In this study we report clinical follow-up data and the results of loss of heterozygosity (LOH) analyses on PrCa tumours from the mutation carriers in this report. We then studied a second validation data set of men with germline mutations in the BRCA2 gene from a cancer genetics clinic and assessed their survival to confirm our results in a different UK data set of male BRCA2 mutation carriers with PrCa.

The UK incidence of prostate cancer has been increasing in men aged 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

Exposure to ionising radiation is an established risk factor for many cancers. We conducted a case-control study to investigate whether exposure to low dose ionisation radiation from diagnostic x-ray procedures could be established as a risk factor for prostate cancer. In all 431 young-onset prostate cancer cases and 409 controls frequency matched by age were included. Exposures to barium meal, barium enema, hip x-rays, leg x-rays and intravenous pyelogram (IVP) were considered. Exposures to barium enema (adjusted odds ratio (OR) 2.06, 95% confidence interval (CI) 1.01-4.20) and hip x-rays (adjusted OR 2.23, 95% CI 1.42-3.49) at least 5 years before diagnosis were significantly associated with increased prostate cancer. For those with a family history of cancer, exposures to hip x-rays dating 10 or 20 years before diagnosis were associated with a significantly increased risk of prostate cancer: adjusted OR 5.01, 95% CI 1.64-15.31 and adjusted OR 14.23, 95% CI 1.83-110.74, respectively. Our findings show that exposure of the prostate gland to diagnostic radiological procedures may be associated with increased cancer risk. This effect seems to be modified by a positive family history of cancer suggesting that genetic factors may play a role in this risk association.

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

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10-8 to P = 2.7 × 10-24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining 425% of the familial risk in this disease, have now been identified. © 2011 Nature America, Inc. All rights reserved.

Objective To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at ≤60 years old. Patients, subjects and methods: In all, 431 prostate cancer cases and 409 controls participated and provided information on their sexual activity. In particular, the frequencies of intercourse and masturbation during the participants’ different age decades (20s, 30s, 40s, 50s) were collected. Results: Whereas frequent overall sexual activity in younger life (20s) increased the disease risk, it appeared to be protective against the disease when older (50s). Alone, frequent masturbation activity was a marker for increased risk in the 20s and 30s but appeared to be associated with a decreased risk in the 50s, while intercourse activity alone was not associated with the disease. Conclusion: These findings could imply different mechanisms by which sexual activity is involved in the aetiology of prostate cancer at different ages. Alternatively, there is a possibility of reverse causation in explaining part of the protective effect seen for men in their 50s.

1517 Background: Previous studies have linked some BRCA1/2 mutations with increased incidence and poor overall survival (OS) in prostate cancer (PCa). In this study both BRCA genes were screened for germline mutations in a larger cohort of PCa and mutation status was correlated with PCa prognostic factors (PFs). Methods: 3818 patients (pts) were enrolled in the UK Genetic Prostate Cancer Study (UKGPCS) between1990-2005. Inclusion criteria for our analysis were available genomic DNA and clinical and survival data in our prospectively maintained UKGPCS database. Genomic DNA was screened for BRCA1/2 mutations. The Kaplan-Meier method and Cox Regression models were used to study the association between BRCA mutation carrier status and other PCa PFs with OS, cause specific OS (CSS), and metastasis free survival (MFS). Results: 2181 pts were eligible for analysis. Median age was 57yrs (range 32-89). BRCA1and BRCA2mutations were detected in 5 and 34 patients respectively. BRCA2 tumors were associated with higher...

The aetiology of prostate cancer (PrCa) is poorly understood. A family history of prostate cancer, particularly at a young age, is a strong risk factor for the disease, indicating that inherited factors are important in PrCa. To date, the strongest genetic risk factor for PrCa is a protein truncating mutation in BRCA2, Studies in breast/ovarian cancer families have estimated a risk of ∼5 fold in BRCA2 carriers. We previously estimated that 2.3% of PrCa cases diagnosed at ≤55 years harbour a BRCA2 mutation. PrCa in BRCA2 carriers has been shown to be more aggressive, with poorer survival. To further evaluate the role of BRCA2 in PrCa predisposition we screened 1910 men with PrCa aged 36 to 86 years. Patients were recruited through the UKGPCS (UK Genetic Prostate Cancer Study Collaborators). The study was enriched for cases with an early age of onset (1639 men ≤65yrs) and/or positive family history of PrCa (271 men >65 with at least 2 affected relatives with PrCa). We analyzed the entire coding region of the BRCA2 gene in 46 PCR fragments by using a high-throughput multiplex fluorescent heteroduplex detection system developed for the ABI3130 genetic analyser. After repeats and QC 32 samples were excluded from the analysis. Fragments were analyzed for peak shifts corresponding to putative mutations in Genemapper v4.0 (Applied Biosystems) by visual inspection and using Bionumerics (Applied Maths). All fragments with peak-shifts were Sanger sequenced to characterise the mutation and validated using re-PCR and Sanger sequencing. We have identified 19 frameshift mutations, 3 in-frame deletions and 56 missense variants of uncertain significance (UV). Based on studies in breast/ovarian cancer families, most UVs and some in-frame deletions are likely to be neutral. All the carriers of frameshift mutations were affected at age ≤65 years, 12 patients had family history of prostate cancer and 9 patients had some family history of breast or ovarian cancer. The prevalence of mutations was 1.25 % (8/638) for cases diagnosed ≤55 years and 1.17 % (19/1620) for cases diagnosed ≤ 65 years. Based on the estimated frequency of BRCA2 mutations in the UK (0.16%) we estimate that mutations in the BRCA2 gene confer a risk of prostate cancer of approximately 7 fold by age 65 (close to previous estimates from breast-ovarian cancer families), corresponding to an absolute risk of ∼4% by age 65. As targeted treatments using drugs such as PARP inhibitors have shown activity in women with cancer who have BRCA mutations and as mutation tests become cheaper, there would be a rationale for testing young onset PrCa cases for BRCA2 mutations to offer such targeted treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3810. doi:10.1158/1538-7445.AM2011-3810

ABSTRACT Background Hand pattern (pattern of index compared to ring finger on the right hand, 2D:4D) has been studied for a number of decades as a potential predictor for disease occurrence. It is known to be associated with certain hormone related diseases developed during adult life but there have been no studies so far of 2D:4D ratio and prostate cancer risk. This study assesses the association between hand and prostate cancer. Methods We analysed the right hand pattern and prostate cancer risk in 1524 cases aged ≤ 80 and 3044 population-based controls. Odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariate logistic regression (to allow for adjustment of confounders) estimating whether there was any association between right hand pattern and the risk of prostate cancer. Results The reference group was chosen to be the commonest hand pattern seen in males which is index finger shorter than ring finger. Compared to this group there was no difference in men with index finger equal to ring finger (OR 1.05, 95% CI 0.88-1.25) whereas men with index finger longer than ring finger showed a negative association indicative of a marker of a protective effect with a 33% risk reduction compared to index finger shorter than ring finger (OR 0.67, 95% CI 0.57-0.80). Conclusion This study showed that the pattern of finger lengths appears to be a community based surrogate marker of prostate cancer risk with length of 2D greater than 4D indicative of lower risk which has previously been shown to be also associated with lower prenatal testicular activity. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5742.