Rosalind Eeles

Institute of Cancer Research, Londinium, England, United Kingdom

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Publications (212)1469.49 Total impact

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    ABSTRACT: Prostate cancer (PrCa) is the most commonly diagnosed cancer in the male UK population, with over 40,000 new cases per year. PrCa has a complex, polygenic predisposition, due to rare variants such as BRCA and common variants such as single nucleotide polymorphisms (SNPs). With the introduction of genome-wide association studies, 78 susceptibility loci (SNPs) associated with PrCa risk have been identified. Genetic profiling could risk-stratify a population, leading to the discovery of a higher proportion of clinically significant disease and a reduction in the morbidity related to age-based prostate-specific antigen screening. Based on the combined risk of the 78 SNPs identified so far, the top 1% of the risk distribution has a 4.7-times higher risk of developing PrCa compared with the average of the general population.
    Future oncology (London, England). 08/2014; 10(9):1679-94.
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    International journal of radiation oncology, biology, physics 07/2014; 89(4):709-13. · 4.59 Impact Factor
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    ABSTRACT: A family history of prostate cancer (PC) is one of the main risk factors for the disease. A number of common single nucleotide polymorphisms (SNPs) that confer small but cumulatively substantial risks of PC have been identified, opening the possibility for the use of SNPs in PC risk stratification for targeted screening and prevention in the future. The objective of this study was to explore the psychosocial impact of receiving information about genetic risk of PC. The participants were men who had a family history of PC and were enrolled in a screening study providing research genetic profiling alongside screening for PC. A combination of questionnaires and in-depth interviews were used. Questionnaires were completed by men at two time points: both before and after joining the study and going through the genetic profiling process. The interviews were completed after all study process were complete and were analysed using a framework analysis. In total 95 men completed both questionnaires and 26 men were interviewed. A number of issues facing men at risk of PC were identified. The results fell into two main categories: personal relevance and societal relevance. The strength of men's innate beliefs about their risk, shaped by genetic and environmental assumptions, outweigh the information provided by genetic testing. Men felt genetic profile results would have future use for accessing prostate screening, being aware of symptoms and in communicating with others. The findings reinforce the importance of providing contextual information alongside genetic profiling test results, and emphasises the importance of the counselling process in providing genetic risk information. This research raises some key issues to facilitate clinical practice and future research related to the use of genetic profiling to determine risk of PC and other diseases.
    Familial Cancer 07/2014; · 1.94 Impact Factor
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    ABSTRACT: Background: Only a minority of the genetic component of prostate cancer (PrCa) risk has been explained. Some observed associations of single nucleotide polymorphisms (SNPs) with PrCa might arise from associations of these SNPs with circulating prostate specific antigen (PSA) because PSA values are used to select controls. Methods: We undertook a genome-wide association study (GWAS) of screen detected PrCa (ProtecT 1146 cases and 1804 controls); meta-analysed the results with those from the previously published UK Genetic Prostate Cancer Study (1854 cases and 1437 controls); investigated associations of SNPs with PrCa using either 'low' (PSA ≤0.5ng/ml) or 'high' (PSA ≥3ng/ml, biopsy negative) PSA controls; and investigated associations of SNPs with PSA. Results: The ProtecT GWAS confirmed previously reported associations of PrCa at 3 loci: 10q11.23, 17q24.3 and 19q13.33. The meta-analysis confirmed associations of PrCa with SNPs near 4 previously identified loci (8q24.21,10q11.23, 17q24.3 and 19q13.33). When comparing PrCa cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849 and rs2735839 were associated with an increased risk of PrCa, but the effect-estimates were attenuated to the null when using high PSA controls (p for heterogeneity in effect-estimates<0.04). We found a novel inverse association of rs9311171-T with circulating PSA. Conclusions: Differences in effect estimates for PrCa observed when comparing low vs. high PSA controls, may be explained by associations of these SNPs with PSA. Impact: These findings highlight the need for inferences from genetic studies of PrCa risk to carefully consider the influence of control selection criteria.
    Cancer Epidemiology Biomarkers &amp Prevention 04/2014; · 4.56 Impact Factor
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    ABSTRACT: Background:Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian and other cancer types. Methods:We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput Q-PCR. Participants were from the EMBRACE study in the UK and Eire (n=4,822) and comprised BRCA1 (n=1,628) and BRCA2 (n=1,506) mutation carriers and their non-carrier relatives (n=1,688). Results:We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, P-trend=0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, P-trend=0.0016). Conclusions:Our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it appears that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers. Impact:Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer.
    Cancer Epidemiology Biomarkers &amp Prevention 03/2014; · 4.56 Impact Factor
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    ABSTRACT: Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.
    Nature Reviews Clinical Oncology 03/2014; · 15.03 Impact Factor
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    ABSTRACT: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
    PLoS Genetics 02/2014; 10(2):e1004129. · 8.52 Impact Factor
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    ABSTRACT: This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL. Citation: Killick E, Tymrakiewicz M, Cieza-Borrella C, Smith P, Thompson DJ, et al. (2014) Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status. PLoS ONE 9(1): e86659. doi:10.1371/journal.pone.0086659 Copyright: ß 2014 Killick et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors acknowledge funding from the Annabel Evans Memorial Fund, CRUK (grant numbers C5047/A13232 and C5047/A15007), NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust and the Ronald and Rita McAulay foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
    PLoS ONE 01/2014; · 3.53 Impact Factor
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    ABSTRACT: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. To report the first year's screening results for all men at enrolment in the study. We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
    European Urology 01/2014; · 10.48 Impact Factor
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    ABSTRACT: The aim of this study was to determine whether BRCA1 and BRCA2 mutation carriers have different baseline CA125 levels compared with non-carriers, and whether a significant difference in pre- and post-operative CA125 levels exists in BRCA mutation carriers undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). The study also considered whether CA125 measurements should continue in unaffected BRCA mutation carriers after RRBSO. 383 Eligible women were identified through retrospective review of the BRCA Carrier Clinic at The Royal Marsden NHS Foundation Trust, London, UK. These women all had CA125 levels measured as they were either a carrier or at risk of a BRCA1 or BRCA2 mutation. Of these, 76 went on to have a negative predictive test for their familial mutation and so are classed as 'non-carriers'. 133 BRCA1 and 87 BRCA2 carriers had RRBSO, with a further 26 BRCA1 carriers, 28 BRCA2 carriers and one non-carrier developing ovarian cancer. The remaining 21 BRCA1 and 28 BRCA2 carriers did not have RRBSO or develop ovarian cancer in the time of study follow-up. CA125 levels were measured as surveillance or as part of pre-RRBSO care. CA125 measurement post-RRBSO was continued in 48 BRCA1 and 40 BRCA2 carriers. In 154 BRCA1 mutation carriers, the median baseline (i.e. before RRBSO and with no clinical signs of ovarian cancer) CA125 level was 9.0 U/ml (range 2-78) and was 10.0 U/ml (range 1-43) in 115 BRCA2 mutation carriers. When compared with the 75 non-carriers (median baseline CA125 10.0 U/ml; range 2-52), there was no significant difference between the BRCA1, BRCA2 and non-carrier groups. There was a significant reduction in CA125 from pre- to post-RRBSO in 48 BRCA1 carriers (p = 0.04) but no significant difference in 40 BRCA2 mutation carriers (p = 0.5). Out of a total of 220 mutation carriers who underwent RRBSO, two had an incidental ovarian cancer found on histopathology and another developed primary peritoneal cancer during the follow-up period. Our study is the first to compare initial serum CA125 levels in BRCA1 and BRCA2 mutation carriers with those of non-carriers. Our study found no significant difference between the three groups. A drop in CA125 levels after RRBSO in BRCA1 carriers supports the finding of earlier studies, but differed in that the fall was not seen in BRCA2 carriers. The finding of only one case of post-operative peritoneal cancer in 220 carriers undergoing RRBSO supports the discontinuation of post-RRBSO serum CA125 monitoring in BRCA mutation carriers.
    Familial Cancer 01/2014; · 1.94 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.
    PLoS Genetics 01/2014; 10(1):e1004102. · 8.52 Impact Factor
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    ABSTRACT: Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated. Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy. However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment.
    Nature Reviews Urology 12/2013; · 4.79 Impact Factor
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    ABSTRACT: Mean telomere length in blood cells (TL) is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2,240) and selected 1,629 variants for replication via the "iCOGS" custom genotyping array. All ∼200,000 iCOGS variants were analysed with TL and those displaying associations in healthy controls (n=15,065) were further tested in breast cancer cases (n=11,024). We found a novel TL association (P-trend<4×10(-10)) at 3p14.4 close to PXK and evidence (P-trend<7×10(-7)) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (P-trend<5×10(-14)) the previously-reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (P-trend<5×10(-4)) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.
    Human Molecular Genetics 07/2013; · 7.69 Impact Factor
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    ABSTRACT: Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.
    Scientific Reports 06/2013; 3:2059. · 5.08 Impact Factor
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    ABSTRACT: BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
    JNCI Journal of the National Cancer Institute 06/2013; 105(11):812. · 14.34 Impact Factor
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    ABSTRACT: Background:To determine whether the alleles that influence type 2 diabetes risk and glycemic traits also influence prostate cancer risk. Methods:We used a multiple single nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type 2 diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the PRACTICAL consortium and 5,504 prostate cancer cases and 5,834 controls from the CRUK prostate cancer study. Results:Calculating the average additive effect of type 2 diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type 2 diabetes, or worsened glycemic status, with prostate cancer risk (odds ratio for type 2 diabetes alleles: 1.00 (P=0.58), fasting glycemia alleles: 1.00 (P=0.67), HbA1c alleles: 1.00 (P=0.93), 2 hour OGTT alleles: 1.01 (P=0.14) and HOMA-B alleles: 0.99 (P=0.57)). Conclusions:Using genetic data from large consortia we found no evidence for a shared genetic etiology of type 2 diabetes, or glycemic risk, with prostate cancer. Impact:Our results showed that alleles influencing type 2 diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer.
    Cancer Epidemiology Biomarkers &amp Prevention 05/2013; · 4.56 Impact Factor
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    ABSTRACT: PURPOSETo 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).ResultsPCa 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.
    Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
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    ABSTRACT: Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
    Nature Genetics 03/2013; 45(4):385-391. · 35.21 Impact Factor
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    ABSTRACT: 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.
    Human Molecular Genetics 03/2013; · 7.69 Impact Factor
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    ABSTRACT: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
    PLoS Genetics 03/2013; 9(3):e1003212. · 8.52 Impact Factor

Publication Stats

7k Citations
1,469.49 Total Impact Points

Institutions

  • 1993–2014
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2013
    • Centro Nacional de Investigaciones Oncológicas
      Madrid, Madrid, Spain
  • 2012
    • University of Pennsylvania
      • Perelman School of Medicine
      Philadelphia, PA, United States
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2011
    • IDIBELL Bellvitge Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2003–2011
    • The College of New Jersey
      • Department of Sociology and Anthropology
      New York City, NY, United States
    • Cancer Research UK
      Londinium, England, United Kingdom
  • 2000–2011
    • The Royal Marsden NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1994–2011
    • University of Cambridge
      • • Department of Public Health and Primary Care
      • • MRC Epidemiology Unit
      • • Department of Pathology
      Cambridge, ENG, United Kingdom
  • 2010
    • Royal Devon and Exeter NHS Foundation Trust
      Exeter, England, United Kingdom
  • 2006–2010
    • Hospital of the University of Pennsylvania
      • • Department of Biostatistics and Epidemiology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2009
    • The University of Manchester
      • Centre for Genetic Medicine
      Manchester, ENG, United Kingdom
  • 2001–2009
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada
  • 2008
    • Memorial Sloan-Kettering Cancer Center
      • Clinical Genetics Service
      New York City, New York, United States
  • 2001–2008
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 2005
    • University of Leeds
      • Leeds Institute of Medical Education
      Leeds, ENG, United Kingdom
  • 1998
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States