Rosalind Eeles

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (160)1086.75 Total impact

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    Rebbeck TR, Nandita Mitra, Fei Wan, Sinilnikova OM, Sue Healey, Lesley McGuffog, Sylvie Mazoyer, Georgia Chenevix-Trench, Easton DF, Antoniou AC, [......], Mads Thomassen, Moeller ST, Kruse TA, Jensen UB, Maria Adelaide Caligo, Paolo Aretini, Teo SH, Selkirk CG, Hulick PJ, Irene Andrulis
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    ABSTRACT: Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
    Nature Genetics 03/2015; DOI:10.1038/ng.3221 · 29.65 Impact Factor
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    ABSTRACT: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies (GWAS) have identified 100 risk variants for prostate cancer, which can explain ~33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' UTR of genes predicted to affect miRNA binding (miRSNPs) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (p<2.3x10-5) with risk of prostate cancer, 10 of which were within the 7 genes previously not mapped by GWASs. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele whilst miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. Significance: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk. Copyright © 2015, American Association for Cancer Research.
    Cancer Discovery 02/2015; DOI:10.1158/2159-8290.CD-14-1057 · 15.93 Impact Factor
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    ABSTRACT: A rare recurrent missense variant in HOXB13 (rs138213197 / G84E) was recently reported to be associated with hereditary prostate cancer. Population based studies have established that since the frequency of this SNP varies between geographic regions the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases and it was associated with a 2.93-fold increased risk of PrCa [95%CI:1.94-4.59; P 6.27x10(-8)]. The risk was even higher among men with family history of PrCa (OR=4.53, 95%CI: 2.86-7.34; P 3.1x10(-8)) and in young-onset PrCa (diagnosed up to the age of 55 years; OR=3.11, 95%CI: 1.98-5.00; P 6.1x10(-7)). There was no significant association between Gleason Score, presenting PSA, TNM stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains about 1% of the familial risk of PrCa in the UK population. The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 01/2015; DOI:10.1093/annonc/mdv004 · 6.58 Impact Factor
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    ABSTRACT: Purpose:This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.Methods:We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.Results:Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.Conclusion:Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.Genet Med advance online publication 08 January 2015Genetics in Medicine (2014); doi:10.1038/gim.2014.192.
    Genetics in medicine: official journal of the American College of Medical Genetics 01/2015; DOI:10.1038/gim.2014.192 · 6.44 Impact Factor
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    ABSTRACT: Prostate cancer is the most common cancer in men, resulting in over 10,000 deaths per year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and down-regulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.
    Endocrine Related Cancer 01/2015; 22(2). DOI:10.1530/ERC-14-0454 · 4.91 Impact Factor
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    ABSTRACT: Diffusion-weighted (DW)-MRI is invaluable in detecting prostate cancer. We determined its sensitivity and specificity and established interobserver agreement for detecting tumour in men with a family history of prostate cancer stratified by genetic risk.
    12/2014; 1. DOI:10.1016/j.ejro.2014.08.002
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    ABSTRACT: Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society. Copyright © 2014 Lalonde et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
    The Lancet Oncology 12/2014; 15(13):1521-32. DOI:10.1016/S1470-2045(14)71021-6 · 24.73 Impact Factor
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    ABSTRACT: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated. To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis-free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT). Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo. Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations. A total of 67 BRCA carriers and 1235 noncarriers were included. At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p<0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p<0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38-4.03; p=0.002) and CSS (HR: 2.17; 95% CI, 1.16-4.07; p=0.016). BRCA carriers had worse outcomes than noncarriers when conventionally treated for local/locally advanced PCa. Prostate cancer patients with germline BRCA mutations had worse outcomes than noncarriers when conventionally treated with surgery or radiation therapy. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 11/2014; DOI:10.1016/j.eururo.2014.10.022 · 12.48 Impact Factor
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    ABSTRACT: Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
    Breast Cancer Research and Treatment 10/2014; 148(2). DOI:10.1007/s10549-014-3134-0 · 4.20 Impact Factor
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    ABSTRACT: Recent genome wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT here we report a three-stage experiment, involving 4,098 cases and 18,972 controls. Stage 1 comprised previously published GWAS analysis of 307,291 SNPs in 986 cases and 4,946 controls. In stage 2 we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1,064 cases and 10,082 controls. Here we report new genotyping of eight SNPs showing some evidence of association in combined analysis of stage 1 and stage 2 in an additional 2,048 cases of TGCT and 3,944 controls (stage 3). Through fixed effects meta-analysis across 3 stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT (per-allele odds ratio (OR)=1.16, 95% confidence interval (CI)=1.06-1.27; P=1.2 x 10(-9)).
    Human Molecular Genetics 10/2014; DOI:10.1093/hmg/ddu511 · 6.68 Impact Factor
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    ABSTRACT: Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
    Science 08/2014; 345(6196):1251343. DOI:10.1126/science.1251343. · 31.48 Impact Factor
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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 08/2014; 10(9):1679-94. DOI:10.2217/fon.14.72 · 2.61 Impact Factor
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    International journal of radiation oncology, biology, physics 07/2014; 89(4):709-13. DOI:10.1016/j.ijrobp.2014.03.009 · 4.18 Impact Factor
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    ABSTRACT: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46,450 cases and 42,600 controls) and analysed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 (rs1053338, per-allele OR=1.07, 95%CI=1.04-1.10, P=2.9x10(-6)), AKAP9-M463I at 7q21 (rs6964587, OR=1.05, 95%CI=1.03-1.07, P=1.7x10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR=1.10, 95%CI=1.07-1.12, P=5.1x10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine GWAS: for ATXN7-K264R, OR=1.07 (95%CI=1.05-1.10, P=1.0x10(-8)); for AKAP9-M463I, OR=1.05 (95%CI=1.04-1.07, P=2.0x10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known genome-wide association study (GWAS) hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
    Human Molecular Genetics 06/2014; DOI:10.1093/hmg/ddu311 · 6.68 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 & Prevention 04/2014; DOI:10.1158/1055-9965.EPI-13-0889 · 4.32 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e714. DOI:10.1016/j.juro.2014.02.1952 · 3.75 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 & Prevention 03/2014; DOI:10.1158/1055-9965.EPI-13-0635-T · 4.32 Impact Factor
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    ABSTRACT: BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
    British Journal of Cancer 02/2014; 110(4):1088-100. DOI:10.1038/bjc.2013.769 · 4.82 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; DOI:10.1007/s10689-013-9697-9 · 1.62 Impact Factor

Publication Stats

6k Citations
1,086.75 Total Impact Points


  • 1998–2015
    • The Royal Marsden NHS Foundation Trust
      • • Cancer Genetics Unit
      • • Department of Diagnostic Radiology
      Londinium, England, United Kingdom
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1993–2015
    • Institute of Cancer Research
      • Division of Genetics and Epidemiology
      Londinium, England, United Kingdom
  • 2013
    • Centro Nacional de Investigaciones Oncológicas
      • Human Cancer Genetics Programme
      Madrid, Madrid, Spain
  • 2012
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
  • 2011
    • The College of New Jersey
      • Department of Sociology and Anthropology
      New York City, NY, United States
  • 2010
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
    • Royal Devon and Exeter NHS Foundation Trust
      Exeter, England, United Kingdom
  • 1997–2008
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
  • 2007
    • Vanderbilt University
      Нашвилл, Michigan, United States
    • Hadassah Medical Center
      • Sharett Institute of Oncology
      Yerushalayim, Jerusalem District, Israel
  • 2001
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada