Douglas Easton

Publications (52)315.64 Total impact

• Article: Genome-wide association study for ovarian cancer susceptibility using pooled DNA.

  Yi Lu, Xiaoqing Chen, Jonathan Beesley, Sharon E Johnatty, Anna Defazio, Sandrina Lambrechts, Diether Lambrechts, Evelyn Despierre, Ignace Vergotes, Jenny Chang-Claude, [......], Susan Ramus, Usha Menon, Alexandra Gentry-Maharaj, Simon A Gayther, Elisa V Bandera, Sara H Olson, Irene Orlow, Lorna Rodriguez-Rodriguez, Stuart Macgregor, Georgia Chenevix-Trench
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  ABSTRACT: Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
  Twin Research and Human Genetics 07/2012; 15(5):615-23. · 1.70 Impact Factor
• Article: Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

  Joan E Bailey-Wilson, Erica J Childs, Cheryl D Cropp, Daniel J Schaid, Jianfeng Xu, Nicola J Camp, Lisa A Cannon-Albright, James M Farnham, Asha George, Isaac Powell, [......], Christiane Maier, Sylvia Borchum, Josef Hoegel, Henrik Grönberg, Fredrik Wiklund, Monica Emanuelsson, Geraldine Cancel-Tassin, Antoine Valeri, Olivier Cussenot, William B Isaacs
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  ABSTRACT: BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant familyspecific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27- q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
  BMC Medical Genetics 06/2012; 13(1):46. · 2.33 Impact Factor
• Article: Genetic variants associated with predisposition to prostate cancer and potential clinical implications.

  C L Goh, F R Schumacher, D Easton, K Muir, B Henderson, Z Kote-Jarai, R A Eeles
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  ABSTRACT: Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.
  Journal of Internal Medicine 02/2012; 271(4):353-65. · 5.48 Impact Factor
• Source

  Available from: Irene Konstantopoulou

  Article: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

  Christopher A Haiman, Gary K Chen, Celine M Vachon, Federico Canzian, Alison Dunning, Robert C Millikan, Xianshu Wang, Foluso Ademuyiwa, Shahana Ahmed, Christine B Ambrosone, [......], Drakoulis Yannoukakos, Wei Zheng, Regina G Ziegler, Afshan Siddiq, Susan L Slager, Daniel O Stram, Douglas Easton, Peter Kraft, Brian E Henderson, Fergus J Couch
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  ABSTRACT: Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
  Nature Genetics 12/2011; 43(12):1210-4. · 35.53 Impact Factor
• Article: Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG.

  Lingyi Lu, Geraldine Cancel-Tassin, Antoine Valeri, Olivier Cussenot, Ethan M Lange, Kathleen A Cooney, James M Farnham, Nicola J Camp, Lisa A Cannon-Albright, Teuvo L J Tammela, [......], Dallas R English, William D Foulkes, Lovise Maehle, Pal Moller, Michael D Badzioch, Steve Edwards, Michelle Guy, Ros Eeles, Douglas Easton, William B Isaacs
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  ABSTRACT: In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.
  The Prostate 07/2011; 72(4):410-26. · 3.48 Impact Factor
• Article: Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers.

  Amanda B Spurdle, Louise Marquart, Lesley McGuffog, Sue Healey, Olga Sinilnikova, Fei Wan, Xiaoqing Chen, Jonathan Beesley, Christian F Singer, Anne-Catharine Dressler, [......], Annelie Liljegren, Hans Ehrencrona, Per Karlsson, Patricia A Ganz, Olufunmilayo I Olopade, Gail Tomlinson, Susan Neuhausen, Antonis C Antoniou, Georgia Chenevix-Trench, Timothy R Rebbeck
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  ABSTRACT: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2011; 20(5):1032-8. · 4.12 Impact Factor
• Article: The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing.

  Paul D P Pharoah, Rachel T Palmieri, Susan J Ramus, Simon A Gayther, Irene L Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, David Goldgar, Mary S Beattie, [......], Ignace Vergote, Robert A Vierkant, Allison F Vitonis, Christine Walsh, Shan Wang-Gohrke, Barbara Wappenschmidt, Anna H Wu, Argyrios Ziogas, Andrew Berchuck, Harvey A Risch
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  ABSTRACT: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52). These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.
  Clinical Cancer Research 03/2011; 17(11):3742-50. · 7.74 Impact Factor
• Article: Endometrial cancer and genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2 within a population-based case-control study.

  James V Lacey, Hannah Yang, Mia M Gaudet, Alison Dunning, Jolanta Lissowska, Mark E Sherman, Beata Peplonska, Louise A Brinton, Catherine S Healey, Shahana Ahmed, Paul Pharoah, Douglas Easton, Stephen Chanock, Montserrat Garcia-Closas
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  ABSTRACT: We assessed whether common genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2-genes that reportedly are frequently altered in endometrial cancer-was associated with risk of endometrial cancer. Using data from a population-based case-control study in Poland (PECS) of 417 cases and 407 matched controls, we genotyped 76 tagging single nucleotide polymorphisms (tagSNPs; located in or within 10 kb upstream or 5 kb downstream of the gene of interest, minor allele frequency >=5% among various ethnic groups, and not already represented by another tagSNP at a LD of r(2) >=0.80) on an Illumina Custom Infinium iSelect assay that included over 29,000 SNPs in 1316 genes. For individual SNPs, we used unconditional logistic regression models, adjusted for age and site, to generate odds ratios (ORs) and 95% confidence intervals (CIs). To replicate the one statistically significant association in PECS, we independently genotyped that tagSNP among 1141 endometrial cancer cases and 2275 controls from the SEARCH study in the UK. We assessed haplotypes via extended haplotype blocks and the sequential haplotype scan method. The rs2677764 tagSNP in PIK3CA was statistically significantly associated with endometrial cancer in PECS (OR=1.42, 95% CI, 1.03-1.95; P=0.03) but not SEARCH (OR=0.98, 95% CI=0.82-1.17). Of the 25 haplotypes observed in at least 5% of cases and controls in PECS, only 1, in PIK3CA, was statistically significantly associated with endometrial cancer (OR=1.39, 95% CI, 1.00-1.93). All haplotype global p-values were null. Common genetic variation in PTEN, PIK3CA, AKT1, MLH1, or MSH2 was not statistically significantly associated with endometrial cancer.
  Gynecologic Oncology 02/2011; 120(2):167-73. · 3.89 Impact Factor
• Article: Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

  Xiaohong R Yang, Jenny Chang-Claude, Ellen L Goode, Fergus J Couch, Heli Nevanlinna, Roger L Milne, Mia Gaudet, Marjanka K Schmidt, Annegien Broeks, Angela Cox, [......], John L Hopper, Fleur Hammet, Helen Tsimiklis, Letitia D Smith, Melissa C Southey, Manjeet K Humphreys, Douglas Easton, Paul Pharoah, Mark E Sherman, Montserrat Garcia-Closas
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  ABSTRACT: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
  CancerSpectrum Knowledge Environment 02/2011; 103(3):250-63. · 14.07 Impact Factor
• Article: Dietary fat and early-onset prostate cancer risk.

  Artitaya Lophatananon, Jane Archer, Douglas Easton, Richard Pocock, David Dearnaley, Michelle Guy, Zsofia Kote-Jarai, Lynne O'Brien, Rosemary A Wilkinson, Amanda L Hall, Emma Sawyer, Elizabeth Page, Jo-Fen Liu, Sandra Barratt, Aneela A Rahman, Rosalind Eeles, Kenneth Muir
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  ABSTRACT: 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.
  The British journal of nutrition 05/2010; 103(9):1375-80. · 3.45 Impact Factor
• Source

  Available from: Kathleen A Cooney

  Article: Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics using novel sumLINK and sumLOD analyses.

  G Bryce Christensen, Agnes B Baffoe-Bonnie, Asha George, Isaac Powell, Joan E Bailey-Wilson, John D Carpten, Graham G Giles, John L Hopper, Gianluca Severi, Dallas R English, [......], Teuvo L J Tammela, Johanna Schleutker, Thomas Paiss, Christiane Maier, Henrik Grönberg, Fredrik Wiklund, Monica Emanuelsson, James M Farnham, Lisa A Cannon-Albright, Nicola J Camp
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  ABSTRACT: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes.
  The Prostate 03/2010; 70(7):735-44. · 3.48 Impact Factor
• Source

  Available from: Helen Ross-Adams

  Article: The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

  Hayley C Whitaker, Zsofia Kote-Jarai, Helen Ross-Adams, Anne Y Warren, Johanna Burge, Anne George, Elizabeth Bancroft, Sameer Jhavar, Daniel Leongamornlert, Malgorzata Tymrakiewicz, [......], Alison Male, Kathy Tucker, Alan Stapleton, Jimmy Lam, Judy Kirk, Hans Lilja, Douglas Easton, Colin Cooper, Rosalind Eeles, David E Neal
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  ABSTRACT: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.
  PLoS ONE 01/2010; 5(10):e13363. · 4.09 Impact Factor
• Chapter: The Identification of Rare and Common Variants Which Predispose to Prostate Cancer

  Rosalind A. Eeles, Zsofia Kote-Jarai, Michelle Guy, Douglas Easton
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  ABSTRACT: Prostate cancer is now the commonest cancer in men in the Western world, with over 34,000 new cases per annum and a lifetime risk of 1 in 11 in the UK (Cancer Research UK Factsheets 2008). However, its aetiology remains very poorly understood. There is substantial worldwide variation in disease incidence, with the disease being much commoner in the Western countries than in the developing world and the Far East (Marugame and Katanoda 2006). These observations, together with studies of incidence rates in migrant populations (Lee et al. 2007), suggest strongly that lifestyle risk factors are important determinants of prostate cancer risk. To date, however, no definite lifestyle risk factors have been identified. Aside from demographic factors, the only long-established risk factor for prostate cancer is a family history of the disease. The risk of the disease in first-degree relatives of cases, estimated consistently from multiple studies, is approximately twice that in the general population (Goldgar et al. 1994; Edwards and Eeles 2004). This familial risk is greater amongst young cases, being more than fourfold for cases below age 60. Analyses based on the Nordic twin registries have found higher risks in monozygotic than dizygotic twins, supporting the hypothesis that much of this familial aggregation is due to genetic rather than shared lifestyle factors (Hemminki and Vaittinen 1998; Lichtenstein et al. 2000). The higher incidence of prostate cancer in African Americans (and lower rate in Americans of Asian ancestry) suggests that genetic factors may also be important determinants of the variation in disease risk at a population level (Zeigler-Johnson et al. 2008) (for more detail, see Chapter by Lange, Section 7.2).
  12/2009: pages 229-248;
• Source

  Available from: Colin Cooper

  Article: Overexpression of RAD51 occurs in aggressive prostatic cancer.

  Anita Mitra, Charles Jameson, Yolanda Barbachano, Lydia Sanchez, Zsofia Kote-Jarai, Susan Peock, Nayanta Sodha, Elizabeth Bancroft, Anne Fletcher, Colin Cooper, Douglas Easton, Rosalind Eeles, Christopher S Foster
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  ABSTRACT: To test the hypothesis that, in a matched series of prostatic cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes. RAD51 expression identified immunohistochemically was compared between prostatic cancers occurring in BRCA1 or BRCA2 mutation carriers and controls. RAD51 protein expression in the cytoplasm and nuclei of the benign tissues was significantly less than in the malignant tissues (P < 0.001). In all cancers, cytoplasmic expression of RAD51 was more prevalent and associated with higher Gleason score (P < 0.05) irrespective of BRCA mutational status, than its expression in benign tissues (P < 0.001). Although nuclear immunoreactivity was not observed in BRCA-associated cancers with Gleason score < or =7, it was significantly increased in all other groups of prostatic cancers when compared with benign tissues (P < 0.001). RAD51 protein is strongly expressed in high-grade prostatic cancers, whether sporadic or associated with BRCA germ-line mutations. Distinct localization of RAD51 between cytoplasm and nucleus, particularly in cancers of Gleason score < or =7, reflects distinct levels of RAD51 regulatory activity, from transcription to DNA repair. This biomarker may be of value in identifying patients requiring urgent treatment at diagnosis as well as in analysing biological mechanisms underlying aggressive phenotype of human prostatic cancer.
  Histopathology 12/2009; 55(6):696-704. · 3.08 Impact Factor
• Source

  Available from: Ruth M L Warren

  Article: Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer: the UK MARIBS study.

  Deborah J Thompson, Martin O Leach, Gek Kwan-Lim, Simon A Gayther, Susan J Ramus, Iqbal Warsi, Fiona Lennard, Michael Khazen, Emilie Bryant, Sadie Reed, Caroline R M Boggis, D Gareth Evans, Rosalind A Eeles, Douglas F Easton, Ruth M L Warren
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  ABSTRACT: Mammographic breast density is one of the strongest known risk factors for breast cancer. We present a novel technique for estimating breast density based on 3D T1-weighted Magnetic Resonance Imaging (MRI) and evaluate its performance, including for breast cancer risk prediction, relative to two standard mammographic density-estimation methods. The analyses were based on MRI (n = 655) and mammography (n = 607) images obtained in the course of the UK multicentre magnetic resonance imaging breast screening (MARIBS) study of asymptomatic women aged 31 to 49 years who were at high genetic risk of breast cancer. The MRI percent and absolute dense volumes were estimated using our novel algorithm (MRIBview) while mammographic percent and absolute dense area were estimated using the Cumulus thresholding algorithm and also using a 21-point Visual Assessment scale for one medio-lateral oblique image per woman. We assessed the relationships of the MRI and mammographic measures to one another, to standard anthropometric and hormonal factors, to BRCA1/2 genetic status, and to breast cancer risk (60 cases) using linear and Poisson regression. MRI percent dense volume is well correlated with mammographic percent dense area (R = 0.76) but overall gives estimates 8.1 percentage points lower (P < 0.0001). Both show strong associations with established anthropometric and hormonal factors. Mammographic percent dense area, and to a lesser extent MRI percent dense volume were lower in BRCA1 carriers (P = 0.001, P = 0.010 respectively) but there was no association with BRCA2 carrier status. The study was underpowered to detect expected associations between percent density and breast cancer, but women with absolute MRI dense volume in the upper half of the distribution had double the risk of those in the lower half (P = 0.009). The MRIBview estimates of volumetric breast density are highly correlated with mammographic dense area but are not equivalent measures; the MRI absolute dense volume shows potential as a predictor of breast cancer risk that merits further investigation.
  Breast cancer research: BCR 11/2009; 11(6):R80. · 5.24 Impact Factor
• Article: Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

  Amanda B Spurdle, Paul Fahey, Xiaoqing Chen, Lesley McGuffog, Douglas Easton, Susan Peock, Margaret Cook, Jacques Simard, Tim R Rebbeck, Antonis C Antoniou, Georgia Chenevix-Trench
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  ABSTRACT: The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.
  Breast Cancer Research and Treatment 11/2009; 122(1):281-5. · 4.43 Impact Factor
• Source

  Available from: Craig Luccarini

  Article: Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design.

  Helen I Field, Serena A Scollen, Craig Luccarini, Caroline Baynes, Jonathan Morrison, Alison M Dunning, Douglas F Easton, Paul D P Pharoah
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  ABSTRACT: In moderate-throughput SNP genotyping there was a gap in the workflow, between choosing a set of SNPs and submitting their sequences to proprietary assay design software, which was not met by existing software. Retrieval and formatting of sequences flanking each SNP, prior to assay design, becomes rate-limiting for more than about ten SNPs, especially if annotated for repetitive regions and adjacent variations. We routinely process up to 50 SNPs at once. We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design. The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5).Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation. Seq4SNPs is available as a service at (http://moya.srl.cam.ac.uk/oncology/bio/s4shome.html) and (http://moya.srl.cam.ac.uk/cgi-bin/oncology/srl/ncbi/seq4snp1.pl), currently for human SNPs, but easily extended to include any species in dbSNP.
  BMC Bioinformatics 07/2009; 10:180. · 2.75 Impact Factor
• Article: Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer.

  Miriam S Udler, Elizabeth M Azzato, Catherine S Healey, Shahana Ahmed, Karen A Pooley, David Greenberg, Mitul Shah, Andrew E Teschendorff, Carlos Caldas, Alison M Dunning, Elaine A Ostrander, Neil E Caporaso, Douglas Easton, Paul D Pharoah
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  ABSTRACT: Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case-control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69-0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
  International Journal of Cancer 07/2009; 125(11):2687-96. · 5.44 Impact Factor
• Article: No evidence that GATA3 rs570613 SNP modifies breast cancer risk.

  Sharon E Johnatty, Fergus J Couch, Zachary Fredericksen, Robert Tarrell, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Daphne Gschwantler-Kaulich, Christian F Singer, Christine Fuerhauser, [......], Hans J P Gille, Marinus J Blok, Claudine Issacs, Manjeet K Humphreys, Lesley McGuffog, Sue Healey, Olga Sinilnikova, Antonis C Antoniou, Douglas F Easton, Georgia Chenevix-Trench
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  ABSTRACT: GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR(per-allele) = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (OR(per-allele) = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RR(per-allele) = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RR(per-allele) = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.
  Breast Cancer Research and Treatment 01/2009; 117(2):371-9. · 4.43 Impact Factor
• Article: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

  Sharon E Plon, Diana M Eccles, Douglas Easton, William D Foulkes, Maurizio Genuardi, Marc S Greenblatt, Frans B L Hogervorst, Nicoline Hoogerbrugge, Amanda B Spurdle, Sean V Tavtigian
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  ABSTRACT: Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.
  Human Mutation 11/2008; 29(11):1282-91. · 5.69 Impact Factor