Publications by authors named "Karoline B Kuchenbaecker"

29 Publications

  • Page 1 of 1

Shared heritability and functional enrichment across six solid cancers.

Nat Commun 2019 01 25;10(1):431. Epub 2019 Jan 25.

Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r = 0.57, p = 4.6 × 10), breast and ovarian cancer (r = 0.24, p = 7 × 10), breast and lung cancer (r = 0.18, p =1.5 × 10) and breast and colorectal cancer (r = 0.15, p = 1.1 × 10). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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http://dx.doi.org/10.1038/s41467-018-08054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347624PMC
January 2019

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet 2017 Dec 23;49(12):1767-1778. Epub 2017 Oct 23.

Department of Epidemiology, University of California, Irvine, Irvine, California, USA.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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http://dx.doi.org/10.1038/ng.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808456PMC
December 2017

Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations.

Sci Rep 2017 09 8;7(1):11008. Epub 2017 Sep 8.

Wellcome Trust Sanger Institute, Hinxton, UK.

Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 × 10) was associated with levels of alanine transaminase, an indicator of liver damage. The variant is located in the gene encoding serine protease inhibitor, low levels of which are associated with alpha-1 antitrypsin deficiency which leads to liver disease. We identified novel associations (rs78900934, beta = 0.05, P = 6 × 10; rs2911280, beta = 0.09, P = 6 × 10) for dihydroepiandrosterone sulphate, a precursor to major sex-hormones, and for glycated haemoglobin (rs12819124, beta = -0.03, P = 4 × 10; rs761772, beta = 0.05, P = 5 × 10). rs12819124 is nominally associated with risk of type 2 diabetes. Our study offers insights into the genetic architecture of well-known and less well-studied biomarkers.
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http://dx.doi.org/10.1038/s41598-017-10812-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591265PMC
September 2017

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.

JAMA 2017 06;317(23):2402-2416

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.

Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location.

Design, Setting, And Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years.

Exposures: BRCA1/2 mutations, family cancer history, and mutation location.

Main Outcomes And Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer.

Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001).

Conclusions And Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
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http://dx.doi.org/10.1001/jama.2017.7112DOI Listing
June 2017

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

J Clin Oncol 2017 Jul 27;35(20):2240-2250. Epub 2017 Apr 27.

Julie Lecarpentier, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Goska Leslie, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Debra Frost, Steve Ellis, Douglas F. Easton, and Antonis C. Antoniou, University of Cambridge; Karoline B. Kuchenbaecker, The Wellcome Trust Sanger Institute, Hinxton; Marc Tischkowitz, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge; D. Gareth Evans, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Alex Henderson, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Carole Brewer, Royal Devon and Exeter Hospital, Exeter; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Jackie Cook, Sheffield Children's Hospital, Sheffield; Kai-ren Ong, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Lisa Walker, Churchill Hospital, Oxford; Lucy E. Side, Great Ormond Street Hospital for Children NHS Trust; Shirley Hodgson, St George's, University of London; Louise Izatt, Guy's and St Thomas' NHS Foundation Trust; Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Nick Orr, The Institute of Cancer Research, London; Mary E. Porteous, Western General Hospital, Edinburgh; Rosemarie Davidson, South Glasgow University Hospitals, Glasgow; Julian Adlard, Chapel Allerton Hospital, Leeds, United Kingdom; Valentina Silvestri, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, and Laura Ottini, Sapienza University of Rome, Rome; Angela Toss, Veronica Medici, and Laura Cortesi, University of Modena and Reggio Emilia, Modena; Ines Zanna and Domenico Palli, Cancer Research and Prevention Institute, Florence; Paolo Radice, Siranoush Manoukian, Bernard Peissel, and Jacopo Azzollini, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Paolo Peterlongo, Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; Alessandra Viel and Giulia Cini, CRO Aviano, National Cancer Institute, Aviano; Giuseppe Damante, University of Udine, Udine; Stefania Tommasi, Istituto Nazionale Tumori "Giovanni Paolo II", Bari; Elisa Alducci, Silvia Tognazzo, and Marco Montagna, Veneto Institute of Oncology IOV - IRCCS, Padua; Maria A. Caligo, University and University Hospital of Pisa, Pisa, Italy; Penny Soucy and Jacques Simard, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec; Anna Marie Mulligan and Irene L. Andrulis, University of Toronto; Gord Glendon and Irene L. Andrulis, Mount Sinai Hospital, Toronto, Ontario, Canada; Melissa Southey, Ian Campbell, Paul James, and Gillian Mitchell, University of Melbourne, Parkville, Victoria; Amanda B. Spurdle, Helene Holland, and Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Ian Campbell, Paul James, and Gillian Mitchell, Peter MacCallum Cancer Centre, East Melbourne, New South Wales, Australia; Esther M. John, Cancer Prevention Institute of California, Fremont; Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, and Jeffrey N. Weitzel, City of Hope, Duarte, CA; Thomas A. Conner and Saundra S. Buys, Huntsman Cancer Institute; David E. Goldgar, University of Utah School of Medicine, Salt Lake City, UT; Andrew K. Godwin, University of Kansas Medical Center, Kansas City; Priyanka Sharma, University of Kansas Medical Center, Westwood, KS; Timothy R. Rebbeck, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, and Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; Jennifer T. Loud and Mark H. Greene, National Cancer Institute, Bethesda, MD; Amanda Ewart Toland and Leigha Senter, The Ohio State University, Columbus, OH; Dezheng Huo, Sarah M. Nielsen, and Olufunmilayo I. Olopade, University of Chicago Medical Center, Chicago, IL; Katherine L. Nathanson and Susan M. Domchek, University of Pennsylvania, Philadelphia; Christa Lorenchick and Rachel C. Jankowitz, University of Pittsburgh Medical Center, Pittsburgh, PA; Fergus J. Couch, Mayo Clinic, Rochester, MN; Ramunas Janavicius, State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Thomas V.O. Hansen, Rigshospitalet, Copenhagen University Hospital, Copenhagen; Anders Bojesen and Henriette Roed Nielsen, Vejle Hospital, Vejle; Anne-Bine Skytte, Lone Sunde, and Uffe Birk Jensen, Aarhus University Hospital, Aarhus; Inge Sokilde Pedersen, Aalborg University Hospital, Aalborg; Lotte Krogh, Torben A. Kruse, and Mads Thomassen, Odense University Hospital, Odense, Denmark; Ana Osorio, National Cancer Research Centre and Spanish Network on Rare Diseases; Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, and Pedro Perez Segura, Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid; Judith Balmaña, University Hospital, Vall d'Hebron; Sara Gutiérrez-Enríquez and Orland Diez, Vall d'Hebron Institute of Oncology; Orland Diez, University Hospital Vall d'Hebron; Alex Teulé, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, and Conxi Lazaro, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona; Angel Izquierdo, Esther Darder, and Joan Brunet, Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain; Florentia Fostira, National Centre for Scientific Research "Demokritos," Athens, Greece; Ute Hamann, German Cancer Research Center (DKFZ); Christian Sutter, University Hospital Heidelberg, Heidelberg; Alfons Meindl, Klinikumrechts der Isar, Technical University Munich; Nina Ditsch, Ludwig-Maximilian University, Munich; Andrea Gehrig, University Würzburg, Würzburg; Bernd Dworniczak, University of Münster, Münster; Christoph Engel, University of Leipzig; Dorothea Wand, University Hospital, Leipzig; Dieter Niederacher, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf; Doris Steinemann, Hannover Medical School, Hannover; Eric Hahnen, Jan Hauke, Kerstin Rhiem, Barbara Wappenschmidt, and Rita K. Schmutzler, University Hospital Cologne, Cologne; Karin Kast, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden; Norbert Arnold, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; Shan Wang-Gohrke, University Hospital Ulm, Ulm, Germany; Christine Lasset, Francesca Damiola, and Laure Barjhoux, Centre Léon Bérard; Sylvie Mazoyer, University of Lyon, Lyon; Dominique Stoppa-Lyonnet and Muriel Belotti, Institut Curie, Paris, France; Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, and Kathleen B.M. Claes, Ghent University, Gent, Belgium; Johanna I. Kiiski, Sofia Khan, and Heli Nevanlinna, University of Helsinki; Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, and Heli Nevanlinna, Helsinki University Hospital, Helsinki, Finland; Christi J. van Asperen, Leiden University Medical Center, Leiden, the Netherlands; Tibor Vaszko, Miklos Kasler, and Edith Olah, National Institute of Oncology, Budapest, Hungary; Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, and Rosa B. Barkardottir, Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland; Manuel R. Teixeira and Pedro Pinto, Portuguese Oncology Institute; Manuel R. Teixeira, Porto University, Porto, Portugal; Jong Won Lee, Ulsan College of Medicine and Asan Medical Center; Min Hyuk Lee and Jihyoun Lee, Soonchunhyang University and Hospital; Sung-Won Kim and Eunyoung Kang, Daerim St Mary's Hospital; Sue Kyung Park, Seoul National University College of Medicine, Seoul; Zisun Kim, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Yen Y. Tan, Andreas Berger, and Christian F. Singer, Medical University of Vienna, Vienna, Austria; Sook-Yee Yoon and Soo-Hwang Teo, Sime Darby Medical Centre, Subang Jaya, Malaysia; and Anna von Wachenfeldt, Karolinska University Hospital, Stockholm, Sweden.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
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http://dx.doi.org/10.1200/JCO.2016.69.4935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501359PMC
July 2017

Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.

J Natl Cancer Inst 2017 07;109(7)

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.

Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.

Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P =  8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P =  7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.

Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
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http://dx.doi.org/10.1093/jnci/djw302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408990PMC
July 2017

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet 2017 May 27;49(5):680-691. Epub 2017 Mar 27.

N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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http://dx.doi.org/10.1038/ng.3826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612337PMC
May 2017

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

PLoS One 2016 27;11(7):e0158801. Epub 2016 Jul 27.

Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963094PMC
July 2017

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Breast Cancer Res 2016 06 21;18(1):64. Epub 2016 Jun 21.

Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.

Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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http://dx.doi.org/10.1186/s13058-016-0718-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962376PMC
June 2016

Selecting instruments for Mendelian randomization in the wake of genome-wide association studies.

Int J Epidemiol 2016 10 24;45(5):1600-1616. Epub 2016 Jun 24.

Institute of Cardiovascular Science, University College London, London, UK.

Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.
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http://dx.doi.org/10.1093/ije/dyw088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100611PMC
October 2016

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

Nat Commun 2016 04 27;7:11375. Epub 2016 Apr 27.

Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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http://dx.doi.org/10.1038/ncomms11375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853421PMC
April 2016

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Nat Genet 2016 Apr 29;48(4):374-86. Epub 2016 Feb 29.

Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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http://dx.doi.org/10.1038/ng.3521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938803PMC
April 2016

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Gynecol Oncol 2016 05 2;141(2):386-401. Epub 2015 May 2.

Sheba Medical Center, Tel Aviv, Israel.

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.

Methods: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).

Results: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.

Conclusions: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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http://dx.doi.org/10.1016/j.ygyno.2015.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630206PMC
May 2016

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

Breast Cancer Res 2015 Apr 25;17:61. Epub 2015 Apr 25.

Holy Cross Hospital, Michael and Dianne Bienes Comprehensive Cancer Center, Fort Lauderdale, FL, USA.

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.

Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.

Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.

Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
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http://dx.doi.org/10.1186/s13058-015-0567-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478717PMC
April 2015

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Nat Genet 2015 Feb 12;47(2):164-71. Epub 2015 Jan 12.

Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/ng.3185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445140PMC
February 2015

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Cancer Epidemiol Biomarkers Prev 2015 Jan 21;24(1):308-16. Epub 2014 Oct 21.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-0532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294951PMC
January 2015

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

Lancet 2015 Jan 24;385(9965):351-61. Epub 2014 Sep 24.

National Institute for Public Health and the Environment, Bilthoven, Netherlands.

Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

Methods: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

Findings: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

Interpretation: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

Funding: The funding sources are cited at the end of the paper.
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http://dx.doi.org/10.1016/S0140-6736(14)61183-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322187PMC
January 2015

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

BMJ 2014 Jul 10;349:g4164. Epub 2014 Jul 10.

Unit of Cancer Epidemiology, San Giovanni Battista Hospital and Center for Cancer Prevention (CPO-Piemonte), 10129, Torino, Italy.

Objective: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

Design: Mendelian randomisation meta-analysis of 56 epidemiological studies.

Participants: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

Main Outcome Measures: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

Results: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

Conclusions: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091648PMC
http://dx.doi.org/10.1136/bmj.g4164DOI Listing
July 2014

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res 2014 Dec 31;16(6):3416. Epub 2014 Dec 31.

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.

Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.

Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.

Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
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http://dx.doi.org/10.1186/s13058-014-0492-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406179PMC
December 2014

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.

J Am Coll Cardiol 2013 Nov 31;62(21):1966-1976. Epub 2013 Jul 31.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.

Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.

Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.

Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.

Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.

Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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http://dx.doi.org/10.1016/j.jacc.2013.06.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826105PMC
November 2013

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

PLoS Genet 2013 27;9(3):e1003212. Epub 2013 Mar 27.

Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

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.
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http://dx.doi.org/10.1371/journal.pgen.1003212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609646PMC
June 2013

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

PLoS Genet 2013 27;9(3):e1003173. Epub 2013 Mar 27.

Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
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http://dx.doi.org/10.1371/journal.pgen.1003173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609647PMC
June 2013

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Nat Genet 2013 Apr;45(4):371-84, 384e1-2

Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
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http://dx.doi.org/10.1038/ng.2566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670748PMC
April 2013

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

Lancet 2012 Mar 14;379(9822):1214-24. Epub 2012 Mar 14.

Background: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.

Methods: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis.

Findings: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)).

Interpretation: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.

Funding: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)60110-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316968PMC
March 2012

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Cancer Epidemiol Biomarkers Prev 2012 Apr 20;21(4):645-57. Epub 2012 Feb 20.

Departments of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.

Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)).

Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.

Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1158/1055-9965.EPI-11-0888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319317PMC
April 2012

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.

Breast Cancer Res 2012 Feb 20;14(1):R33. Epub 2012 Feb 20.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK.

Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1186/bcr3121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496151PMC
February 2012

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Hum Mutat 2012 Apr 14;33(4):690-702. Epub 2012 Feb 14.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, California, USA.

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
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http://dx.doi.org/10.1002/humu.22025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458423PMC
April 2012

The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res Treat 2012 Apr 3;132(3):1119-26. Epub 2012 Jan 3.

The Susanne Levy Gertner Oncogenetics Unit 1, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.

Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1007/s10549-011-1938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352679PMC
April 2012
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