Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk
Wei‐Yu Lin(Chang Gung Memorial Hospital), Nicola J. Camp(University of Utah), Maya Ghoussaini, Jonathan Beesley, Kyriaki Michailidou, John L. Hopper, Carmel Apicella, Melissa C. Southey, Jennifer Stone, Marjanka K. Schmidt(The Netherlands Cancer Institute), Annegien Broeks(The Netherlands Cancer Institute), Laura J. van’t Veer(The Netherlands Cancer Institute), Emiel J. Rutgers(The Netherlands Cancer Institute), Kenneth Muir(University of Manchester), Artitaya Lophatananon(University of Warwick), Sarah Stewart‐Brown(University of Warwick), Pornthep Siriwanarangsan(Ministry of Public Health), Peter A. Fasching(University of California, Los Angeles), Lothar Haeberle(Breast Center), Arif B. Ekici(Friedrich-Alexander-Universität Erlangen-Nürnberg), Matthias W. Beckmann(Breast Center), Julian Peto(London School of Hygiene & Tropical Medicine), Isabel dos‐Santos‐Silva(London School of Hygiene & Tropical Medicine), Olivia Fletcher(Breast Cancer Research Foundation), Nichola Johnson(Breast Cancer Research Foundation), Manjeet K. Bolla, Qin Wang, Joe Dennis, Elinor J. Sawyer(Guy's Hospital), Timothy Cheng(Centre for Human Genetics), Ian Tomlinson(Centre for Human Genetics), Michael J. Kerin(Ollscoil na Gaillimhe – University of Galway), Nicola Miller(Ollscoil na Gaillimhe – University of Galway), Frederik Marmé(Heidelberg University), Harald Surowy, Barbara Burwinkel, Pascal Guénel(Université Paris-Sud), Thérèse Truong(Université Paris-Sud), F. Ménégaux(Université Paris-Sud), Claire Mulot(Inserm), Stig E. Bojesen(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), Sune F. Nielsen(Herlev Hospital), Henrik Flyger(Herlev Hospital), Javier Benı́tez(Centre for Biomedical Network Research on Rare Diseases), M. Pilar Zamora(Hospital Universitario La Paz), José Ignacio Arias Pérez(Hospital de Especialidades), Primitiva Menéndez(Hospital Monte Naranco), Anna González‐Neira(Spanish National Cancer Research Centre), Guillermo Pita(Spanish National Cancer Research Centre), M. Rosario Alonso(Spanish National Cancer Research Centre), Núria Álvarez(Spanish National Cancer Research Centre), Daniel Herrero(Spanish National Cancer Research Centre), Hoda Anton‐Culver(University of California, Irvine), Hermann Brenner(German Cancer Research Center), Aida Karina Dieffenbach(German Cancer Research Center), Volker Arndt(Institute of Aging), Christa Stegmaier(Krebsregister Saarland), Alfons Meindl, Peter Lichtner(Technical University of Munich), Rita K. Schmutzler(University of Cologne), Bertram Müller‐Myhsok(Max Planck Institute of Psychiatry), Hiltrud Brauch(Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology), Thomas Brüning(Institute for Prevention and Occupational Medicine), Yon‐Dschun Ko(Johanniter-Krankenhaus Bonn), The GENICA Network(McGill University and Génome Québec Innovation Centre), Daniel C. Tessier(McGill University and Génome Québec Innovation Centre), Daniel Vincent(McGill University and Génome Québec Innovation Centre), François Bacot(Helsinki University Hospital), Heli Nevanlinna(Helsinki University Hospital), Kristiina Aittomäki(University of Helsinki), Carl Blomqvist(University of Helsinki), Sofia Khan(Kyushu University), Keitaro Matsuo(Kyushu University), Hidemi Ito(Aichi Cancer Center), Hiroji Iwata(Aichi Cancer Center), Akiyo Horio(Medizinische Hochschule Hannover), Natalia Bogdanova(Medizinische Hochschule Hannover), Natalia Antonenkova(N.N. Alexandrov National Cancer Centre), Thilo Dörk, Annika Lindblom, Sara Margolin(University of Eastern Finland), Arto Mannermaa(University of Eastern Finland), Vesa Kataja(University of Eastern Finland), Veli‐Matti Kosma(University of Eastern Finland), Jaana M. Hartikainen(University of Southern California), kConFab Investigators(University of Southern California), Australian Ovarian Cancer Study Group(University of Southern California), Anna H. Wu(University of Southern California), Chiu-Chen Tseng(University of Southern California), David Van Den Berg(University of Southern California), Daniel O. Stram(University of Southern California), Patrick Neven(Universitair Ziekenhuis Leuven), Els Wauters, Hans Wildiers(KU Leuven), Diether Lambrechts(Translational Research in Oncology), Jenny Chang‐Claude(Universität Hamburg), Anja Rudolph, Petra Seibold(IFOM), Dieter Flesch‐Janys(Universität Hamburg), Paolo Radice(European Institute of Oncology), Paolo Peterlongo(IFOM), Siranoush Manoukian(Fondazione IRCCS Istituto Nazionale dei Tumori), Bernardo Bonanni(Mayo Clinic in Florida), Fergus J. Couch(The Barbara Ann Karmanos Cancer Institute), Xianshu Wang(Cancer Council Victoria), Celine M. Vachon(Cancer Council Victoria), Kristen S. Purrington(The Alfred Hospital), Graham G. Giles(University of Southern California), Roger L. Milne(University of Southern California), Catriona McLean(University of Southern California), Christopher A. Haiman(University of Southern California), Brian E. Henderson(University of Southern California), Fredrick R. Schumacher(University of Southern California), Loı̈c Le Marchand(University of Hawaiʻi at Mānoa), Jacques Simard(Centre hospitalier universitaire de Québec), Mark S. Goldberg(University Malaya Medical Centre), France Labrèche(University Malaya Medical Centre), Martine Dumont(University Malaya Medical Centre), Soo‐Hwang Teo(University Malaya Medical Centre), Cheng Har Yip(Oslo University Hospital), Norhashimah Hassan(University Malaya Medical Centre), Eranga N. Vithana(National University of Singapore), Vessela N. Kristensen(Oslo University Hospital), Wei Zheng(Vanderbilt University), Sandra Deming-Halverson(Vanderbilt University), Martha J. Shrubsole(Vanderbilt University), Jirong Long(Vanderbilt University), Robert Winqvist(Oulu University Hospital), Katri Pylkäs(NordLab), Arja Jukkola‐Vuorinen(3M (United States)), Saila Kauppila(Oulu University Hospital), Irene L. Andrulis(Lunenfeld-Tanenbaum Research Institute), Julia A. Knight(3M (United States)), Gord Glendon(Cancer Genetics (United States)), Sandrine Tchatchou(Lunenfeld-Tanenbaum Research Institute), Peter Devilee(Leiden University Medical Center), Robert A.E.M. Tollenaar(Breast Cancer Research Foundation), Caroline Seynaeve(National Cancer Institute), Christi J. van Asperen(Leiden University Medical Center), Montserrat García‐Closas(Breast Cancer Research Foundation), Jonine D. Figueroa(Karolinska Institutet), Jolanta Lissowska(Karolinska Institutet), Louise A. Brinton(Karolinska Institutet), Kamila Czene(Karolinska Institutet), Hatef Darabi(Karolinska Institutet), Mikael Eriksson(Karolinska Institutet), Judith S. Brand(Erasmus MC), Maartje J. Hooning(Erasmus MC Cancer Institute), Antoinette Hollestelle(Erasmus MC Cancer Institute), Ans M.W. van den Ouweland(Erasmus MC), Agnes Jager(Karolinska Institutet), Jingmei Li(Vanderbilt University), Jianjun Liu(Shanghai Municipal Center For Disease Control Prevention), Keith Humphreys(Karolinska Institutet), Xiao‐Ou Shu(Vanderbilt University), Wei Lu(Royal Hallamshire Hospital), Yu‐Tang Gao(Shanghai Cancer Institute), Hui Cai(Vanderbilt University), Simon S. Cross(Vanderbilt University), Malcolm Reed(Vanderbilt University), William J. Blot(Vanderbilt University), Lisa B. Signorello(Vanderbilt University), Qiuyin Cai(Vanderbilt University), Paul D.P. Pharoah(University of Cambridge), Barbara Perkins(Seoul National University), Mitul Shah(Seoul National University), Fiona M. Blows(University of Cambridge), Daehee Kang(Seoul National University), Keun-Young Yoo(Seoul National University), Dong‐Young Noh(National University Health System), Mikael Hartman(Yong In University), Hui Miao(Cancer Genetics (United States)), Kee Seng Chia(University of Cambridge), Thomas Choudary Putti(National University of Singapore), Ute Hamann(University of Cambridge), Craig Luccarini(University of Cambridge), Caroline Baynes(University of Cambridge), Shahana Ahmed(University of Cambridge), Mel Maranian(University of Cambridge), Catherine S. Healey(University of Cambridge), Anna Jakubowska(Pomeranian Medical University), Jan Lubiński(National Cancer Institute of Thailand), Katarzyna Jaworska–Bieniek(Centre international de recherche sur le cancer), Katarzyna Durda(Centre international de recherche sur le cancer), Suleeporn Sangrajrang(National Cancer Institute of Thailand), Valérie Gaborieau(Mayo Clinic in Florida), Paul Brennan(Centre international de recherche sur le cancer), James McKay(National Centre of Scientific Research "Demokritos"), Susan Slager(China Medical University), Amanda E. Toland(Institute of Biomedical Science), Drakoulis Yannoukakos(National Centre of Scientific Research "Demokritos"), Chen‐Yang Shen(China Medical University), Chia‐Ni Hsiung(Breast Cancer Research Foundation), Pei‐Ei Wu(Institute of Biomedical Sciences, Academia Sinica), Shian-ling Ding(Institute of Cancer Research), Alan Ashworth(Institute of Cancer Research), Michael E. Jones(Institute of Cytology and Genetics), Nick Orr(Institute of Cancer Research), Anthony J. Swerdlow(Institute of Cancer Research), Helen Tsimiklis(The University of Melbourne), Enes Makalic(The University of Melbourne), Daniel F. Schmidt(Harvard University), Minh Bui(The University of Melbourne), Stephen J. Chanock(Johannes Gutenberg University Mainz), David J. Hunter(Harvard University), Rebecca Hein(German Cancer Research Center), Norbert Dahmen(Johannes Gutenberg University Mainz), Lars Beckmann(Helsinki University Hospital), Kirsimari Aaltonen(Helsinki University Hospital), Taru Muranen(Helsinki University Hospital), Tuomas Heikkinen(Helsinki University Hospital), Astrid Irwanto(Genome Institute of Singapore), Nazneen Rahman(Institute of Cytology and Genetics), Clare Turnbull(Institute of Cytology and Genetics), The Breast and Ovarian Cancer Susceptibility (BOCS) Study(University Medical Center Utrecht), Quinten Waisfisz(Karolinska Institutet), Hanne Meijers‐Heijboer(Amsterdam UMC Location Vrije Universiteit Amsterdam), Muriel A. Adank(University of Cambridge), Rob B. van der Luijt(University of Cambridge), Per Hall(Karolinska Institutet), Georgia Chenevix‐Trench, Alison M. Dunning(University of Cambridge), Douglas F. Easton(University of Cambridge), Angela Cox(University of Sheffield)
Cited by 45Open Access
Abstract
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
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