Identification of Novel Genetic Markers of Breast Cancer Survival

Qi Guo(Harvard University), Marjanka K. Schmidt(University of Copenhagen), Peter Kraft(Harvard University), Sander Canisius(University of Copenhagen), Constance Chen(Harvard University), Sofia Khan(University of Helsinki), Jonathan P. Tyrer(Harvard University), Manjeet K. Bolla(Harvard University), Qin Wang(Harvard University), Joe Dennis(Harvard University), Kyriaki Michailidou(Harvard University), Michael Lush(Harvard University), Siddhartha Kar(Harvard University), Jonathan Beesley(Harvard University), Alison M. Dunning(Harvard University), Mitul Shah(Harvard University), Kamila Czene(Harvard University), Hatef Darabi(Harvard University), Mikael Eriksson(Harvard University), Diether Lambrechts(Harvard University), Caroline Weltens(Harvard University), Karin Leunen(Harvard University), Stig E. Bojesen(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), Sune F. Nielsen(University of Copenhagen), Henrik Flyger(University of Copenhagen), Jenny Chang‐Claude(Harvard University), Anja Rudolph(Harvard University), Petra Seibold(Harvard University), Dieter Flesch‐Janys(Harvard University), Carl Blomqvist(University of Helsinki), Kristiina Aittomäki(University of Helsinki), Rainer Fagerholm(University of Helsinki), Taru Muranen(University of Helsinki), Fergus J. Couch(Mayo Clinic), Janet E. Olson(Mayo Clinic), Celine M. Vachon(Mayo Clinic), Irene L. Andrulis(Harvard University), Julia A. Knight(Harvard University), Gord Glendon(Harvard University), Anna Marie Mulligan(University Health Network), Annegien Broeks(University of Copenhagen), Frans B.L. Hogervorst(University of Copenhagen), 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 Copenhagen), John L. Hopper(Harvard University), Helen Tsimiklis(Harvard University), Carmel Apicella(Harvard University), Melissa C. Southey(Harvard University), Angela Cox(Harvard University), Simon S. Cross(Harvard University), Malcolm Reed(Harvard University), Graham G. Giles(Harvard University), Roger L. Milne(Harvard University), Catriona McLean(University of Copenhagen), Robert Winqvist(Harvard University), Katri Pylkäs(University of Copenhagen), Arja Jukkola‐Vuorinen(Harvard University), Mervi Grip(Harvard University), Maartje J. Hooning(Harvard University), Antoinette Hollestelle(Harvard University), John W.M. Martens(Harvard University), Ans M.W. van den Ouweland(Harvard University), F. Marmé(Harvard University), Andreas Schneeweiß(Harvard University), Rongxi Yang(Harvard University), Barbara Burwinkel(Harvard University), Jonine D. Figueroa(National Institutes of Health), Stephen J. Chanock(Leidos (United States)), Jolanta Lissowska(Harvard University), Elinor J. Sawyer(Harvard University), Ian Tomlinson(Harvard University), Michael J. Kerin(University of Copenhagen), Nicola Miller(University of Copenhagen), Hermann Brenner(Harvard University), Aida Karina Dieffenbach(Harvard University), Volker Arndt(Harvard University), Bernd Holleczek(University of Copenhagen), Arto Mannermaa(Harvard University), Vesa Kataja(Harvard University), Veli‐Matti Kosma(Harvard University), Jaana M. Hartikainen(Harvard University), Jingmei Li(Harvard University), Judith S. Brand(Harvard University), Keith Humphreys(Harvard University), Peter Devilee(Harvard University), Rob A.�E.�M. Tollenaar(Leiden University), Caroline Seynaeve(Leiden University), Paolo Radice(Harvard University), Paolo Peterlongo(University of Copenhagen), Bernardo Bonanni(University of Copenhagen), P. Mariani(University of Copenhagen), Peter A. Fasching(Harvard University), Matthias W. Beckmann(Harvard University), Alexander Hein(Harvard University), Arif B. Ekici(Harvard University), Georgia Chenevix‐Trench(Harvard University), Rosemary L. Balleine(Harvard University), Kelly‐Anne Phillips(Harvard University), Javier Benı́tez(University of Copenhagen), M. Pilar Zamora(University of Copenhagen), José Ignacio Arias Pérez(Universidad Complutense de Madrid), Primitiva Menéndez(University of Copenhagen), Anna Jakubowska(University of Copenhagen), Jan Lubiński(University of Copenhagen), Katarzyna Jaworska–Bieniek(University of Copenhagen), Katarzyna Durda(University of Copenhagen), Ute Hamann(Harvard University), Maria Kabisch(Harvard University), Hans Ulrich Ulmer(Harvard University), Thomas Rüdiger(University of Copenhagen), Sara Margolin(University of Copenhagen), Vessela N. Kristensen(Harvard University), Silje Nord(Harvard University), D. Gareth Evans(Harvard University), Jean Abraham(Harvard University), Helena Earl(Harvard University), Louise Hiller(University of Copenhagen), Janet Dunn(University of Copenhagen), S. Bowden(Harvard University), Christine D. Berg(Harvard University), Daniele Campa(National Institutes of Health), W. Ryan Diver(University of Pisa), Susan M. Gapstur(University of Pisa), Mia M. Gaudet(University of Pisa), Susan E. Hankinson(American Cancer Society), Robert N. Hoover(Harvard University), Anika Hüsing(Harvard University), Rudolf Kaaks(Harvard University), Mitchell J. Machiela(Harvard University), Walter C. Willett(National Institutes of Health), Myrto Barrdahl(Harvard University), Federico Canzian(Harvard University), Suet‐Feung Chin(Harvard University), Carlos Caldas(Harvard University), David J. Hunter(Harvard University), Sara Lindström(Harvard University), Montserrat García‐Closas(Harvard University), Per Hall(Harvard University), Douglas F. Easton(Harvard University), Diana M. Eccles(Harvard University), Nazneen Rahman(Harvard University), Heli Nevanlinna(University of Helsinki), Paul D.P. Pharoah(Harvard University)
JNCI Journal of the National Cancer Institute
April 18, 2015
10.1093/jnci/djv081
Cited by 244Open Access
Full Text

Abstract

BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

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