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J Natl Cancer Inst. 2015 Apr 18;107(5). pii: djv081. doi: 10.1093/jnci/djv081. Print 2015 May.

Identification of novel genetic markers of breast cancer survival.

Guo Q1, Schmidt MK1, Kraft P1, Canisius S1, Chen C1, Khan S1, Tyrer J1, Bolla MK1, Wang Q1, Dennis J1, Michailidou K1, Lush M1, Kar S1, Beesley J1, Dunning AM1, Shah M1, Czene K1, Darabi H1, Eriksson M1, Lambrechts D1, Weltens C1, Leunen K1, Bojesen SE1, Nordestgaard BG1, Nielsen SF1, Flyger H1, Chang-Claude J1, Rudolph A1, Seibold P1, Flesch-Janys D1, Blomqvist C1, Aittomäki K1, Fagerholm R1, Muranen TA1, Couch FJ1, Olson JE1, Vachon C1, Andrulis IL1, Knight JA1, Glendon G1, Mulligan AM1, Broeks A1, Hogervorst FB1, Haiman CA1, Henderson BE1, Schumacher F1, Le Marchand L1, Hopper JL1, Tsimiklis H1, Apicella C1, Southey MC1, Cox A1, Cross SS1, Reed MW1, Giles GG1, Milne RL1, McLean C1, Winqvist R1, Pylkäs K1, Jukkola-Vuorinen A1, Grip M1, Hooning MJ1, Hollestelle A1, Martens JW1, van den Ouweland AM1, Marme F1, Schneeweiss A1, Yang R1, Burwinkel B1, Figueroa J1, Chanock SJ1, Lissowska J1, Sawyer EJ1, Tomlinson I1, Kerin MJ1, Miller N1, Brenner H1, Dieffenbach AK1, Arndt V1, Holleczek B1, Mannermaa A1, Kataja V1, Kosma VM1, Hartikainen JM1, Li J1, Brand JS1, Humphreys K1, Devilee P1, Tollenaar RA1, Seynaeve C1, Radice P1, Peterlongo P1, Bonanni B1, Mariani P1, Fasching PA1, Beckmann MW1, Hein A1, Ekici AB1, Chenevix-Trench G1, Balleine R1; kConFab Investigators, Phillips KA1, Benitez J1, Zamora MP1, Arias Perez JI1, Menéndez P1, Jakubowska A1, Lubinski J1, Jaworska-Bieniek K1, Durda K1, Hamann U1, Kabisch M1, Ulmer HU1, Rüdiger T1, Margolin S1, Kristensen V1, Nord S1, Evans DG1, Abraham JE1, Earl HM1, Hiller L1, Dunn JA1, Bowden S1, Berg C1, Campa D1, Diver WR1, Gapstur SM1, Gaudet MM1, Hankinson SE1, Hoover RN1, Hüsing A1, Kaaks R1, Machiela MJ1, Willett W1, Barrdahl M1, Canzian F1, Chin SF1, Caldas C1, Hunter DJ1, Lindstrom S1, García-Closas M1, Hall P1, Easton DF1, Eccles DM1, Rahman N1, Nevanlinna H1, Pharoah PD1.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK (QG, JT, AMD, MS, JEA, DFE, PDPP); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, SC, AB, FBH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, SH, DJH, SL); Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, CCh, DJH, SL); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (SK, RF, TAM, HN); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (MKB, QW, JD, KM, ML, SK, DFE, PDPP); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (JBee, GCT); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden (KC, HD, ME, JiL, JBr, KH, PH); Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium (DL); Vesalius Research Center, VIB, Leuven, Belgium (DL); Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium (CW, KL); Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Denmark (HF); Division of Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany (JCC, AR, PS, DC, AHü, RK, MB); Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ); Department of Oncology

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.

PMID:
25890600
PMCID:
PMC4555642
DOI:
10.1093/jnci/djv081
[Indexed for MEDLINE]
Free PMC Article

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