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Title: Identification of novel genetic markers of breast cancer survival.
Authors: Guo Q,  Schmidt MK,  Kraft P,  Canisius S,  Chen C,  Khan S,  Tyrer J,  Bolla MK,  Wang Q,  Dennis J,  Michailidou K,  Lush M,  Kar S,  Beesley J,  Dunning AM,  Shah M,  Czene K,  Darabi H,  Eriksson M,  Lambrechts D,  Weltens C,  Leunen K,  Bojesen SE,  Nordestgaard BG,  Nielsen SF,  Flyger H,  Chang-Claude J,  Rudolph A,  Seibold P,  Flesch-Janys D,  Blomqvist C,  Aittomäki K,  Fagerholm R,  Muranen TA,  Couch FJ,  Olson JE,  Vachon C,  Andrulis IL,  Knight JA,  Glendon G,  Mulligan AM,  Broeks A,  Hogervorst FB,  Haiman CA,  Henderson BE,  Schumacher F,  Le Marchand L,  Hopper JL,  Tsimiklis H,  Apicella C,  Southey MC,  Cox A,  Cross SS,  Reed MW,  Giles GG,  Milne RL,  McLean C,  Winqvist R,  Pylkäs K,  Jukkola-Vuorinen A,  Grip M,  Hooning MJ,  Hollestelle A,  Martens JW,  van den Ouweland AM,  Marme F,  Schneeweiss A,  Yang R,  Burwinkel B,  Figueroa J,  Chanock SJ,  Lissowska J,  Sawyer EJ,  Tomlinson I,  Kerin MJ,  Miller N,  Brenner H,  Dieffenbach AK,  Arndt V,  Holleczek B,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Li J,  Brand JS,  Humphreys K,  Devilee P,  Tollenaar RA,  Seynaeve C,  Radice P,  Peterlongo P,  Bonanni B,  Mariani P,  Fasching PA,  Beckmann MW,  Hein A,  Ekici AB,  Chenevix-Trench G,  Balleine R,  kConFab Investigators,  Phillips KA,  Benitez J,  Zamora MP,  Arias Perez JI,  Menéndez P,  Jakubowska A,  Lubinski J,  Jaworska-Bieniek K,  Durda K,  Hamann U,  Kabisch M,  Ulmer HU,  Rüdiger T,  Margolin S,  Kristensen V,  Nord S,  Evans DG,  Abraham JE,  Earl HM,  Hiller L,  Dunn JA,  Bowden S,  Berg C,  Campa D,  Diver WR,  Gapstur SM,  Gaudet MM,  Hankinson SE,  Hoover RN,  Hüsing A,  Kaaks R,  Machiela MJ,  Willett W,  Barrdahl M,  Canzian F,  Chin SF,  Caldas C,  Hunter DJ,  Lindstrom S,  García-Closas M,  Hall P,  Easton DF,  Eccles DM,  Rahman N,  Nevanlinna H,  Pharoah PD
Journal: J Natl Cancer Inst
Date: 2015 May
Branches: EBP, MEB, LGS, OD, OEEB
PubMed ID: 25890600
PMC ID: PMC4555642
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.