乳腺癌生存新遗传标志物的鉴定。
Identification of novel genetic markers of breast cancer survival.
作者信息
Guo Qi, Schmidt Marjanka K, Kraft Peter, Canisius Sander, Chen Constance, Khan Sofia, Tyrer Jonathan, Bolla Manjeet K, Wang Qin, Dennis Joe, Michailidou Kyriaki, Lush Michael, Kar Siddhartha, Beesley Jonathan, Dunning Alison M, Shah Mitul, Czene Kamila, Darabi Hatef, Eriksson Mikael, Lambrechts Diether, Weltens Caroline, Leunen Karin, Bojesen Stig E, Nordestgaard Børge G, Nielsen Sune F, Flyger Henrik, Chang-Claude Jenny, Rudolph Anja, Seibold Petra, Flesch-Janys Dieter, Blomqvist Carl, Aittomäki Kristiina, Fagerholm Rainer, Muranen Taru A, Couch Fergus J, Olson Janet E, Vachon Celine, Andrulis Irene L, Knight Julia A, Glendon Gord, Mulligan Anna Marie, Broeks Annegien, Hogervorst Frans B, Haiman Christopher A, Henderson Brian E, Schumacher Fredrick, Le Marchand Loic, Hopper John L, Tsimiklis Helen, Apicella Carmel, Southey Melissa C, Cox Angela, Cross Simon S, Reed Malcolm W R, Giles Graham G, Milne Roger L, McLean Catriona, Winqvist Robert, Pylkäs Katri, Jukkola-Vuorinen Arja, Grip Mervi, Hooning Maartje J, Hollestelle Antoinette, Martens John W M, van den Ouweland Ans M W, Marme Federik, Schneeweiss Andreas, Yang Rongxi, Burwinkel Barbara, Figueroa Jonine, Chanock Stephen J, Lissowska Jolanta, Sawyer Elinor J, Tomlinson Ian, Kerin Michael J, Miller Nicola, Brenner Hermann, Dieffenbach Aida Karina, Arndt Volker, Holleczek Bernd, Mannermaa Arto, Kataja Vesa, Kosma Veli-Matti, Hartikainen Jaana M, Li Jingmei, Brand Judith S, Humphreys Keith, Devilee Peter, Tollenaar Rob A E M, Seynaeve Caroline, Radice Paolo, Peterlongo Paolo, Bonanni Bernardo, Mariani Paolo, Fasching Peter A, Beckmann Matthias W, Hein Alexander, Ekici Arif B, Chenevix-Trench Georgia, Balleine Rosemary, Phillips Kelly-Anne, Benitez Javier, Zamora M Pilar, Arias Perez Jose Ignacio, Menéndez Primitiva, Jakubowska Anna, Lubinski Jan, Jaworska-Bieniek Katarzyna, Durda Katarzyna, Hamann Ute, Kabisch Maria, Ulmer Hans Ulrich, Rüdiger Thomas, Margolin Sara, Kristensen Vessela, Nord Silje, Evans D Gareth, Abraham Jean E, Earl Helena M, Hiller Louise, Dunn Janet A, Bowden Sarah, Berg Christine, Campa Daniele, Diver W Ryan, Gapstur Susan M, Gaudet Mia M, Hankinson Susan E, Hoover Robert N, Hüsing Anika, Kaaks Rudolf, Machiela Mitchell J, Willett Walter, Barrdahl Myrto, Canzian Federico, Chin Suet-Feung, Caldas Carlos, Hunter David J, Lindstrom Sara, García-Closas Montserrat, Hall Per, Easton Douglas F, Eccles Diana M, Rahman Nazneen, Nevanlinna Heli, Pharoah Paul D P
机构信息
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
出版信息
J Natl Cancer Inst. 2015 Apr 18;107(5). doi: 10.1093/jnci/djv081. Print 2015 May.
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.
背景
乳腺癌诊断后的患者生存率差异很大，其中一些差异可能是由于种系基因变异。我们旨在确定与乳腺癌特异性生存相关的基因标记。
方法
我们对欧洲血统人群的研究进行了一项大型荟萃分析，包括37954例乳腺癌患者，其中2900例死于乳腺癌。每项研究对全基因组200000至900000个单核苷酸多态性（SNP）进行了基因分型；使用来自千人基因组计划的通用参考面板对900万个常见变异的基因型进行了推算。我们还基于6881例雌激素受体（ER）阴性患者（920例事件）和23059例ER阳性患者（1333例事件）进行了亚型特异性分析。所有统计检验均为双侧检验。
结果
我们在ER阴性乳腺癌病例中鉴定出一个与生存相关的新位点（11q24.2处的rs2059614）（风险比[HR]=1.95，95%置信区间[CI]=1.55至2.47，P=1.91×10-8）。对2113例病例患者的一个子集进行基因分型，其中300例为ER阴性，为推算质量提供了支持证据。在这组病例患者中，观察到的基因型之间的关联比推算的基因型更强。在初步分析中，第二个位点（2q24.2处的rs148760487）在全基因组统计学意义上相关；在ER阳性和ER阴性病例患者中，这种关联相似。此处基因分型结果表明该发现不太可靠。
结论
这是目前调查与乳腺癌生存相关基因变异的最大规模研究。我们的结果具有潜在的临床意义，因为它们证实种系基因型除了标准的肿瘤预后因素外，还可以提供预后信息。
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