Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics

Montserrat García‐Closas(National Cancer Institute), Per Hall(Karolinska Institutet), Heli Nevanlinna(Helsinki University Hospital), Karen A. Pooley(University of Cambridge), Jonathan J. Morrison(University of Cambridge), Douglas Richesson(National Cancer Institute), Stig E. Bojesen(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), C. K. Axelsson(University of Copenhagen), José Ignacio Arias(Spanish National Cancer Research Centre), Roger L. Milne(Spanish National Cancer Research Centre), Gloría Ribas(Spanish National Cancer Research Centre), Anna González‐Neira(Spanish National Cancer Research Centre), Javier Benı́tez(Spanish National Cancer Research Centre), Pilar Zamora(Hospital Universitario La Paz), Hiltrud Brauch(Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology), Christina Justenhoven(Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology), Ute Hamann(German Cancer Research Center), Yon‐Dschun Ko(Johanniter-Krankenhaus Bonn), Thomas Bruening(Ruhr University Bochum), Susanne Haas, Thilo Dörk(Medizinische Hochschule Hannover), Peter Schürmann(Medizinische Hochschule Hannover), Peter Hillemanns(Medizinische Hochschule Hannover), Natalia Bogdanova(Medizinische Hochschule Hannover), Michael Bremer(Medizinische Hochschule Hannover), Johann H. Karstens(Medizinische Hochschule Hannover), Rainer Fagerholm(Helsinki University Hospital), Kirsimari Aaltonen(Helsinki University Hospital), Kristiina Aittomäki(Helsinki University Hospital), Karl von Smitten(Helsinki University Hospital), Carl Blomqvist(Helsinki University Hospital), Arto Mannermaa(Kuopio University Hospital), Matti Uusitupa, Matti Eskelinen(Kuopio University Hospital), Maria Tengström(Kuopio University Hospital), Veli‐Matti Kosma(Kuopio University Hospital), Vesa Kataja(Kuopio University Hospital), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), Jonathan Beesley(QIMR Berghofer Medical Research Institute), Xiaoqing Chen(QIMR Berghofer Medical Research Institute), Australian Ovarian Cancer Management Group(QIMR Berghofer Medical Research Institute), Peter Devilee(Leiden University Medical Center), Christi J. van Asperen(Leiden University Medical Center), Catharina E. Jacobi(Leiden University Medical Center), Rob A.�E.�M. Tollenaar(Leiden University Medical Center), Petra E.A. Huijts(Erasmus MC Cancer Institute), Jan G.M. Klijn(German Cancer Research Center), Jenny Chang‐Claude(German Cancer Research Center), Silke Kropp(German Cancer Research Center), Tracy Slanger(Universität Hamburg), Dieter Flesch‐Janys(Universität Hamburg), Elke Mutschelknauss(Universität Hamburg), Ramona Salazar(Universität Ulm), Shan Wang‐Gohrke(Mayo Clinic), Fergus J. Couch(Mayo Clinic), Ellen L. Goode(Mayo Clinic), Janet E. Olson(Mayo Clinic), Celine M. Vachon(Mayo Clinic), Zachary S. Fredericksen(Mayo Clinic), Graham G. Giles(Cancer Council Victoria), Laura Baglietto(Cancer Council Victoria), Gianluca Severi(The University of Melbourne), John L. Hopper(The University of Melbourne), Dallas R. English(The University of Melbourne), Melissa C. Southey(University of Southern California), Christopher A. Haiman(University of Southern California), Brian E. Henderson(University of Southern California), Laurence N. Kolonel(University of Hawaiʻi at Mānoa), Loı̈c Le Marchand(University of Southern California), Daniel O. Stram(University of Southern California), David J. Hunter(Brigham and Women's Hospital), Susan E. Hankinson(Brigham and Women's Hospital), David G. Cox(Brigham and Women's Hospital), Rulla M. Tamimi(Brigham and Women's Hospital), Peter Kraft(Harvard University), Mark E. Sherman(National Cancer Institute), Stephen J. Chanock(National Cancer Institute), Jolanta Lissowska(National Cancer Institute), Louise A. Brinton(Nofer Institute of Occupational Medicine), Beata Pepłońska(Nofer Institute of Occupational Medicine), Jan G.M. Klijn(Erasmus MC Cancer Institute), Maartje J. Hooning(Erasmus MC), Han Meijers-Heijboer(Erasmus MC), J. Margriet Collée(Erasmus MC), Ans van den Ouweland(Erasmus MC), André G. Uitterlinden(Erasmus MC), Jianjun Liu(Genome Institute of Singapore), Low Yen Lin(Genome Institute of Singapore), Yuqing Li(Karolinska Institutet), Keith Humphreys(Karolinska Institutet), Kamila Czene(Karolinska Institutet), Angela Cox(University of Sheffield), Sabapathy P. Balasubramanian(University of Sheffield), Simon S. Cross(University of Sheffield), Malcolm Reed(University of Cambridge), Fiona M. Blows(University of Cambridge), Kristy Driver(University of Cambridge), Alison M. Dunning(University of Cambridge), Jonathan P. Tyrer(University of Cambridge), Bruce A.J. Ponder(Cancer Research UK Cambridge Center), Suleeporn Sangrajrang(National Cancer Institute of Thailand), Paul Brennan(Centre international de recherche sur le cancer), James McKay(Centre international de recherche sur le cancer), Fabrice Odefrey(Centre international de recherche sur le cancer), Valerie Gabrieau(National Cancer Institute), Alice J. Sigurdson(National Cancer Institute), Michele M. Doody(National Human Genome Research Institute), Jeffery P. Struewing(University of Minnesota), Bruce H. Alexander(University of Minnesota), Douglas F. Easton(University of Cambridge), Paul D. Pharoah(University of Cambridge)
PLoS Genetics
April 25, 2008
10.1371/journal.pgen.1000054
Cited by 395Open Access
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Abstract

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

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