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

posted on 25.04.2008, 00:09 by Montserrat Garcia-Closas, Per Hall, Heli Nevanlinna, Karen Pooley, Jonathan Morrison, Douglas A. Richesson, Stig E. Bojesen, Børge G. Nordestgaard, Christen K. Axelsson, Jose I. Arias, Roger L. Milne, Gloria Ribas, Anna González-Neira, Javier Benítez, Pilar Zamora, Hiltrud Brauch, Christina Justenhoven, Ute Hamann, Yon-Dschun Ko, Thomas Bruening, Susanne Haas, Thilo Dörk, Peter Schürmann, Peter Hillemanns, Natalia Bogdanova, Michael Bremer, Johann Hinrich Karstens, Rainer Fagerholm, Kirsimari Aaltonen, Kristiina Aittomäki, Karl von Smitten, Carl Blomqvist, Arto Mannermaa, Matti Uusitupa, Matti Eskelinen, Maria Tengström, Veli-Matti Kosma, Vesa Kataja, Georgia Chenevix-Trench, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Australian Ovarian Cancer Management Group, The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Peter Devilee, Christi J. van Asperen, Catharina E. Jacobi, Rob A. E. M. Tollenaar, Petra E.A. Huijts, Jan G. M. Klijn, Jenny Chang-Claude, Silke Kropp, Tracy Slanger, Dieter Flesch-Janys, Elke Mutschelknauss, Ramona Salazar, Shan Wang-Gohrke, Fergus Couch, Ellen L. Goode, Janet E. Olson, Celine Vachon, Zachary S. Fredericksen, Graham G. Giles, Laura Baglietto, Gianluca Severi, John L. Hopper, Dallas R. English, Melissa C. Southey, Christopher A. Haiman, Brian E. Henderson, Laurence N. Kolonel, Loic Le Marchand, Daniel O. Stram, David J. Hunter, Susan E. Hankinson, David G. Cox, Rulla Tamimi, Peter Kraft, Mark E. Sherman, Stephen J. Chanock, Jolanta Lissowska, Louise A. Brinton, Beata Peplonska, Maartje J. Hooning, Han Meijers-Heijboer, J. Margriet Collee, Ans van den Ouweland, Andre G. Uitterlinden, Jianjun Liu, Low Yen Lin, Li Yuqing, Keith Humphreys, Kamila Czene, Angela Cox, Sabapathy P. Balasubramanian, Simon S. Cross, Malcolm W. R. Reed, Fiona Blows, Kristy Driver, Alison Dunning, Jonathan Tyrer, Bruce A. J. Ponder, Suleeporn Sangrajrang, Paul Brennan, James McKay, Fabrice Odefrey, Valerie Gabrieau, Alice Sigurdson, Michele Doody, Jeffrey P. Struewing, Bruce Alexander, Douglas F. Easton, Paul D. Pharoah

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.