Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics
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Author
Garcia-Closas, Montserrat
Hall, Per
Nevanlinna, Heli
Pooley, Karen
Morrison, Jonathan
Richesson, Douglas A.
Bojesen, Stig E.
Nordestgaard, Børge G.
Axelsson, Christen K.
Arias, Jose I.
Milne, Roger L.
Ribas, Gloria
González-Neira, Anna
Benítez, Javier
Zamora, Pilar
Brauch, Hiltrud
Justenhoven, Christina
Hamann, Ute
Ko, Yon-Dschun
Bruening, Thomas
Haas, Susanne
Dörk, Thilo
Schürmann, Peter
Hillemanns, Peter
Bogdanova, Natalia
Bremer, Michael
Karstens, Johann Hinrich
Fagerholm, Rainer
Aaltonen, Kirsimari
Aittomäki, Kristiina
von Smitten, Karl
Blomqvist, Carl
Mannermaa, Arto
Uusitupa, Matti
Eskelinen, Matti
Tengström, Maria
Kosma, Veli-Matti
Kataja, Vesa
Chenevix-Trench, Georgia
Spurdle, Amanda B.
Beesley, Jonathan
Chen, Xiaoqing
Australian Ovarian Cancer Management Group
Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Devilee, Peter
van Asperen, Christi J.
Jacobi, Catharina E.
Tollenaar, Rob A. E. M.
Huijts, Petra E. A.
Klijn, Jan G. M.
Chang-Claude, Jenny
Kropp, Silke
Slanger, Tracy
Flesch-Janys, Dieter
Mutschelknauss, Elke
Salazar, Ramona
Wang-Gohrke, Shan
Couch, Fergus
Goode, Ellen L.
Olson, Janet E.
Vachon, Celine
Fredericksen, Zachary S.
Giles, Graham G.
Baglietto, Laura
Severi, Gianluca
Hopper, John L.
English, Dallas R.
Southey, Melissa C.
Haiman, Christopher A.
Henderson, Brian E.
Kolonel, Laurence N.
Le Marchand, Loic
Stram, Daniel O.
Hunter, David J.
Hankinson, Susan E.
Cox, David G.
Tamimi, Rulla
Kraft, Peter
Sherman, Mark E.
Chanock, Stephen J.
Lissowska, Jolanta
Brinton, Louise A.
Peplonska, Beata
Klijn, Jan G. M.
Hooning, Maartje J.
Meijers-Heijboer, Han
Collee, J. Margriet
van den Ouweland, Ans
Uitterlinden, Andre G.
Liu, Jianjun
Lin, Low Yen
Yuqing, Li
Humphreys, Keith
Czene, Kamila
Cox, Angela
Balasubramanian, Sabapathy P.
Cross, Simon S.
Reed, Malcolm W. R.
Blows, Fiona
Driver, Kristy
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https://doi.org/10.1371/journal.pgen.1000054Metadata
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Garcia-Closas, Montserrat, Per Hall, Heli Nevanlinna, Karen Pooley, Jonathan Morrison, Douglas A. Richesson, Stig E. Bojesen, et al. 2008. “Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics.” Edited by Suzanne M. Leal. PLoS Genetics 4 (4): e1000054. https://doi.org/10.1371/journal.pgen.1000054.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.Terms of Use
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