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Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

  • Author(s): Horne, Hisani N
  • Chung, Charles C
  • Zhang, Han
  • Yu, Kai
  • Prokunina-Olsson, Ludmila
  • Michailidou, Kyriaki
  • Bolla, Manjeet K
  • Wang, Qin
  • Dennis, Joe
  • Hopper, John L
  • Southey, Melissa C
  • Schmidt, Marjanka K
  • Broeks, Annegien
  • Muir, Kenneth
  • Lophatananon, Artitaya
  • Fasching, Peter A
  • Beckmann, Matthias W
  • Fletcher, Olivia
  • Johnson, Nichola
  • Sawyer, Elinor J
  • Tomlinson, Ian
  • Burwinkel, Barbara
  • Marme, Frederik
  • Guénel, Pascal
  • Truong, Thérèse
  • Bojesen, Stig E
  • Flyger, Henrik
  • Benitez, Javier
  • González-Neira, Anna
  • Anton-Culver, Hoda
  • Neuhausen, Susan L
  • Brenner, Hermann
  • Arndt, Volker
  • Meindl, Alfons
  • Schmutzler, Rita K
  • Brauch, Hiltrud
  • Hamann, Ute
  • Nevanlinna, Heli
  • Khan, Sofia
  • Matsuo, Keitaro
  • Iwata, Hiroji
  • Dörk, Thilo
  • Bogdanova, Natalia V
  • Lindblom, Annika
  • Margolin, Sara
  • Mannermaa, Arto
  • Kosma, Veli-Matti
  • Chenevix-Trench, Georgia
  • kConFab/AOCS Investigators
  • Wu, Anna H
  • Ven den Berg, David
  • Smeets, Ann
  • Zhao, Hui
  • Chang-Claude, Jenny
  • Rudolph, Anja
  • Radice, Paolo
  • Barile, Monica
  • Couch, Fergus J
  • Vachon, Celine
  • Giles, Graham G
  • Milne, Roger L
  • Haiman, Christopher A
  • Marchand, Loic Le
  • Goldberg, Mark S
  • Teo, Soo H
  • Taib, Nur AM
  • Kristensen, Vessela
  • Borresen-Dale, Anne-Lise
  • Zheng, Wei
  • Shrubsole, Martha
  • Winqvist, Robert
  • Jukkola-Vuorinen, Arja
  • Andrulis, Irene L
  • Knight, Julia A
  • Devilee, Peter
  • Seynaeve, Caroline
  • García-Closas, Montserrat
  • Czene, Kamila
  • Darabi, Hatef
  • Hollestelle, Antoinette
  • Martens, John WM
  • Li, Jingmei
  • Lu, Wei
  • Shu, Xiao-Ou
  • Cox, Angela
  • Cross, Simon S
  • Blot, William
  • Cai, Qiuyin
  • Shah, Mitul
  • Luccarini, Craig
  • Baynes, Caroline
  • Harrington, Patricia
  • Kang, Daehee
  • Choi, Ji-Yeob
  • Hartman, Mikael
  • Chia, Kee Seng
  • Kabisch, Maria
  • Torres, Diana
  • Jakubowska, Anna
  • Lubinski, Jan
  • Sangrajrang, Suleeporn
  • Brennan, Paul
  • Slager, Susan
  • Yannoukakos, Drakoulis
  • Shen, Chen-Yang
  • Hou, Ming-Feng
  • Swerdlow, Anthony
  • Orr, Nick
  • Simard, Jacques
  • Hall, Per
  • Pharoah, Paul DP
  • Easton, Douglas F
  • Chanock, Stephen J
  • Dunning, Alison M
  • Figueroa, Jonine D
  • et al.
Abstract

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

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