- Main
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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