Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.
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Date
2016-08-24Author
Horne, HN
Chung, CC
Zhang, H
Yu, K
Prokunina-Olsson, L
Michailidou, K
Bolla, MK
Wang, Q
Dennis, J
Hopper, JL
Southey, MC
Schmidt, MK
Broeks, A
Muir, K
Lophatananon, A
Fasching, PA
Beckmann, MW
Fletcher, O
Johnson, N
Sawyer, EJ
Tomlinson, I
Burwinkel, B
Marme, F
Guénel, P
Truong, T
Bojesen, SE
Flyger, H
Benitez, J
González-Neira, A
Anton-Culver, H
Neuhausen, SL
Brenner, H
Arndt, V
Meindl, A
Schmutzler, RK
Brauch, H
Hamann, U
Nevanlinna, H
Khan, S
Matsuo, K
Iwata, H
Dörk, T
Bogdanova, NV
Lindblom, A
Margolin, S
Mannermaa, A
Kosma, V-M
Chenevix-Trench, G
kConFab/AOCS Investigators,
Wu, AH
Ven den Berg, D
Smeets, A
Zhao, H
Chang-Claude, J
Rudolph, A
Radice, P
Barile, M
Couch, FJ
Vachon, C
Giles, GG
Milne, RL
Haiman, CA
Marchand, LL
Goldberg, MS
Teo, SH
Taib, NAM
Kristensen, V
Borresen-Dale, A-L
Zheng, W
Shrubsole, M
Winqvist, R
Jukkola-Vuorinen, A
Andrulis, IL
Knight, JA
Devilee, P
Seynaeve, C
García-Closas, M
Czene, K
Darabi, H
Hollestelle, A
Martens, JWM
Li, J
Lu, W
Shu, X-O
Cox, A
Cross, SS
Blot, W
Cai, Q
Shah, M
Luccarini, C
Baynes, C
Harrington, P
Kang, D
Choi, J-Y
Hartman, M
Chia, KS
Kabisch, M
Torres, D
Jakubowska, A
Lubinski, J
Sangrajrang, S
Brennan, P
Slager, S
Yannoukakos, D
Shen, C-Y
Hou, M-F
Swerdlow, A
Orr, N
Simard, J
Hall, P
Pharoah, PDP
Easton, DF
Chanock, SJ
Dunning, AM
Figueroa, JD
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
kConFab/AOCS Investigators
Chromosomes, Human, Pair 1
Humans
Breast Neoplasms
Genetic Predisposition to Disease
Population Surveillance
Risk Assessment
Case-Control Studies
Chromosome Mapping
Computational Biology
Gene Frequency
Genotype
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
Female
Genetic Association Studies
Neoplasm Grading
Research team
Complex Trait Genetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Language
eng
Date accepted
2016-07-18
License start date
2016-01
Citation
PloS one, 2016, 11 (8), pp. e0160316 - ?
Publisher
PUBLIC LIBRARY SCIENCE