Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2016-08-24
Date Accepted
2016-07-18
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.
Citation
PloS one, 2016, 11 (8), pp. e0160316 - ?
Rights
Source Title
Publisher
PUBLIC LIBRARY SCIENCE
ISSN
1932-6203
eISSN
1932-6203
Research Team
Complex Trait Genetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Functional Genetic Epidemiology
Aetiological Epidemiology