TY - JOUR
T1 - Novel breast cancer susceptibility locus at 9q31.2
T2 - Results: of a genome-wide association study
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - Orr, Nick
AU - Hosking, Fay J.
AU - Gibson, Lorna J.
AU - Walker, Kate
AU - Zelenika, Diana
AU - Gut, Ivo
AU - Heath, Simon
AU - Palles, Claire
AU - Coupland, Ben
AU - Broderick, Peter
AU - Schoemaker, Minouk
AU - Jones, Michael
AU - Williamson, Jill
AU - Chilcott-Burns, Sarah
AU - Tomczyk, Katarzyna
AU - Simpson, Gemma
AU - Jacobs, Kevin B.
AU - Chanock, Stephen J.
AU - Hunter, David J.
AU - Tomlinson, Ian P.
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Ross, Gillian
AU - Dos Santos Silva, Isabel
AU - Lathrop, Mark
AU - Houlston, Richard S.
AU - Peto, Julian
N1 - Funding Information:
Research Network (NCRN). Funding for the project was provided by the Wellcome Trust under award 076113 and 085475.
Funding Information:
Cancer Research UK (C150/A5660 and C1178/A3947 to J.P. and I.d.S.S.); Breakthrough Breast Cancer (A.A. and O.F.); the Institut National de Cancer (M.L.); the Cridlan Trust (G.R.). We acknowledge National Health Service funding to the NIHR Biomedical Research Centre and the National Cancer
PY - 2011/3/2
Y1 - 2011/3/2
N2 - Background: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. Methods: We compared 296114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11 880 case subjects and 12487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I2 statistics. All statistical tests were two-sided. Results: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10-10). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10-7; rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10-7). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10-6). Conclusions: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects. The Author 2011. Published by Oxford University Press.2011
AB - Background: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. Methods: We compared 296114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11 880 case subjects and 12487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I2 statistics. All statistical tests were two-sided. Results: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10-10). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10-7; rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10-7). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10-6). Conclusions: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects. The Author 2011. Published by Oxford University Press.2011
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U2 - 10.1093/jnci/djq563
DO - 10.1093/jnci/djq563
M3 - Article
C2 - 21263130
AN - SCOPUS:79952329937
SN - 0027-8874
VL - 103
SP - 425
EP - 435
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 5
ER -