Novel Breast Cancer Susceptibility Locus at 9q31.2... [J Natl Cancer Inst. 2011] - PubMed result

J Natl Cancer Inst. 2011 Jan 24. [Epub ahead of print]
Novel Breast Cancer Susceptibility Locus at 9q31.2: Results of a Genome-Wide Association Study.

Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ, Walker K, Zelenika D, Gut I, Heath S, Palles C, Coupland B, Broderick P, Schoemaker M, Jones M, Williamson J, Chilcott-Burns S, Tomczyk K, Simpson G, Jacobs KB, Chanock SJ, Hunter DJ, Tomlinson IP, Swerdlow A, Ashworth A, Ross G, Dos Santos Silva I, Lathrop M, Houlston RS, Peto J.

Affiliations of authors: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (OF, NJ, NO, CP, BC, JW, SC-B, KT, GS, AA); Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK (FJH, PB, RSH); Non-communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK (LJG, KW, IdSS, JP); Centre National de Génotypage, IG/CEA, Evry Cedex, France (DZ, IG, SH, ML); Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK (MS, MJ, AS); Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick Inc, National Cancer Institute at Frederick, Frederick, MD (KBJ); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (KBJ, SJC); BioInformed LLC, Gaithersburg, MD (KBJ); Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA (DJH); Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, Oxford, UK (IPT); The Royal Marsden NHS Foundation Trust, London, UK (GR); Foundation Jean Dausett-CEPH, Paris, France (ML); Cancer Research UK Genetics and Epidemiology Group, Institute of Cancer Research, Sutton, Surrey, UK (JP).


Abstract

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 296 114 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 12 487 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 I (2) 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.

PMID: 21263130 [PubMed - as supplied by publisher]
Novel Breast Cancer Susceptibility Locus at 9q31.2... [J Natl Cancer Inst. 2011] - PubMed result