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Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus

2010; Public Library of Science; Volume: 6; Issue: 7 Linguagem: Inglês

10.1371/journal.pgen.1001029

1553-7404

Simon Stacey, Patrick Sulem, Carlo Zanon, Sigurjón A. Guðjónsson, Guðmar Þorleifsson, Agnar Helgason, Áslaug Jónasdóttir, Søren Besenbacher, Jelena P. Kostic, James D. Fackenthal, Dezheng Huo, Clement Adebamowo, Temidayo O. Ogundiran, Janet E. Olson, Zachary S. Fredericksen, Xianshu Wang, Maxime P. Look, Anieta M. Sieuwerts, John W.M. Martens, Isabel Pajares, María Dolores García-Prats, José Manuel Ramón-Cajal, Ana De Juan, Angeles Panadero, Eugenia Ortega, Katja K.H. Aben, Sita H. Vermeulen, Fatemeh Asadzadeh, K. C. Anton van Engelenburg, Sara Margolin, Chen‐Yang Shen, Pei-Ei Wu, Asta Försti, Per Lenner, Roger Henriksson, Robert Johansson, Kerstin Enquist, Göran Hallmans, Þorvaldur Jónsson, Helgi Sigurðsson, Kristín Alexíusdóttir, Jūlı́us Guðmundsson, Ásgeir Sigurðsson, Michael L. Frigge, Lárus J. Gudmundsson, Kristleifur Kristjánsson, Bjarni V. Halldórsson, Unnur Styrkársdóttir, Jeffrey R. Gulcher, Kari Hemminki, Annika Lindblom, Lambertus A. Kiemeney, José Mayordomo, John A. Foekens, Fergus J. Couch, Olufunmilayo I. Olopade, Daníel F. Guðbjartsson, Unnur Þorsteinsdóttir, Þórunn Rafnar, Oskar T. Johannsson, Kāri Stefánsson,

Genomics and Chromatin Dynamics

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.