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Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers.

Abstract

Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

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  • Authors+Show Affiliations

    ,

    Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL 60637, USA.

    , , , , , , , , , , , , , , , , , , , ,

    Source

    Carcinogenesis 34:7 2013 Jul pg 1520-8

    MeSH

    Adult
    African Continental Ancestry Group
    Alleles
    Biomarkers, Tumor
    Breast Neoplasms
    Case-Control Studies
    Chromosome Mapping
    Chromosomes, Human, Pair 16
    Chromosomes, Human, Pair 6
    Confidence Intervals
    Female
    Genetic Loci
    Genetic Predisposition to Disease
    Genome-Wide Association Study
    Humans
    Middle Aged
    Odds Ratio
    Polymorphism, Single Nucleotide

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23475944

    Citation

    Zheng, Yonglan, et al. "Fine Mapping of Breast Cancer Genome-wide Association Studies Loci in Women of African Ancestry Identifies Novel Susceptibility Markers." Carcinogenesis, vol. 34, no. 7, 2013, pp. 1520-8.
    Zheng Y, Ogundiran TO, Falusi AG, et al. Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers. Carcinogenesis. 2013;34(7):1520-8.
    Zheng, Y., Ogundiran, T. O., Falusi, A. G., Nathanson, K. L., John, E. M., Hennis, A. J., ... Huo, D. (2013). Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers. Carcinogenesis, 34(7), pp. 1520-8. doi:10.1093/carcin/bgt090.
    Zheng Y, et al. Fine Mapping of Breast Cancer Genome-wide Association Studies Loci in Women of African Ancestry Identifies Novel Susceptibility Markers. Carcinogenesis. 2013;34(7):1520-8. PubMed PMID: 23475944.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers. AU - Zheng,Yonglan, AU - Ogundiran,Temidayo O, AU - Falusi,Adeyinka G, AU - Nathanson,Katherine L, AU - John,Esther M, AU - Hennis,Anselm J M, AU - Ambs,Stefan, AU - Domchek,Susan M, AU - Rebbeck,Timothy R, AU - Simon,Michael S, AU - Nemesure,Barbara, AU - Wu,Suh-Yuh, AU - Leske,Maria Cristina, AU - Odetunde,Abayomi, AU - Niu,Qun, AU - Zhang,Jing, AU - Afolabi,Chibuzor, AU - Gamazon,Eric R, AU - Cox,Nancy J, AU - Olopade,Christopher O, AU - Olopade,Olufunmilayo I, AU - Huo,Dezheng, Y1 - 2013/03/08/ PY - 2013/3/12/entrez PY - 2013/3/12/pubmed PY - 2013/9/7/medline SP - 1520 EP - 8 JF - Carcinogenesis JO - Carcinogenesis VL - 34 IS - 7 N2 - Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/23475944/Fine_mapping_of_breast_cancer_genome_wide_association_studies_loci_in_women_of_African_ancestry_identifies_novel_susceptibility_markers_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgt090 DB - PRIME DP - Unbound Medicine ER -