A genome-wide association study of breast cancer in women of African ancestry

Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10−6 and 10−5 in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10−6; rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10−5). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

Clement Adebamowo | Olufunmilayo I. Olopade | Gary K. Chen | Carolyn M. Hutter | Guoliang Li | Christopher A. Haiman | Susan M. Domchek | Stephen J. Chanock | Nancy J. Cox | Dezheng Huo | Daniel O. Stram | Jirong Long | Charles Kooperberg | Brian E. Henderson | Wei Zheng | Ulrike Peters | Julie R. Palmer | Regina G. Ziegler | Xin Sheng | Anselm Hennis | Barbara Nemesure | M. C. Leske | Leslie Bernstein | Christine B. Ambrosone | Angela DeMichele | Sue A. Ingles | R. Millikan | C. Adebamowo | S. Chanock | O. Olopade | J. Palmer | T. Rebbeck | C. Kooperberg | B. Henderson | C. Haiman | S. Ingles | E. John | L. Kolonel | L. Marchand | L. Le Marchand | D. Stram | R. Ziegler | Suh‐Yuh Wu | J. Long | W. Zheng | L. Signorello | W. Blot | S. Ambs | K. Nathanson | B. Nemesure | L. Bernstein | Q. Cai | U. Peters | A. DeMichele | C. Hutter | D. J. Van Den Berg | C. Kooperberg | S. Domchek | A. Hennis | D. Huo | S. Deming | T. Ogundiran | M. Press | C. Ambrosone | Guoliang Li | S. Rhie | M. Simon | E. Bandera | S. Nyante | J. Rodriguez-Gil | E. Ruiz-Narváez | Yonglan Zheng | Jennifer J. Hu | P. Wan | Xin Sheng | Loreall Pooler | A. Young | Alicia Young | Esther M. John | Robert C. Millikan | Elisa V. Bandera | Katherine L. Nathanson | Qiuyin Cai | Suhn K. Rhie | Loreall C. Pooler | Laurence N. Kolonel | Peggy Wan | William Blot | Stefan Ambs | Sandra L. Deming | Sarah Nyante | Michael F. Press | Jorge L. Rodriguez-Gil | Edward A. Ruiz-Narvaez | Suh-Yuh Wu | Loic Marchand | M. Cristina Leske | Temidayo O. Ogundiran | Yonglan Zheng | Fang Chen | Tim R. Rebbeck | Lisa Signorello | Michael S. Simon | David J. Den Berg | Fang Chen | N. Cox | M. Leske | D. Berg | Peggy C Wan | R. Ziegler | B. Henderson | J. Palmer | Peggy Wan

[1]  J. Long,et al.  Evaluation of 11 Breast Cancer Susceptibility Loci in African-American Women , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[2]  Gary K. Chen,et al.  Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21 , 2011, Nature Genetics.

[3]  Giske Ursin,et al.  FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. , 2009, Human molecular genetics.

[4]  A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study , 2012, Breast Cancer Research.

[5]  Gary K. Chen,et al.  Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans. , 2011, Human molecular genetics.

[6]  P. Pharoah,et al.  Polygenic susceptibility to breast cancer: current state-of-the-art. , 2009, Future oncology.

[7]  D. Noh,et al.  Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer , 2012, PLoS genetics.

[8]  Jane E. Carpenter,et al.  A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer , 2011, Nature Genetics.

[9]  S. West,et al.  RAD51 localization and activation following DNA damage. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[10]  M. Tenhagen.  FGFRs in breast cancer: expression, downstream effects and possible drug targets , 2012 .

[11]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[12]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[13]  B. Ponder,et al.  Allele-Specific Up-Regulation of FGFR2 Increases Susceptibility to Breast Cancer , 2008, PLoS biology.

[14]  B. Henderson,et al.  Caution in generalizing known genetic risk markers for breast cancer across all ethnic/racial populations , 2011, European Journal of Human Genetics.

[15]  W. Willett,et al.  A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer , 2007, Nature Genetics.

[16]  D. Reich,et al.  Sensitive Detection of Chromosomal Segments of Distinct Ancestry in Admixed Populations , 2009, PLoS genetics.

[17]  Christiana Kartsonaki,et al.  A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population , 2010, Nature Genetics.

[18]  Douglas F. Easton,et al.  Polygenic susceptibility to breast cancer and implications for prevention , 2002, Nature Genetics.

[19]  A. Sigurdsson,et al.  Common variants on chromosome 5p12 confer susceptibility to estrogen receptor–positive breast cancer , 2008, Nature Genetics.

[20]  D. Gudbjartsson,et al.  Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer , 2007, Nature Genetics.

[21]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[22]  L. Shulman,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2008 .

[23]  Gary K. Chen,et al.  Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium , 2011, PLoS genetics.

[24]  Deborah Hughes,et al.  Genome-wide association study identifies five new breast cancer susceptibility loci , 2010, Nature Genetics.

[25]  Michael Jones,et al.  Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. , 2011, Journal of the National Cancer Institute.

[26]  S. Tishkoff,et al.  African human diversity, origins and migrations. , 2006, Current opinion in genetics & development.

[27]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[28]  W. Willett,et al.  A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) , 2009, Nature Genetics.

[29]  M. C. Leske,et al.  Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry. , 2012, Carcinogenesis.

[30]  Michael Jones,et al.  Genome-wide association analysis identifies three new breast cancer susceptibility loci , 2012, Nature Genetics.

[31]  J. Palmer,et al.  Polymorphisms in the TOX3/LOC643714 Locus and Risk of Breast Cancer in African-American Women , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[32]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[33]  J. Haines,et al.  Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1 , 2009, Nature Genetics.

[34]  M. Thun,et al.  Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 , 2009, Nature Genetics.

[35]  M. Tenhagen,et al.  Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets. , 2012, Endocrine-related cancer.

[36]  S. Tishkoff,et al.  African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. , 2008, Annual review of genomics and human genetics.

[37]  J. Palmer,et al.  Polymorphisms in the TOX 3 / LOC 643714 Locus and Risk of Breast Cancer in African-American Women , 2010 .

[38]  C. Carty,et al.  Replication of Breast Cancer GWAS Susceptibility Loci in the Women's Health Initiative African American SHARe Study , 2011, Cancer Epidemiology, Biomarkers & Prevention.