Replication of genome-wide discovered breast cancer risk loci in the Cypriot population

Genome-wide association studies (GWAS) have identified associations with robust statistical support for influencing breast cancer susceptibility. Most GWAS and replications have been conducted in Northern European populations and to a lesser extent in Asians, and Ashkenazi Jews. It is important to evaluate whether these variants confer risk across different populations and also to assess the magnitude of risk conferred. The aim of this study was to evaluate previously GWAS-identified breast cancer risk variants in the Cypriot population. Eleven GWAS-discovered single nucleotide polymorphisms (SNPs) were analyzed for association with breast cancer in 1,109 Cypriot female breast cancer patients and 1,177 healthy female controls. Four of the 11 SNPs evaluated were found to be nominally significantly associated (P < 0.05) with breast cancer risk in the Cypriot population. Based on estimated power, five associations would be expected to be nominally significant. The correlation coefficient of effect sizes (per-allele odds ratio) between the Cypriot population and the original GWAS populations where these SNPs had been discovered was 0.58 (P = 0.064), while allele frequencies were very similar (r = 0.88, P < 0.001). Overall, we show modest concordance for breast cancer GWAS-discovered alleles and their effect sizes in the Cypriot population. The effects sizes of GWAS-discovered SNPs need to be verified separately in different populations.

[1]  W. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.

[2]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[3]  D. Bentley,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1995, Nature.

[4]  John S Witte,et al.  Point: population stratification: a problem for case-control studies of candidate-gene associations? , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

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

[6]  J. Gray,et al.  The genetics and genomics of cancer , 2003, Nature Genetics.

[7]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[8]  J. Peto,et al.  The search for low-penetrance cancer susceptibility alleles , 2004, Oncogene.

[9]  Gudmundur A. Thorisson,et al.  The International HapMap Project Web site. , 2005, Genome research.

[10]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[11]  S. Seal,et al.  A genome wide linkage search for breast cancer susceptibility genes , 2006, Genes, chromosomes & cancer.

[12]  Joan Valls,et al.  SNPStats: a web tool for the analysis of association studies , 2006, Bioinform..

[13]  C. Plass,et al.  20q11.1 amplification in giant‐cell tumor of bone: Array CGH, FISH, and association with outcome , 2006, Genes, chromosomes & cancer.

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

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

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

[17]  Nazneen Rahman,et al.  The emerging landscape of breast cancer susceptibility , 2007, Nature Genetics.

[18]  C. Hoggart,et al.  Genome‐wide significance for dense SNP and resequencing data , 2008, Genetic epidemiology.

[19]  P. Gregersen,et al.  Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 , 2008, Proceedings of the National Academy of Sciences.

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

[21]  Amit R. Indap,et al.  Genes mirror geography within Europe , 2008, Nature.

[22]  M. McCarthy,et al.  Underlying genetic models of inheritance in established type 2 diabetes associations. , 2009, American journal of epidemiology.

[23]  John P A Ioannidis,et al.  Discovery properties of genome-wide association signals from cumulatively combined data sets. , 2009, American journal of epidemiology.

[24]  John P A Ioannidis,et al.  Population-wide generalizability of genome-wide discovered associations. , 2009, Journal of the National Cancer Institute.

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

[26]  P. Gregersen,et al.  The 6q22.33 Locus and Breast Cancer Susceptibility , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[27]  M. Gail.  Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. , 2009, Journal of the National Cancer Institute.

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

[30]  J. Ioannidis,et al.  STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement , 2009, PLoS medicine.

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

[32]  John P A Ioannidis,et al.  Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. , 2010, Trends in genetics : TIG.

[33]  John P A Ioannidis,et al.  A compendium of genome-wide associations for cancer: critical synopsis and reappraisal. , 2010, Journal of the National Cancer Institute.

[34]  A. Jemal,et al.  Global Cancer Statistics , 2011 .