Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.

[1]  J R Marshall,et al.  Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. , 2000, American journal of epidemiology.

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

[3]  Patrick Neven,et al.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci , 2013, Nature Genetics.

[4]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[5]  Tsun-Po Yang,et al.  Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies , 2010, Bioinform..

[6]  Jane E. Carpenter,et al.  A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. , 2012, Human molecular genetics.

[7]  David Tritchler,et al.  Heritability of mammographic density, a risk factor for breast cancer. , 2002, The New England journal of medicine.

[8]  Chuong B. Do,et al.  Genetic variants associated with breast size also influence breast cancer risk , 2012, BMC Medical Genetics.

[9]  Aleix Prat Aparicio.  Comprehensive molecular portraits of human breast tumours , 2012 .

[10]  T. Sellers,et al.  Mammographic density, breast cancer risk and risk prediction , 2007, Breast Cancer Research.

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

[12]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[13]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[14]  C. Vachon,et al.  Mammographic density phenotypes and risk of breast cancer: a meta-analysis. , 2014, Journal of the National Cancer Institute.

[15]  N F Boyd,et al.  Symmetry of projection in the quantitative analysis of mammographic images , 1996, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[16]  Jane E. Carpenter,et al.  A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. , 2012, Human molecular genetics.

[17]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[18]  Clement Adebamowo,et al.  Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus , 2010, PLoS genetics.

[19]  John L Hopper,et al.  The Heritability of Mammographically Dense and Nondense Breast Tissue , 2006, Cancer Epidemiology Biomarkers & Prevention.

[20]  References , 1971 .

[21]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[22]  Jane E. Carpenter,et al.  Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. , 2014, Carcinogenesis.

[23]  Simon C. Potter,et al.  The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study , 2011, PLoS genetics.

[24]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[25]  David N. Rider,et al.  Identification of a novel percent mammographic density locus at 12q24. , 2012, Human molecular genetics.

[26]  W. Willett,et al.  Nondense mammographic area and risk of breast cancer , 2011, Breast Cancer Research.

[27]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[28]  Gretchen L. Gierach,et al.  Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[29]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[30]  Mingfeng Zhang,et al.  Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study , 2014, PLoS medicine.

[31]  Peter Kraft,et al.  Common variants in ZNF365 are associated with both mammographic density and breast cancer risk , 2011, Nature Genetics.

[32]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

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

[34]  W. Willett,et al.  Body fatness at young ages and risk of breast cancer throughout life. , 2008, American journal of epidemiology.

[35]  Jeffrey E. Lee,et al.  Genome-wide association study identifies nidogen 1 ( NID1 ) as a susceptibility locus to cutaneous nevi and melanoma risk , 2022 .

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

[37]  Laura Baglietto,et al.  Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort , 2014, PLoS medicine.

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

[39]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[40]  Yurii S. Aulchenko,et al.  ProbABEL package for genome-wide association analysis of imputed data , 2010, BMC Bioinformatics.

[41]  Denis Habauzit,et al.  Activation of the MKL1/actin signaling pathway induces hormonal escape in estrogen-responsive breast cancer cell lines , 2014, Molecular and Cellular Endocrinology.

[42]  Jaana M. Hartikainen,et al.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk , 2013, Nature Genetics.

[43]  Andrew W Roddam,et al.  Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies , 2010, The Lancet. Oncology.

[44]  Nazneen Rahman,et al.  Mammographic breast density and breast cancer: evidence of a shared genetic basis. , 2012, Cancer research.

[45]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[46]  D. Noh,et al.  Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. , 2011, Human molecular genetics.

[47]  P. Harrison,et al.  Profiling early head and neck cancer , 2005, Nature Reviews Cancer.

[48]  C. Amos.  Robust variance-components approach for assessing genetic linkage in pedigrees. , 1994, American journal of human genetics.