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Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures.


Type

Article

Change log

Authors

Stone, Jennifer 
Thompson, Deborah J 
Dos Santos Silva, Isabel 
Scott, Christopher 
Tamimi, Rulla M 

Abstract

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10(-5)). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.

Description

Keywords

Aged, Breast Density, Breast Neoplasms, Disease Susceptibility, Female, Genetic Predisposition to Disease, Genotype, Humans, Mammary Glands, Human, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors

Journal Title

Cancer Res

Conference Name

Journal ISSN

0008-5472
1538-7445

Volume Title

75

Publisher

American Association for Cancer Research (AACR)
Sponsorship
National Cancer Institute (U19CA148537)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
Medical Research Council (G1000143)
Medical Research Council (MC_UU_12015/1)
European Commission (223175)
Cancer Research UK (16565)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Medical Research Council (G0401527)
Medical Research Council (MC_U106179471)
Cancer Research UK (12014)
Cancer Research UK (10118)
Medical Research Council (G0401527/1)
ABCFS: The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia), and by grant UM1CA164920 from the USA National Cancer Institute. The Genetic Epidemiology Laboratory at the University of Melbourne has also received generous support from Mr B. Hovey and Dr and Mrs R.W. Brown to whom we are most grateful. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Breast Cancer Susceptibility Variants and Mammographic Density 5 Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. BBCC: This study was funded in part by the ELAN-Program of the University Hospital Erlangen; Katharina Heusinger was funded by the ELAN program of the University Hospital Erlangen. BBCC was supported in part by the ELAN program of the Medical Faculty, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg. EPIC-Norfolk: This study was funded by research programme grant funding from Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing and Academy of Medical Sciences. MCBCS: This study was supported by Public Health Service Grants P50 CA 116201, R01 CA 128931, R01 CA 128931-S01, R01 CA 122340, CCSG P30 CA15083, from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. MCCS: Melissa C. Southey is a National Health and Medical Research Council Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The study was supported by the Cancer Council of Victoria and by the Victorian Breast Cancer Research Consortium. MEC: National Cancer Institute: R37CA054281, R01CA063464, R01CA085265, R25CA090956, R01CA132839. MMHS: This work was supported by grants from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. (R01 CA128931, R01 CA 128931-S01, R01 CA97396, P50 CA116201, and Cancer Center Support Grant P30 CA15083). Breast Cancer Susceptibility Variants and Mammographic Density 6 NBCS: This study has been supported with grants from Norwegian Research Council (#183621/S10 and #175240/S10), The Norwegian Cancer Society (PK80108002, PK60287003), and The Radium Hospital Foundation as well as S-02036 from South Eastern Norway Regional Health Authority. NHS: This study was supported by Public Health Service Grants CA131332, CA087969, CA089393, CA049449, CA98233, CA128931, CA 116201, CA 122340 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. OOA study was supported by CA122822 and X01 HG005954 from the NIH; Breast Cancer Research Fund; Elizabeth C. Crosby Research Award, Gladys E. Davis Endowed Fund, and the Office of the Vice President for Research at the University of Michigan. Genotyping services for the OOA study were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096. OFBCR: This work was supported by grant UM1 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. SASBAC: The SASBAC study was supported by Märit and Hans Rausing’s Initiative against Breast Cancer, National Institutes of Health, Susan Komen Foundation and Agency for Science, Technology and Research of Singapore (A*STAR). Breast Cancer Susceptibility Variants and Mammographic Density 7 SIBS: SIBS was supported by program grant C1287/A10118 and project grants from Cancer Research UK (grant numbers C1287/8459). COGS grant: Collaborative Oncological Gene-environment Study (COGS) that enabled the genotyping for this study. Funding for the BCAC component is provided by grants from the EU FP7 programme (COGS) and from Cancer Research UK. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post- Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAMEON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.