Heritability of Mammographic Density, a Risk Factor for Breast Cancer
Norman F. Boyd, M.D., Gillian S. Dite, B.Sc., Jennifer Stone, M.Sc., Anoma Gunasekara, B.Sc., Dallas R. English, Ph.D., Margaret R.E. McCredie, Ph.D., Graham G. Giles, Ph.D., David Tritchler, D.Sc., Anna Chiarelli, Ph.D., Martin J. Yaffe, Ph.D., and John L. Hopper, Ph.D.
Background Women with extensive dense breast tissue visibleon a mammogram have a risk of breast cancer that is 1.8 to 6.0times that of women of the same age with little or no density.Menopausal status, weight, and parity account for 20 to 30 percentof the age-adjusted variation in the percentage of dense tissue.
Methods We undertook two studies of twins to determine the proportionof the residual variation in the percentage of density measuredby mammography that can be explained by unmeasured additivegenetic factors (heritability). A total of 353 pairs of monozygotictwins and 246 pairs of dizygotic twins were recruited from theAustralian Twin Registry, and 218 pairs of monozygotic twinsand 134 pairs of dizygotic twins were recruited in Canada andthe United States. Information on putative determinants of breastdensity was obtained by questionnaire. Mammograms were digitized,randomly ordered, and read by a blinded investigator.
Results After adjustment for age and measured covariates, thecorrelation coefficient for the percentage of dense tissue was0.61 for monozygotic pairs in Australia, 0.67 for monozygoticpairs in North America, 0.25 for dizygotic pairs in Australia,and 0.27 for dizygotic pairs in North America. According tothe classic twin model, heritability (the proportion of variantsattributable to additive genetic factors) accounted for 60 percentof the variation in density (95 percent confidence interval,54 to 66) in Australian twins, 67 percent (95 percent confidenceinterval, 59 to 75) in North American twins, and 63 percent(95 percent confidence interval, 59 to 67) in all twins studied.
Conclusions These results show that the population variationin the percentage of dense tissue on mammography at a givenage has high heritability. Because mammographic density is associatedwith an increased risk of breast cancer, finding the genes responsiblefor this phenotype could be important for understanding thecauses of the disease.
Source Information
From the Division of Epidemiology and Statistics, Ontario Cancer Institute (N.F.B., J.S., A.G., D.T.); Cancer Care Ontario (A.C.); and Imaging Research, Sunnybrook and Women's College Health Sciences Centre (M.J.Y.) — all in Toronto; the Centre for Genetic Epidemiology, University of Melbourne (G.S.D., J.L.H.); and the Centre for Cancer Epidemiology, Cancer Council Victoria (D.R.E., G.G.G.) — both in Melbourne, Australia; and the Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand (M.R.E.M.).
Address reprint requests to Dr. Boyd at the Division of Epidemiology and Statistics, Ontario Cancer Institute, 610 University Ave., Toronto, ON M5G 2M9, Canada, or at boyd{at}uhnres.utoronto.ca.
Mammographic Density of the Breast
Vachon C. M., Sellers T. A., Pankratz V. S., Hall F. M., Boyd N. F., Hopper J. L., Thurfjell E.
Extract |
Full Text |
PDF
N Engl J Med 2003;
348:174-175, Jan 9, 2003.
Correspondence
This article has been cited by other articles:
McCormack, V. A., Perry, N., Vinnicombe, S. J., Silva, I. d. S.
(2008). Ethnic Variations in Mammographic Density: A British Multiethnic Longitudinal Study. Am J Epidemiol
168: 412-421
[Abstract][Full Text]
Xing, J., Chen, M., Wood, C. G., Lin, J., Spitz, M. R., Ma, J., Amos, C. I., Shields, P. G., Benowitz, N. L., Gu, J., de Andrade, M., Swan, G. E., Wu, X.
(2008). Mitochondrial DNA Content: Its Genetic Heritability and Association With Renal Cell Carcinoma. JNCI J Natl Cancer Inst
100: 1104-1112
[Abstract][Full Text]
Eng-Wong, J., Orzano-Birgani, J., Chow, C. K., Venzon, D., Yao, J., Galbo, C. E., Zujewski, J. A., Prindiville, S.
(2008). Effect of Raloxifene on Mammographic Density and Breast Magnetic Resonance Imaging in Premenopausal Women at Increased Risk for Breast Cancer. Cancer Epidemiol. Biomarkers Prev.
17: 1696-1701
[Abstract][Full Text]
Kelemen, L. E., Pankratz, V. S., Sellers, T. A., Brandt, K. R., Wang, A., Janney, C., Fredericksen, Z. S., Cerhan, J. R., Vachon, C. M.
(2008). Age-specific Trends in Mammographic Density: The Minnesota Breast Cancer Family Study. Am J Epidemiol
167: 1027-1036
[Abstract][Full Text]
Radisky, D. C., Przybylo, J. A.
(2008). Matrix Metalloproteinase-induced Fibrosis and Malignancy in Breast and Lung. Proc Am Thorac Soc
5: 316-322
[Abstract][Full Text]
Diorio, C., Brisson, J., Berube, S., Pollak, M.
(2008). Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels. Cancer Epidemiol. Biomarkers Prev.
17: 880-888
[Abstract][Full Text]
Peters, T. M., Ekelund, U., Leitzmann, M., Easton, D., Warren, R., Luben, R., Bingham, S., Khaw, K.-T., Wareham, N. J.
(2008). Physical Activity and Mammographic Breast Density in the EPIC-Norfolk Cohort Study. Am J Epidemiol
167: 579-585
[Abstract][Full Text]
Lee, E., Haiman, C. A., Ma, H., Van Den Berg, D., Bernstein, L., Ursin, G.
(2008). The Role of Established Breast Cancer Susceptibility Loci in Mammographic Density in Young Women. Cancer Epidemiol. Biomarkers Prev.
17: 258-260
[Full Text]
Tilanus-Linthorst, M. M.A., Obdeijn, I.-M., Hop, W. C.J., Causer, P. A., Leach, M. O., Warner, E., Pointon, L., Hill, K., Klijn, J. G.M., Warren, R. M.L., Gilbert, F. J.
(2007). BRCA1 Mutation and Young Age Predict Fast Breast Cancer Growth in the Dutch, United Kingdom, and Canadian Magnetic Resonance Imaging Screening Trials. Clin. Cancer Res.
13: 7357-7362
[Abstract][Full Text]
Hwang, E. S., Miglioretti, D. L., Ballard-Barbash, R., Weaver, D. L., Kerlikowske, K., for the National Cancer Institute Breast Cancer Su,
(2007). Association between Breast Density and Subsequent Breast Cancer Following Treatment for Ductal Carcinoma In situ. Cancer Epidemiol. Biomarkers Prev.
16: 2587-2593
[Abstract][Full Text]
Vachon, C. M., Sellers, T. A., Carlson, E. E., Cunningham, J. M., Hilker, C. A., Smalley, R. L., Schaid, D. J., Kelemen, L. E., Couch, F. J., Pankratz, V. S.
(2007). Strong Evidence of a Genetic Determinant for Mammographic Density, a Major Risk Factor for Breast Cancer. Cancer Res.
67: 8412-8418
[Abstract][Full Text]
Sellers, T., Vachon, C., Pankratz, V., Janney, C., Fredericksen, Z, Brandt, K., Huang, Y, Couch, F., Kushi, L., Cerhan, J.
(2007). Association of Childhood and Adolescent Anthropometric Factors, Physical Activity, and Diet with Adult Mammographic Breast Density. Am J Epidemiol
166: 456-464
[Abstract][Full Text]
Tamimi, R. M., Byrne, C., Colditz, G. A., Hankinson, S. E.
(2007). Endogenous Hormone Levels, Mammographic Density, and Subsequent Risk of Breast Cancer in Postmenopausal Women. JNCI J Natl Cancer Inst
99: 1178-1187
[Abstract][Full Text]
Stone, J., Gurrin, L. C., Byrnes, G. B., Schroen, C. J., Treloar, S. A., Padilla, E. J.D., Dite, G. S., Southey, M. C., Hayes, V. M., Hopper, J. L.
(2007). Mammographic Density and Candidate Gene Variants: A Twins and Sisters Study. Cancer Epidemiol. Biomarkers Prev.
16: 1479-1484
[Abstract][Full Text]
Vachon, C. M., Pankratz, V. S., Scott, C. G., Maloney, S. D., Ghosh, K., Brandt, K. R., Milanese, T., Carston, M. J., Sellers, T. A.
(2007). Longitudinal Trends in Mammographic Percent Density and Breast Cancer Risk. Cancer Epidemiol. Biomarkers Prev.
16: 921-928
[Abstract][Full Text]
Kerlikowske, K., Ichikawa, L., Miglioretti, D. L., Buist, D. S. M., Vacek, P. M., Smith-Bindman, R., Yankaskas, B., Carney, P. A., Ballard-Barbash, R.
(2007). Longitudinal Measurement of Clinical Mammographic Breast Density to Improve Estimation of Breast Cancer Risk. JNCI J Natl Cancer Inst
99: 386-395
[Abstract][Full Text]
Weitzel, J. N., Buys, S. S., Sherman, W. H., Daniels, A. M., Ursin, G., Daniels, J. R., MacDonald, D. J., Blazer, K. R., Pike, M. C., Spicer, D. V.
(2007). Reduced Mammographic Density with Use of a Gonadotropin-Releasing Hormone Agonist-Based Chemoprevention Regimen in BRCA1 Carriers. Clin. Cancer Res.
13: 654-658
[Abstract][Full Text]
Boyd, N. F., Martin, L. J., Sun, L., Guo, H., Chiarelli, A., Hislop, G., Yaffe, M., Minkin, S.
(2006). Body Size, Mammographic Density, and Breast Cancer Risk.. Cancer Epidemiol. Biomarkers Prev.
15: 2086-2092
[Abstract][Full Text]
Fabian, C. J., Kimler, B. F.
(2006). Mammographic Density: Use in Risk Assessment and as a Biomarker in Prevention Trials. J. Nutr.
136: 2705S-2708S
[Full Text]
Ursin, G., Pike, M.
(2006). Mammographic density, hormone therapy, and risk of breast cancer.. Cancer Epidemiol. Biomarkers Prev.
15: 1750-1750
[Full Text]
Martin, K. E., Helvie, M. A., Zhou, C., Roubidoux, M. A., Bailey, J. E., Paramagul, C., Blane, C. E., Klein, K. A., Sonnad, S. S., Chan, H.-P.
(2006). Mammographic Density Measured with Quantitative Computer-aided Method: Comparison with Radiologists' Estimates and BI-RADS Categories. Radiology
240: 656-665
[Abstract][Full Text]
Warren, R., Skinner, J., Sala, E., Denton, E., Dowsett, M., Folkerd, E., Healey, C. S., Dunning, A., Doody, D., Ponder, B., Luben, R. N., Day, N.E., Easton, D.
(2006). Associations among Mammographic Density, Circulating Sex Hormones, and Polymorphisms in Sex Hormone Metabolism Genes in Postmenopausal Women.. Cancer Epidemiol. Biomarkers Prev.
15: 1502-1508
[Abstract][Full Text]
Palomares, M. R., Machia, J. R.B., Lehman, C. D., Daling, J. R., McTiernan, A.
(2006). Mammographic density correlation with gail model breast cancer risk estimates and component risk factors.. Cancer Epidemiol. Biomarkers Prev.
15: 1324-1330
[Abstract][Full Text]
Wu, X., Spitz, M. R., Amos, C. I., Lin, J., Shao, L., Gu, J., de Andrade, M., Benowitz, N. L., Shields, P. G., Swan, G. E.
(2006). Mutagen sensitivity has high heritability: evidence from a twin study.. Cancer Res.
66: 5993-5996
[Abstract][Full Text]
McCormack, V. A., dos Santos Silva, I.
(2006). Breast Density and Parenchymal Patterns as Markers of Breast Cancer Risk: A Meta-analysis.. Cancer Epidemiol. Biomarkers Prev.
15: 1159-1169
[Abstract][Full Text]
Boyd, N. F., Martin, L. J., Li, Q., Sun, L., Chiarelli, A. M., Hislop, G., Yaffe, M. J., Minkin, S.
(2006). Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer.. Cancer Epidemiol. Biomarkers Prev.
15: 961-966
[Abstract][Full Text]
Stone, J., Dite, G. S., Gunasekara, A., English, D. R., McCredie, M. R.E, Giles, G. G., Cawson, J. N., Hegele, R. A., Chiarelli, A. M., Yaffe, M. J., Boyd, N. F., Hopper, J. L.
(2006). The heritability of mammographically dense and nondense breast tissue.. Cancer Epidemiol. Biomarkers Prev.
15: 612-617
[Abstract][Full Text]
dos Santos Silva, I., Johnson, N., De Stavola, B., Torres-Mejia, G., Fletcher, O., Allen, D. S., Allen, N. E., Key, T. J., Fentiman, I. S., Holly, J. M.P., Peto, J.
(2006). The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women.. Cancer Epidemiol. Biomarkers Prev.
15: 449-455
[Abstract][Full Text]
Mitchell, G., Antoniou, A. C., Warren, R., Peock, S., Brown, J., Davies, R., Mattison, J., Cook, M., Warsi, I., Evans, D. G., Eccles, D., Douglas, F., Paterson, J., Hodgson, S., Izatt, L., Cole, T., Burgess, L., EMBRACE collaborators, , Eeles, R., Easton, D. F.
(2006). Mammographic Density and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Cancer Res.
66: 1866-1872
[Abstract][Full Text]
Mulhall, C., Hegele, R. A., Cao, H., Tritchler, D., Yaffe, M., Boyd, N. F.
(2005). Pituitary Growth Hormone and Growth Hormone-Releasing Hormone Receptor Genes and Associations with Mammographic Measures and Serum Growth Hormone. Cancer Epidemiol. Biomarkers Prev.
14: 2648-2654
[Abstract][Full Text]
van Duijnhoven, F. J.B., Bezemer, I. D., Peeters, P. H.M., Roest, M., Uitterlinden, A. G., Grobbee, D. E., van Gils, C. H.
(2005). Polymorphisms in the Estrogen Receptor {alpha} Gene and Mammographic Density. Cancer Epidemiol. Biomarkers Prev.
14: 2655-2660
[Abstract][Full Text]
Greendale, G. A., Palla, S. L., Ursin, G., Laughlin, G. A., Crandall, C., Pike, M. C., Reboussin, B. A.
(2005). The Association of Endogenous Sex Steroids and Sex Steroid Binding Proteins with Mammographic Density: Results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study. Am J Epidemiol
162: 826-834
[Abstract][Full Text]
Pisano, E. D., Gatsonis, C., Hendrick, E., Yaffe, M., Baum, J. K., Acharyya, S., Conant, E. F., Fajardo, L. L., Bassett, L., D'Orsi, C., Jong, R., Rebner, M., the Digital Mammographic Imaging Screening Trial (,
(2005). Diagnostic Performance of Digital versus Film Mammography for Breast-Cancer Screening. NEJM
353: 1773-1783
[Abstract][Full Text]
Dite, G. S., Wark, J. D., Giles, G. G., English, D. R., McCredie, M. R.E., Hopper, J. L.
(2005). Is There Overlap Between the Genetic Determinants of Mammographic Density and Bone Mineral Density?. Cancer Epidemiol. Biomarkers Prev.
14: 2266-2268
[Abstract][Full Text]
Santen, R. J., Mansel, R.
(2005). Benign Breast Disorders. NEJM
353: 275-285
[Full Text]
Torres-Mejia, G., De Stavola, B., Allen, D. S., Perez-Gavilan, J. J., Ferreira, J. M., Fentiman, I. S., dos Santos Silva, I.
(2005). Mammographic Features and Subsequent Risk of Breast Cancer: A Comparison of Qualitative and Quantitative Evaluations in the Guernsey Prospective Studies. Cancer Epidemiol. Biomarkers Prev.
14: 1052-1059
[Abstract][Full Text]
Li, T., Sun, L., Miller, N., Nicklee, T., Woo, J., Hulse-Smith, L., Tsao, M.-S., Khokha, R., Martin, L., Boyd, N.
(2005). The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer. Cancer Epidemiol. Biomarkers Prev.
14: 343-349
[Abstract][Full Text]
Brem, R. F., Hoffmeister, J. W., Rapelyea, J. A., Zisman, G., Mohtashemi, K., Jindal, G., DiSimio, M. P., Rogers, S. K.
(2005). Impact of Breast Density on Computer-Aided Detection for Breast Cancer. Am. J. Roentgenol.
184: 439-444
[Abstract][Full Text]
Bluemke, D. A., Gatsonis, C. A., Chen, M. H., DeAngelis, G. A., DeBruhl, N., Harms, S., Heywang-Kobrunner, S. H., Hylton, N., Kuhl, C. K., Lehman, C., Pisano, E. D., Causer, P., Schnitt, S. J., Smazal, S. F., Stelling, C. B., Weatherall, P. T., Schnall, M. D.
(2004). Magnetic Resonance Imaging of the Breast Prior to Biopsy. JAMA
292: 2735-2742
[Abstract][Full Text]
Ziv, E., Tice, J., Smith-Bindman, R., Shepherd, J., Cummings, S., Kerlikowske, K.
(2004). Mammographic Density and Estrogen Receptor Status of Breast Cancer. Cancer Epidemiol. Biomarkers Prev.
13: 2090-2095
[Abstract][Full Text]
Maskarinec, G., Takata, Y., Franke, A. A., Williams, A. E., Murphy, S. P.
(2004). A 2-Year Soy Intervention in Premenopausal Women Does Not Change Mammographic Densities. J. Nutr.
134: 3089-3094
[Abstract][Full Text]
Cuzick, J., Warwick, J., Pinney, E., Warren, R. M. L., Duffy, S. W.
(2004). Tamoxifen and Breast Density in Women at Increased Risk of Breast Cancer. JNCI J Natl Cancer Inst
96: 621-628
[Abstract][Full Text]
Lai, J. H., Vesprini, D., Zhang, W., Yaffe, M. J., Pollak, M., Narod, S. A.
(2004). A Polymorphic Locus in the Promoter Region of the IGFBP3 Gene Is Related to Mammographic Breast Density. Cancer Epidemiol. Biomarkers Prev.
13: 573-582
[Abstract][Full Text]
Lillie, E. O., Bernstein, L., Ingles, S. A., Gauderman, W. J., Rivas, G. E., Gagalang, V., Krontiris, T., Ursin, G.
(2004). Polymorphism in the Androgen Receptor and Mammographic Density in Women Taking and Not Taking Estrogen and Progestin Therapy. Cancer Res.
64: 1237-1241
[Abstract][Full Text]
Harvey, J. A., Bovbjerg, V. E.
(2004). Quantitative Assessment of Mammographic Breast Density: Relationship with Breast Cancer Risk. Radiology
230: 29-41
[Abstract][Full Text]
Hall, T. J.
(2003). AAPM/RSNA Physics Tutorial for Residents: Topics in US: Beyond the Basics: Elasticity Imaging with US. RadioGraphics
23: 1657-1671
[Abstract][Full Text]
Hong, C.-C., Thompson, H. J., Jiang, C., Hammond, G. L., Tritchler, D., Yaffe, M., Boyd, N. F.
(2003). Val158Met Polymorphism in Catechol-O-methyltransferase Gene Associated with Risk Factors for Breast Cancer. Cancer Epidemiol. Biomarkers Prev.
12: 838-847
[Abstract][Full Text]
Roubidoux, M. A., Kaur, J. S., Griffith, K. A., Sloan, J., Wilson, C., Novotny, P., Lobell, M.
(2003). Correlates of Mammogram Density in Southwestern Native-American Women. Cancer Epidemiol. Biomarkers Prev.
12: 552-558
[Abstract][Full Text]
Hall, F. M., Kolb, T. M., Lichy, J., Newhouse, J. H.
(2003). Screening Breast US [letter] * Dr Kolb and colleagues respond:. Radiology
227: 607-609
[Full Text]
Ziv, E., Shepherd, J., Smith-Bindman, R., Kerlikowske, K.
(2003). Mammographic Breast Density and Family History of Breast Cancer. JNCI J Natl Cancer Inst
95: 556-558
[Abstract][Full Text]
Vachon, C. M., Sellers, T. A., Pankratz, V. S., Hall, F. M., Boyd, N. F., Hopper, J. L., Thurfjell, E.
(2003). Mammographic Density of the Breast. NEJM
348: 174-175
[Full Text]
Chlebowski, R. T., McTiernan, A.
(2003). Biological Significance of Interventions That Change Breast Density. JNCI J Natl Cancer Inst
95: 4-5
[Full Text]
(2002). Twins and Mammographic Density: New Insights into Familial Breast Cancer. JWatch Women's Health
2002: 3-3
[Full Text]
(2002). Genetics, Breast Density, and Breast Cancer. JWatch General
2002: 1-1
[Full Text]
Previous
