{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T10:25:06Z","timestamp":1783938306247,"version":"3.55.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Dyason Fellowship"},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Br J Cancer"],"published-print":{"date-parts":[[2020,4,14]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Current risk prediction models estimate the probability of developing breast cancer over a defined period based on information such as family history, non-genetic breast cancer risk factors, genetic information from high and moderate risk breast cancer susceptibility genes and, over the past several years, polygenic risk scores (PRS) from more than 300 common variants. The inclusion of additional data such as PRS improves risk stratification, but it is anticipated that the inclusion of epigenetic marks could further improve model performance accuracy. Here, we present the case for including information on DNA methylation marks to improve the accuracy of these risk prediction models, and consider how this approach contrasts genetic information, as identifying DNA methylation marks associated with breast cancer risk differs inherently according to the source of DNA, approaches to the measurement of DNA methylation, and the timing of measurement. We highlight several DNA-methylation-specific challenges that should be considered when incorporating information on DNA methylation marks into risk prediction models, using <jats:italic>BRCA1<\/jats:italic>, a highly penetrant breast cancer susceptibility gene, as an example. Only after careful consideration of study design and DNA methylation\u00a0measurement will prospective performance of the incorporation of information regarding DNA methylation marks into risk prediction models be valid.<\/jats:p>","DOI":"10.1038\/s41416-019-0720-2","type":"journal-article","created":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T15:45:17Z","timestamp":1582040717000},"page":"1133-1140","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1\u00a0methylation marks to improve clinical risk assessment of breast cancer"],"prefix":"10.1038","volume":"122","author":[{"given":"Ee Ming","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa C.","family":"Southey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Beth","family":"Terry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,18]]},"reference":[{"key":"720_CR1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S1470-2045(18)30902-1","volume":"20","author":"MB Terry","year":"2019","unstructured":"Terry, M. B., Liao, Y., Whittemore, A. S., Leoce, N., Buchsbaum, R., Zeinomar, N. et al. 10-year performance of four models of breast cancer risk: a validation study. Lancet Oncol. 20, 504\u2013517 (2019).","journal-title":"Lancet Oncol."},{"key":"720_CR2","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/sj.bjc.6600008","volume":"86","author":"AC Antoniou","year":"2002","unstructured":"Antoniou, A. C., Pharoah, P. D., McMullan, G., Day, N. E., Stratton, M. R., Peto, J. et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br. J. Cancer 86, 76\u201383 (2002).","journal-title":"Br. J. Cancer"},{"key":"720_CR3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1093\/jnci\/89.3.227","volume":"89","author":"DA Berry","year":"1997","unstructured":"Berry, D. A., Parmigiani, G., Sanchez, J., Schildkraut, J. & Winer, E. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J. Natl Cancer Inst. 89, 227\u2013238 (1997).","journal-title":"J. Natl Cancer Inst."},{"key":"720_CR4","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/sim.1668","volume":"23","author":"J Tyrer","year":"2004","unstructured":"Tyrer, J., Duffy, S. W. & Cuzick, J. A breast cancer prediction model incorporating familial and personal risk factors. Stat. Med. 23, 1111\u20131130 (2004).","journal-title":"Stat. Med."},{"key":"720_CR5","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1038\/gim.2016.31","volume":"18","author":"AJ Lee","year":"2016","unstructured":"Lee, A. J., Cunningham, A. P., Tischkowitz, M., Simard, J., Pharoah, P. D., Easton, D. F. et al. Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. Genet. Med. 18, 1190\u20131198 (2016).","journal-title":"Genet. Med."},{"key":"720_CR6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ajhg.2018.11.002","volume":"104","author":"N Mavaddat","year":"2019","unstructured":"Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A. et al. Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am. J. Hum. Genet. 104, 21\u201334 (2019).","journal-title":"Am. J. Hum. Genet."},{"key":"720_CR7","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/s41588-018-0183-z","volume":"50","author":"AV Khera","year":"2018","unstructured":"Khera, A. V., Chaffin, M., Aragam, K. G., Haas, M. E., Roselli, C., Choi, S. H. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet. 50, 1219\u20131224 (2018).","journal-title":"Nat. Genet."},{"key":"720_CR8","unstructured":"Widschwendter, M., Jones, A., Evans, I., Reisel, D., Dillner, J., Sundstr\u00f6m, K. et al. Epigenome-based cancer risk prediction: rationale, opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 292 (2018)."},{"key":"720_CR9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-3-319-22909-6_2","volume":"882","author":"MB Terry","year":"2016","unstructured":"Terry, M. B., McDonald, J. A., Wu, H. C., Eng, S. & Santella, R. M. epigenetic biomarkers of breast cancer risk: across the breast cancer prevention continuum. Adv. Exp. Med. Biol. 882, 33\u201368 (2016).","journal-title":"Adv. Exp. Med. Biol."},{"key":"720_CR10","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/jnci\/djt045","volume":"105","author":"Z Xu","year":"2013","unstructured":"Xu, Z., Bolick, S. C., DeRoo, L. A., Weinberg, C. R., Sandler, D. P. & Taylor, J. A. Epigenome-wide association study of breast cancer using prospectively collected sister study samples. J. Natl Cancer Inst. 105, 694\u2013700 (2013).","journal-title":"J. Natl Cancer Inst."},{"key":"720_CR11","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s10549-014-3209-y","volume":"148","author":"G Severi","year":"2014","unstructured":"Severi, G., Southey, M. C., English, D. R., Jung, C. H., Lonie, A., McLean, C. et al. Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer. Breast Cancer Res. Treat. 148, 665\u2013673 (2014).","journal-title":"Breast Cancer Res. Treat."},{"key":"720_CR12","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-015-0104-2","volume":"7","author":"K van Veldhoven","year":"2015","unstructured":"van Veldhoven, K., Polidoro, S., Baglietto, L., Severi, G., Sacerdote, C., Panico, S. et al. Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin. Epigenetics 7, 67 (2015).","journal-title":"Clin. Epigenetics"},{"key":"720_CR13","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nsmb.2489","volume":"20","author":"I Cantone","year":"2013","unstructured":"Cantone, I. & Fisher, A. G. Epigenetic programming and reprogramming during development. Nat. Struct. Mol. Biol. 20, 282\u2013289 (2013).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"720_CR14","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1038\/sj.onc.1202086","volume":"17","author":"JC Rice","year":"1998","unstructured":"Rice, J. C., Massey-Brown, K. S. & Futscher, B. W. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17, 1807\u20131812 (1998).","journal-title":"Oncogene"},{"key":"720_CR15","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1093\/hmg\/ddp033","volume":"18","author":"JM Flanagan","year":"2009","unstructured":"Flanagan, J. M., Munoz-Alegre, M., Henderson, S., Tang, T., Sun, P., Johnson, N. et al. Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum. Mol. Genet. 18, 1332\u20131342 (2009).","journal-title":"Hum. Mol. Genet."},{"key":"720_CR16","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/cam4.1285","volume":"7","author":"D Pinto","year":"2018","unstructured":"Pinto, D., Pinto, C., Guerra, J., Pinheiro, M., Santos, R., Vedeld, H. M. et al. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation. Cancer Med. 7, 433\u2013444 (2018).","journal-title":"Cancer Med."},{"key":"720_CR17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/gim.2012.91","volume":"15","author":"RL Ward","year":"2013","unstructured":"Ward, R. L., Dobbins, T., Lindor, N. M., Rapkins, R. W. & Hitchins, M. P. Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet Med. 15, 25\u201335 (2013).","journal-title":"Genet Med."},{"key":"720_CR18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","volume":"70","author":"M Kulis","year":"2010","unstructured":"Kulis, M. & Esteller, M. DNA methylation and cancer. Adv. Genet. 70, 27\u201356 (2010).","journal-title":"Adv. Genet."},{"key":"720_CR19","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.cell.2007.01.029","volume":"128","author":"PA Jones","year":"2007","unstructured":"Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683\u2013692 (2007).","journal-title":"Cell"},{"key":"720_CR20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s10549-010-1188-1","volume":"129","author":"T Iwamoto","year":"2011","unstructured":"Iwamoto, T., Yamamoto, N., Taguchi, T., Tamaki, Y. & Noguchi, S. BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast Cancer Res. Treat. 129, 69\u201377 (2011).","journal-title":"Breast Cancer Res. Treat."},{"key":"720_CR21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1158\/1940-6207.CAPR-10-0212","volume":"4","author":"EM Wong","year":"2011","unstructured":"Wong, E. M., Southey, M. C., Fox, S. B., Brown, M. A., Dowty, J. G., Jenkins, M. A. et al. Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev. Res. (Phila) 4, 23\u201333 (2011).","journal-title":"Cancer Prev. Res. (Phila)"},{"key":"720_CR22","doi-asserted-by":"crossref","first-page":"4669","DOI":"10.1093\/hmg\/dds308","volume":"21","author":"T Hansmann","year":"2012","unstructured":"Hansmann, T., Pliushch, G., Leubner, M., Kroll, P., Endt, D., Gehrig, A. et al. Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer. Hum. Mol. Genet 21, 4669\u20134679 (2012).","journal-title":"Hum. Mol. Genet"},{"key":"720_CR23","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1158\/0008-5472.CAN-11-3157","volume":"72","author":"K Brennan","year":"2012","unstructured":"Brennan, K., Garcia-Closas, M., Orr, N., Fletcher, O., Jones, M., Ashworth, A. et al. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 72, 2304\u20132313 (2012).","journal-title":"Cancer Res."},{"key":"720_CR24","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1158\/0008-5472.CAN-07-2418","volume":"68","author":"A Potapova","year":"2008","unstructured":"Potapova, A., Hoffman, A. M., Godwin, A. K., Al-Saleem, T. & Cairns, P. Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer Res. 68, 998\u20131002 (2008).","journal-title":"Cancer Res."},{"key":"720_CR25","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1093\/carcin\/bgs201","volume":"33","author":"HC Wu","year":"2012","unstructured":"Wu, H. C., Delgado-Cruzata, L., Flom, J. D., Perrin, M., Liao, Y., Ferris, J. S. et al. Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry. Carcinogenesis 33, 1946\u20131952 (2012).","journal-title":"Carcinogenesis"},{"key":"720_CR26","first-page":"3347","volume":"57","author":"A Dobrovic","year":"1997","unstructured":"Dobrovic, A. & Simpfendorfer, D. Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res. 57, 3347\u20133350 (1997).","journal-title":"Cancer Res."},{"key":"720_CR27","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/carcin\/21.2.147","volume":"21","author":"T Bianco","year":"2000","unstructured":"Bianco, T., Chenevix-Trench, G., Walsh, D. C., Cooper, J. E. & Dobrovic, A. Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis 21, 147\u2013151 (2000).","journal-title":"Carcinogenesis"},{"key":"720_CR28","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nm.2305","volume":"17","author":"M Rodriguez-Paredes","year":"2011","unstructured":"Rodriguez-Paredes, M. & Esteller, M. Cancer epigenetics reaches mainstream oncology. Nat. Med. 17, 330\u2013339 (2011).","journal-title":"Nat. Med."},{"key":"720_CR29","doi-asserted-by":"crossref","DOI":"10.1186\/gm325","volume":"4","author":"M Szyf","year":"2012","unstructured":"Szyf, M. DNA methylation signatures for breast cancer classification and prognosis. Genome Med. 4, 26 (2012).","journal-title":"Genome Med."},{"key":"720_CR30","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-05564-z","volume":"9","author":"O Kondrashova","year":"2018","unstructured":"Kondrashova, O., Topp, M., Nesic, K., Lieschke, E., Ho, G. Y., Harrell, M. I. et al. Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nat. Commun. 9, 3970 (2018).","journal-title":"Nat. Commun."},{"key":"720_CR31","doi-asserted-by":"crossref","first-page":"6195","DOI":"10.1158\/0008-5472.CAN-11-1630","volume":"71","author":"MJ Fackler","year":"2011","unstructured":"Fackler, M. J., Umbricht, C. B., Williams, D., Argani, P., Cruz, L. A., Merino, V. F. et al. Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence. Cancer Res. 71, 6195\u20136207 (2011).","journal-title":"Cancer Res."},{"key":"720_CR32","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms6899","volume":"6","author":"C Stirzaker","year":"2015","unstructured":"Stirzaker, C., Zotenko, E., Song, J. Z., Qu, W., Nair, S. S., Locke, W. J. et al. Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value. Nat. Commun. 6, 5899 (2015).","journal-title":"Nat. Commun."},{"key":"720_CR33","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1002\/1878-0261.12309","volume":"12","author":"S Zhang","year":"2018","unstructured":"Zhang, S., Wang, Y., Gu, Y., Zhu, J., Ci, C., Guo, Z. et al. Specific breast cancer prognosis-subtype distinctions based on DNA methylation patterns. Mol. Oncol. 12, 1047\u20131060 (2018).","journal-title":"Mol. Oncol."},{"key":"720_CR34","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-016-0282-6","volume":"8","author":"Q Tang","year":"2016","unstructured":"Tang, Q., Cheng, J., Cao, X., Surowy, H. & Burwinkel, B. Blood-based DNA methylation as biomarker for breast cancer: a systematic review. Clin. Epigenetics 8, 115 (2016).","journal-title":"Clin. Epigenetics"},{"key":"720_CR35","doi-asserted-by":"crossref","first-page":"e46705","DOI":"10.1371\/journal.pone.0046705","volume":"7","author":"BT Adalsteinsson","year":"2012","unstructured":"Adalsteinsson, B. T., Gudnason, H., Aspelund, T., Harris, T. B., Launer, L. J., Eiriksdottir, G. et al. Heterogeneity in white blood cells has potential to confound DNA methylation measurements. PLoS ONE 7, e46705 (2012).","journal-title":"PLoS ONE"},{"key":"720_CR36","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-13-86","volume":"13","author":"EA Houseman","year":"2012","unstructured":"Houseman, E. A., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H. et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinforma. 13, 86 (2012).","journal-title":"BMC Bioinforma."},{"key":"720_CR37","doi-asserted-by":"crossref","DOI":"10.1186\/s13058-019-1145-9","volume":"21","author":"C Bodelon","year":"2019","unstructured":"Bodelon, C., Ambatipudi, S., Dugue, P. A., Johansson, A., Sampson, J. N., Hicks, B. et al. Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies. Breast Cancer Res. 21, 62 (2019).","journal-title":"Breast Cancer Res."},{"key":"720_CR38","volume":"5","author":"L Zhang","year":"2015","unstructured":"Zhang, L. & Long, X. Association of BRCA1 promoter methylation with sporadic breast cancers: evidence from 40 studies. Sci Rep. 5, 17869 (2015).","journal-title":"Sci Rep."},{"key":"720_CR39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s10549-008-0121-3","volume":"116","author":"T Kontorovich","year":"2009","unstructured":"Kontorovich, T., Cohen, Y., Nir, U. & Friedman, E. Promoter methylation patterns of ATM, ATR, BRCA1, BRCA2 and P53 as putative cancer risk modifiers in Jewish BRCA1\/BRCA2 mutation carriers. Breast Cancer Res. Treat. 116, 195\u2013200 (2009).","journal-title":"Breast Cancer Res. Treat."},{"key":"720_CR40","doi-asserted-by":"crossref","first-page":"e177","DOI":"10.1016\/j.canep.2012.02.001","volume":"36","author":"R Bosviel","year":"2012","unstructured":"Bosviel, R., Garcia, S., Lavediaux, G., Michard, E., Dravers, M., Kwiatkowski, F. et al. BRCA1 promoter methylation in peripheral blood DNA was identified in sporadic breast cancer and controls. Cancer Epidemiol. 36, e177\u2013e182 (2012).","journal-title":"Cancer Epidemiol."},{"key":"720_CR41","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.yexmp.2018.11.006","volume":"105","author":"CM Scott","year":"2018","unstructured":"Scott, C. M., Wong, E. M., Joo, J. E., Dugue, P. A., Jung, C. H., O\u2019Callaghan, N. et al. Genome-wide DNA methylation assessment of \u2018BRCA1-like\u2019 early-onset breast cancer: Data from the Australian Breast Cancer Family Registry. Exp. Mol. Pathol. 105, 404\u2013410 (2018).","journal-title":"Exp. Mol. Pathol."},{"key":"720_CR42","volume":"8","author":"EM Wong","year":"2015","unstructured":"Wong, E. M., Joo, J. E., McLean, C. A., Baglietto, L., English, D. R., Severi, G. et al. Tools for translational epigenetic studies involving formalin-fixed paraffin-embedded human tissue: applying the Infinium HumanMethyation450 Beadchip assay to large population-based studies. BMC Res. Notes 8, 543 (2015).","journal-title":"BMC Res. Notes"},{"key":"720_CR43","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature12433","volume":"500","author":"MJ Ziller","year":"2013","unstructured":"Ziller, M. J., Gu, H., Muller, F., Donaghey, J., Tsai, L. T., Kohlbacher, O. et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477\u2013481 (2013).","journal-title":"Nature"},{"key":"720_CR44","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1089\/gte.2006.10.281","volume":"10","author":"Y Chen","year":"2006","unstructured":"Chen, Y., Toland, A. E., McLennan, J., Fridlyand, J., Crawford, B., Costello, J. F. et al. Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer. Genet. Test 10, 281\u2013284 (2006).","journal-title":"Genet. Test"},{"key":"720_CR45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ajhg.2018.07.002","volume":"103","author":"DGR Evans","year":"2018","unstructured":"Evans, D. G. R., van Veen, E. M., Byers, H. J., Wallace, A. J., Ellingford, J. M., Beaman, G. et al. A dominantly inherited 5' UTR variant causing methylation-associated silencing of BRCA1 as a cause of breast and ovarian cancer. Am. J. Hum. Genet 103, 213\u2013220 (2018).","journal-title":"Am. J. Hum. Genet"},{"key":"720_CR46","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1006\/meth.2001.1268","volume":"25","author":"BN Trinh","year":"2001","unstructured":"Trinh, B. N., Long, T. I. & Laird, P. W. DNA methylation analysis by MethyLight technology. Methods 25, 456\u2013462 (2001).","journal-title":"Methods"},{"key":"720_CR47","doi-asserted-by":"crossref","first-page":"9821","DOI":"10.1073\/pnas.93.18.9821","volume":"93","author":"JG Herman","year":"1996","unstructured":"Herman, J. G., Graff, J. R., Myohanen, S., Nelkin, B. D. & Baylin, S. B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad. Sci. USA 93, 9821\u20139826 (1996).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"720_CR48","doi-asserted-by":"crossref","first-page":"15785","DOI":"10.1073\/pnas.0507816102","volume":"102","author":"M Ehrich","year":"2005","unstructured":"Ehrich, M., Nelson, M. R., Stanssens, P., Zabeau, M., Liloglou, T., Xinarianos, G. et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc. Natl Acad. Sci. USA 102, 15785\u201315790 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"720_CR49","doi-asserted-by":"crossref","first-page":"152","DOI":"10.2144\/03351md02","volume":"35","author":"J Tost","year":"2003","unstructured":"Tost, J., Dunker, J. & Gut, I. G. Analysis and quantification of multiple methylation variable positions in CpG islands by Pyrosequencing. Biotechniques 35, 152\u2013156 (2003).","journal-title":"Biotechniques"},{"key":"720_CR50","doi-asserted-by":"crossref","first-page":"692","DOI":"10.4161\/epi.6.6.16196","volume":"6","author":"J Sandoval","year":"2011","unstructured":"Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M. A., Bibikova, M. et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6, 692\u2013702 (2011).","journal-title":"Epigenetics"},{"key":"720_CR51","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2217\/epi.11.105","volume":"3","author":"S Dedeurwaerder","year":"2011","unstructured":"Dedeurwaerder, S., Defrance, M., Calonne, E., Denis, H., Sotiriou, C. & Fuks, F. Evaluation of the Infinium Methylation 450K technology. Epigenomics 3, 771\u2013784 (2011).","journal-title":"Epigenomics"},{"key":"720_CR52","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-1066-1","volume":"17","author":"R Pidsley","year":"2016","unstructured":"Pidsley, R., Zotenko, E., Peters, T. J., Lawrence, M. G., Risbridger, G. P., Molloy, P. et al. Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol 17, 208 (2016).","journal-title":"Genome Biol"},{"key":"720_CR53","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1093\/ije\/dyv189","volume":"44","author":"PA Dugue","year":"2015","unstructured":"Dugue, P. A., English, D. R., MacInnis, R. J., Joo, J. E., Jung, C. H. & Milne, R. L. The repeatability of DNA methylation measures may also affect the power of epigenome-wide association studies. Int. J. Epidemiol. 44, 1460\u20131461 (2015).","journal-title":"Int. J. Epidemiol."},{"key":"720_CR54","doi-asserted-by":"crossref","DOI":"10.1038\/srep15375","volume":"5","author":"T De Meyer","year":"2015","unstructured":"De Meyer, T., Bady, P., Trooskens, G., Kurscheid, S., Bloch, J., Kros, J. M. et al. Genome-wide DNA methylation detection by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison. Sci. Rep. 5, 15375 (2015).","journal-title":"Sci. Rep."},{"key":"720_CR55","volume":"13","author":"JE Joo","year":"2013","unstructured":"Joo, J. E., Wong, E. M., Baglietto, L., Jung, C. H., Tsimiklis, H., Park, D. J. et al. The use of DNA from archival dried blood spots with the Infinium HumanMethylation450 array. BMC Biotechnol. 13, 23 (2013).","journal-title":"BMC Biotechnol."},{"key":"720_CR56","doi-asserted-by":"crossref","DOI":"10.1186\/s13104-017-3110-y","volume":"11","author":"FJ Bruinsma","year":"2018","unstructured":"Bruinsma, F. J., Joo, J. E., Wong, E. M., Giles, G. G. & Southey, M. C. The utility of DNA extracted from saliva for genome-wide molecular research platforms. BMC Res. Notes 11, 8 (2018).","journal-title":"BMC Res. Notes"},{"key":"720_CR57","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1093\/nar\/gki901","volume":"33","author":"A Meissner","year":"2005","unstructured":"Meissner, A., Gnirke, A., Bell, G. W., Ramsahoye, B., Lander, E. S. & Jaenisch, R. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res. 33, 5868\u20135877 (2005).","journal-title":"Nucleic Acids Res."},{"key":"720_CR58","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nprot.2014.114","volume":"10","author":"MA Urich","year":"2015","unstructured":"Urich, M. A., Nery, J. R., Lister, R., Schmitz, R. J. & Ecker, J. R. MethylC-seq library preparation for base-resolution whole-genome bisulfite sequencing. Nat. Protoc. 10, 475\u2013483 (2015).","journal-title":"Nat. Protoc."},{"key":"720_CR59","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature08514","volume":"462","author":"R Lister","year":"2009","unstructured":"Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315\u2013322 (2009).","journal-title":"Nature"},{"key":"720_CR60","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1073\/pnas.0806560105","volume":"105","author":"BT Heijmans","year":"2008","unstructured":"Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046\u201317049 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"720_CR61","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.envint.2017.08.006","volume":"108","author":"M Plusquin","year":"2017","unstructured":"Plusquin, M., Guida, F., Polidoro, S., Vermeulen, R., Raaschou-Nielsen, O., Campanella, G. et al. DNA methylation and exposure to ambient air pollution in two prospective cohorts. Environ. Int. 108, 127\u2013136 (2017).","journal-title":"Environ. Int."},{"key":"720_CR62","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s10552-017-0958-z","volume":"28","author":"DJ Boyne","year":"2017","unstructured":"Boyne, D. J., Friedenreich, C. M., McIntyre, J. B., Stanczyk, F. Z., Courneya, K. S. & King, W. D. Endogenous sex hormone exposure and repetitive element DNA methylation in healthy postmenopausal women. Cancer Causes Control 28, 1369\u20131379 (2017).","journal-title":"Cancer Causes Control"},{"key":"720_CR63","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-019-0664-7","volume":"11","author":"A Johansson","year":"2019","unstructured":"Johansson, A., Palli, D., Masala, G., Grioni, S., Agnoli, C., Tumino, R. et al. Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. Clin. Epigenetics 11, 66 (2019).","journal-title":"Clin. Epigenetics"},{"key":"720_CR64","first-page":"129","volume":"39","author":"N Al-Moghrabi","year":"2011","unstructured":"Al-Moghrabi, N., Al-Qasem, A. J. & Aboussekhra, A. Methylation-related mutations in the BRCA1 promoter in peripheral blood cells from cancer-free women. Int. J. Oncol. 39, 129\u2013135 (2011).","journal-title":"Int. J. Oncol."},{"key":"720_CR65","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s10549-014-3179-0","volume":"148","author":"S Gupta","year":"2014","unstructured":"Gupta, S., Jaworska-Bieniek, K., Narod, S. A., Lubinski, J., Wojdacz, T. K. & Jakubowska, A. Methylation of the BRCA1 promoter in peripheral blood DNA is associated with triple-negative and medullary breast cancer. Breast Cancer Res. Treat. 148, 615\u2013622 (2014).","journal-title":"Breast Cancer Res. Treat."},{"key":"720_CR66","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2407-14-830","volume":"14","author":"N Al-Moghrabi","year":"2014","unstructured":"Al-Moghrabi, N., Nofel, A., Al-Yousef, N., Madkhali, S., Bin Amer, S. M., Alaiya, A. et al. The molecular significance of methylated BRCA1 promoter in white blood cells of cancer-free females. BMC Cancer 14, 830 (2014).","journal-title":"BMC Cancer"},{"key":"720_CR67","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.2217\/fon.11.123","volume":"7","author":"TK Wojdacz","year":"2011","unstructured":"Wojdacz, T. K., Thestrup, B. B., Cold, S., Overgaard, J. & Hansen, L. L. No difference in the frequency of locus-specific methylation in the peripheral blood DNA of women diagnosed with breast cancer and age-matched controls. Future Oncol. 7, 1451\u20131455 (2011).","journal-title":"Future Oncol."},{"key":"720_CR68","doi-asserted-by":"crossref","first-page":"819","DOI":"10.7150\/jca.12174","volume":"6","author":"YH Cho","year":"2015","unstructured":"Cho, Y. H., McCullough, L. E., Gammon, M. D., Wu, H. C., Zhang, Y. J., Wang, Q. et al. Promoter hypermethylation in white blood cell DNA and breast cancer risk. J. Cancer 6, 819\u2013824 (2015).","journal-title":"J. Cancer"},{"key":"720_CR69","doi-asserted-by":"crossref","DOI":"10.1186\/bcr1858","volume":"10","author":"C Snell","year":"2008","unstructured":"Snell, C., Krypuy, M., Wong, E. M., Loughrey, M. B. & Dobrovic, A. BRCA1 promoter methylation in peripheral blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast Cancer Res. 10, R12 (2008).","journal-title":"Breast Cancer Res."},{"key":"720_CR70","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1093\/jnci\/95.6.448","volume":"95","author":"GS Dite","year":"2003","unstructured":"Dite, G. S., Jenkins, M. A., Southey, M. C., Hocking, J. S., Giles, G. G., McCredie, M. R. et al. Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. J. Natl Cancer Inst. 95, 448\u2013457 (2003).","journal-title":"J. Natl Cancer Inst."},{"key":"720_CR71","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ebiom.2016.02.008","volume":"5","author":"YJBT Zheng","year":"2016","unstructured":"Zheng, Y. J. B. T., Colicino, E., Liu, L., Zhang, W., Dai, Q., Shrubsole, M. J., Kibbe, W. A., Gao, T., Zhang, Z., Jafari, N., Vokonas, P., Schwartz, J., Baccarelli, A. A. & HouL Blood epigenetic age may predict cancer incidence and mortality. EBioMedicine 5, 68\u201373 (2016).","journal-title":"EBioMedicine"},{"key":"720_CR72","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10522-017-9695-7","volume":"18","author":"N Gensous","year":"2017","unstructured":"Gensous, N., Bacalini, M. G., Pirazzini, C., Marasco, E., Giuliani, C., Ravaioli, F. et al. The epigenetic landscape of age-related diseases: the geroscience perspective. Biogerontology 18, 549\u2013559 (2017).","journal-title":"Biogerontology"},{"key":"720_CR73","volume":"11","author":"D Peter","year":"2019","unstructured":"Peter, D., Fransquet, J. W., Robyn, L., Woods, Michael, E., Ernst & Ryan, Joanne The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis. Clin. Epigenetics 11, 62 (2019).","journal-title":"Clin. Epigenetics"},{"key":"720_CR74","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2013-14-10-r115","volume":"14","author":"S Horvath","year":"2013","unstructured":"Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).","journal-title":"Genome Biol."},{"key":"720_CR75","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molcel.2012.10.016","volume":"49","author":"G Hannum","year":"2013","unstructured":"Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49, 359\u2013367 (2013).","journal-title":"Mol Cell"},{"key":"720_CR76","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","volume":"10","author":"ME Levine","year":"2018","unstructured":"Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10, 573\u2013591 (2018).","journal-title":"Aging (Albany NY)"},{"key":"720_CR77","doi-asserted-by":"crossref","unstructured":"Kresovich, J. K., Xu. Z., O\u2019Brien. K. M., Weinberg. C. R., Sandler, D. P., Taylor, J. A. Methylation-based biological age and breast cancer risk. J. Natl Cancer Inst. 111, 1051\u20131058 (2019).","DOI":"10.1093\/jnci\/djz020"},{"key":"720_CR78","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1001\/jama.2012.145018","volume":"309","author":"RH Johnson","year":"2013","unstructured":"Johnson, R. H., Chien, F. L. & Bleyer, A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA 309, 5 (2013).","journal-title":"JAMA"},{"key":"720_CR79","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S1470-2045(17)30677-0","volume":"18","author":"MM Fidler","year":"2017","unstructured":"Fidler, M. M., Gupta, S., Soerjomataram, I., Ferlay, J., Steliarova-Foucher, E. & Bray, F. Cancer incidence and mortality among young adults aged 20\u201339 years worldwide in 2012: a population-based study. Lancet Oncol. 18, 1579\u20131589 (2017).","journal-title":"Lancet Oncol."},{"key":"720_CR80","unstructured":"Cho, Y. H., Yazici, H., Wu, H. C., Terry, M. B., Gonzalez, K., Qu, M. et al. Aberrant promoter hypermethylation and genomic hypomethylation in tumor, adjacent normal tissues and blood from breast cancer patients. Anticancer Res.\u00a030, 2489\u20132496 (2010)."}],"container-title":["British Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41416-019-0720-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41416-019-0720-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41416-019-0720-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:06:46Z","timestamp":1684616806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41416-019-0720-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,18]]},"references-count":80,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,4,14]]}},"alternative-id":["720"],"URL":"https:\/\/doi.org\/10.1038\/s41416-019-0720-2","relation":{},"ISSN":["0007-0920","1532-1827"],"issn-type":[{"value":"0007-0920","type":"print"},{"value":"1532-1827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,18]]},"assertion":[{"value":"4 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"No data were generated for this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"E.M.W. is a recipient of the Dyason Fellowship. M.C.S. is a NHMRC Senior Research Fellow. M.B.T. is supported by the Breast Cancer Research Foundation.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}