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Breast Cancer Research
Published in: Breast Cancer Research 1/2022

Open Access 01-12-2022 | Breast Cancer | Research

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies

Authors: Pierre-Antoine Dugué, Clara Bodelon, Felicia F. Chung, Hannah R. Brewer, Srikant Ambatipudi, Joshua N. Sampson, Cyrille Cuenin, Veronique Chajès, Isabelle Romieu, Giovanni Fiorito, Carlotta Sacerdote, Vittorio Krogh, Salvatore Panico, Rosario Tumino, Paolo Vineis, Silvia Polidoro, Laura Baglietto, Dallas English, Gianluca Severi, Graham G. Giles, Roger L. Milne, Zdenko Herceg, Montserrat Garcia-Closas, James M. Flanagan, Melissa C. Southey

Published in: Breast Cancer Research | Issue 1/2022

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Abstract

Background

DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer.

Methods

Using data from four prospective case–control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.

Results

None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath ‘age acceleration’ (AA): OR per SD = 1.02, 95%CI: 0.95–1.10; AA-Hannum: OR = 1.03, 95%CI:0.95–1.12; PhenoAge: OR = 1.01, 95%CI: 0.94–1.09 and GrimAge: OR = 1.03, 95%CI: 0.94–1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01–1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics.

Conclusion

We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.
Appendix
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Literature
1.
Wong EM, Southey MC, Fox SB, Brown MA, Dowty JG, Jenkins MA, Giles GG, Hopper JL, Dobrovic A. Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila). 2011;4(1):23–33.CrossRef
2.
Flanagan JM, Munoz-Alegre M, Henderson S, Tang T, Sun P, Johnson N, Fletcher O, dos Santos SI, Peto J, Boshoff C. Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum Mol Genet. 2009;18(7):1332–42.PubMedPubMedCentralCrossRef
3.
Brennan K, Garcia-Closas M, Orr N, Fletcher O, Jones M, Ashworth A, Swerdlow A, Thorne H, Riboli E, Vineis P. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Can Res. 2012;72(9):2304–13.CrossRef
4.
Tang Q, Cheng J, Cao X, Surowy H, Burwinkel B. Blood-based DNA methylation as biomarker for breast cancer: a systematic review. Clin Epigenet. 2016;8(1):1–18.CrossRef
5.
Brennan K, Flanagan JM. Is there a link between genome-wide hypomethylation in blood and cancer risk? Cancer Prev Res (Phila). 2012;5(12):1345–57.CrossRef
6.
Severi G, Southey MC, English DR, Jung C-H, Lonie A, McLean C, Tsimiklis H, Hopper JL, Giles GG, Baglietto L. Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer. Breast Cancer Res Treat. 2014;148(3):665–73.PubMedCrossRef
7.
van Veldhoven K, Polidoro S, Baglietto L, Severi G, Sacerdote C, Panico S, Mattiello A, Palli D, Masala G, Krogh V, et al. Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin Epigenet. 2015;7(1):67.CrossRef
8.
Ambatipudi S, Horvath S, Perrier F, Cuenin C, Hernandez-Vargas H, Le Calvez-Kelm F, Durand G, Byrnes G, Ferrari P, Bouaoun L, et al. DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility. Eur J Cancer. 2017;75:299–307.PubMedPubMedCentralCrossRef
9.
Sturgeon SR, Pilsner JR, Arcaro KF, Ikuma K, Wu H, Kim SM, Chopra-Tandon N, Karpf AR, Ziegler RG, Schairer C, et al. White blood cell DNA methylation and risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Breast Cancer Res. 2017;19(1):94.PubMedPubMedCentralCrossRef
10.
Bodelon C, Ambatipudi S, Dugué P-A, Johansson A, Sampson JN, Hicks B, Karlins E, Hutchinson A, Cuenin C, Chajès V, et al. Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies. Breast Cancer Res. 2019;21(1):62.PubMedPubMedCentralCrossRef
11.
Xu Z, Sandler DP, Taylor JA. Blood DNA methylation and breast cancer: a prospective case-cohort analysis in the Sister Study. J Natl Cancer Inst. 2019;112:87–94.PubMedCentralCrossRef
12.
Yang Y, Wu L, Shu X-O, Cai Q, Shu X, Li B, Guo X, Ye F, Michailidou K, Bolla MK. Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228,951 women of European descent. J Natl Cancer Inst. 2019;112:295–304.PubMedCentralCrossRef
13.
Geurts YM, Dugué PA, Joo JE, Makalic E, Jung CH, Guan W, Nguyen S, Grove ML, Wong EM, Hodge AM, et al. Novel associations between blood DNA methylation and body mass index in middle-aged and older adults. Int J Obes (Lond). 2018;42(4):887–96.CrossRef
14.
Dugué PA, Jung CH, Joo JE, Wang X, Wong EM, Makalic E, Schmidt DF, Baglietto L, Severi G, Southey MC, et al. Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility. Epigenetics. 2020;15(4):358–68.PubMedCrossRef
15.
Dugué PA, Wilson R, Lehne B, Jayasekara H, Wang X, Jung CH, Joo JE, Makalic E, Schmidt DF, Baglietto L, et al. Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data. Addict Biol. 2021;26(1): e12855.PubMedCrossRef
16.
Yu C, Wong EM, Joo JE, Hodge AM, Makalic E, Schmidt D, Buchanan DD, Severi G, Hopper JL, English DR. Epigenetic drift association with cancer risk and survival, and modification by sex. Cancers. 2021;13(8):1881.PubMedPubMedCentralCrossRef
17.
18.
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359–67.PubMedCrossRef
19.
Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10(4):573–91.PubMedPubMedCentralCrossRef
20.
Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging. 2019;11(2):303–27.PubMedPubMedCentralCrossRef
21.
Kresovich JK, Xu Z, O’Brien KM, Weinberg CR, Sandler DP, Taylor JA. Methylation-based biological age and breast cancer risk. J Natl Cancer Inst. 2019;111:1051–8.PubMedPubMedCentralCrossRef
22.
Kresovich JK, Xu Z, O’Brien KM, Weinberg CR, Sandler DP, Taylor JA. Epigenetic mortality predictors and incidence of breast cancer. Aging. 2019;11(24):11975–87.PubMedPubMedCentralCrossRef
23.
Dugué PA, Bassett JK, Joo JE, Jung CH, Ming Wong E, Moreno-Betancur M, Schmidt D, Makalic E, Li S, Severi G, et al. DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies. Int J Cancer. 2018;142(8):1611–9.PubMedCrossRef
24.
Dugué PA, Bassett JK, Wong EM, Joo JE, Li S, Yu C, Schmidt DF, Makalic E, Doo NW, Buchanan DD, et al. Biological aging measures based on blood DNA methylation and risk of cancer: a prospective study. JNCI Cancer Spectr. 2021;5(1):109.CrossRef
25.
Joehanes R, Just AC, Marioni RE, Pilling LC, Reynolds LM, Mandaviya PR, Guan W, Xu T, Elks CE, Aslibekyan S, et al. Epigenetic signatures of cigarette smoking. Circ Cardiovasc Genet. 2016;9(5):436–47.PubMedPubMedCentralCrossRef
26.
Liu C, Marioni RE, Hedman ÅK, Pfeiffer L, Tsai PC, Reynolds LM, Just AC, Duan Q, Boer CG, Tanaka T, et al. A DNA methylation biomarker of alcohol consumption. Mol Psychiatry. 2016;23(2):422–33.PubMedPubMedCentralCrossRef
27.
Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, Tsai PC, Ried JS, Zhang W, Yang Y, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541(7635):81–6.PubMedCrossRef
28.
Mendelson MM, Marioni RE, Joehanes R, Liu C, Hedman AK, Aslibekyan S, Demerath EW, Guan W, Zhi D, Yao C, et al. Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a Mendelian randomization approach. PLoS Med. 2017;14(1): e1002215.PubMedPubMedCentralCrossRef
29.
Milne RL, Fletcher AS, MacInnis RJ, Hodge AM, Hopkins AH, Bassett JK, Bruinsma FJ, Lynch BM, Dugué PA, Jayasekara H, et al. Cohort profile: the Melbourne collaborative cohort study (Health 2020). Int J Epidemiol. 2017;46(6):1757–1757i.PubMedCrossRef
30.
Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, Fogel R, Gelmann EP, Gilbert F, Hasson MA. Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control Clin Trials. 2000;21(6):273S-309S.PubMedCrossRef
31.
Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, Wiencke JK, Kelsey KT. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform. 2012;13(1):86.CrossRef
32.
33.
McCartney DL, Hillary RF, Stevenson AJ, Ritchie SJ, Walker RM, Zhang Q, Morris SW, Bermingham ML, Campbell A, Murray AD, et al. Epigenetic prediction of complex traits and death. Genome Biol. 2018;19(1):136.PubMedPubMedCentralCrossRef
34.
Kresovich JK, Xu Z, O’Brien KM, Weinberg CR, Sandler DP, Taylor JA. Methylation-based biological age and breast cancer risk. J Natl Cancer Inst. 2019;111(10):1051–8.PubMedPubMedCentralCrossRef
35.
Durso DF, Bacalini MG, Sala C, Pirazzini C, Marasco E, Bonafé M, do Valle ÍF, Gentilini D, Castellani G, Faria AMC, et al. Acceleration of leukocytes’ epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer. Oncotarget. 2017;8(14):23237–45.PubMedPubMedCentralCrossRef
36.
Hillary RF, Stevenson AJ, McCartney DL, Campbell A, Walker RM, Howard DM, Ritchie CW, Horvath S, Hayward C, McIntosh AM. Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden. Clin Epigenet. 2020;12(1):1–12.CrossRef
37.
Langdon RJ, Beynon RA, Ingarfield K, Marioni RE, McCartney DL, Martin RM, Ness AR, Pawlita M, Waterboer T, Relton C, et al. Epigenetic prediction of complex traits and mortality in a cohort of individuals with oropharyngeal cancer. Clin Epigenet. 2020;12(1):58.CrossRef
38.
Dugué P-A, Yu C, Hodge AM, Wong EM, Joo JE, Jung C-H, Schmidt D, Makalic E, Buchanan DD, Severi G, et al. Methylation scores for smoking, alcohol consumption, and body mass index and risk of seven types of cancer. Int J Cancer. 2021;142:691.
39.
Tao K, Sutton J, Flanagan JM. Pan-cancer DNA methylation signature quantification of lifestyle exposures and cancer prognosis; 2021.
40.
Dugué P-A, Hodge AM, Wong EM, Joo JE, Jung C-H, Hopper JL, English DR, Giles GG, Milne RL, Southey MC. Methylation marks of prenatal exposure to maternal smoking and risk of cancer in adulthood. Int J Epidemiol. 2020;50:105–15.CrossRef
41.
Kresovich JK, Xu Z, O’Brien KM, Shi M, Weinberg CR, Sandler DP, Taylor JA. Blood DNA methylation profiles improve breast cancer prediction. Mol Oncol. 2022;16(1):42–53.PubMedCrossRef
42.
Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O’Brien KM, Adami H-O, Baglietto L, Bernstein L, Bertrand KA. Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncol. 2018;4(11):e181771–e181771.PubMedPubMedCentralCrossRef
43.
James F, Wootton S, Jackson A, Wiseman M, Copson E, Cutress R. Obesity in breast cancer—what is the risk factor? Eur J Cancer. 2015;51(6):705–20.PubMedCrossRef
44.
Li S, Dugué PA, Baglietto L, Severi G, Wong EM, Nguyen TL, Stone J, English DR, Southey MC, Giles GG, et al. Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures. Int J Cancer. 2019;145(7):1768–73.PubMedCrossRef
45.
Johansson A, Palli D, Masala G, Grioni S, Agnoli C, Tumino R, Giurdanella MC, Fasanelli F, Sacerdote C, Panico S, et al. Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. Clin Epigenet. 2019;11(1):66.CrossRef
Metadata
Title
Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies
Authors
Pierre-Antoine Dugué
Clara Bodelon
Felicia F. Chung
Hannah R. Brewer
Srikant Ambatipudi
Joshua N. Sampson
Cyrille Cuenin
Veronique Chajès
Isabelle Romieu
Giovanni Fiorito
Carlotta Sacerdote
Vittorio Krogh
Salvatore Panico
Rosario Tumino
Paolo Vineis
Silvia Polidoro
Laura Baglietto
Dallas English
Gianluca Severi
Graham G. Giles
Roger L. Milne
Zdenko Herceg
Montserrat Garcia-Closas
James M. Flanagan
Melissa C. Southey
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2022
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-022-01554-8

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