DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative

Morgan E Levine, H Dean Hosgood, Brian Chen, Devin Absher, Themistocles Assimes, Steve Horvath, Morgan E Levine, H Dean Hosgood, Brian Chen, Devin Absher, Themistocles Assimes, Steve Horvath

Abstract

Lung cancer is considered an age-associated disease, whose progression is in part due to accumulation of genomic instability as well as age-related decline in system integrity and function. Thus even among individuals exposed to high levels of genotoxic carcinogens, such as those found in cigarette smoke, lung cancer susceptibility may vary as a function of individual differences in the rate of biological aging. We recently developed a highly accurate candidate biomarker of aging based on DNA methylation (DNAm) levels, which may prove useful in assessing risk of aging-related diseases, such as lung cancer. Using data on 2,029 females from the Women's Health Initiative, we examined whether baseline measures of "intrinsic epigenetic age acceleration" (IEAA) predicted subsequent lung cancer incidence. We observed 43 lung cancer cases over the nearly twenty years of follow-up. Results showed that standardized measures of IEAA were significantly associated with lung cancer incidence (HR: 1.50, P=3.4x10-3). Furthermore, stratified Cox proportional hazard models suggested that the association may be even stronger among older individuals (70 years or above) or those who are current smokers. Overall, our results suggest that IEAA may be a useful biomarker for evaluating lung cancer susceptibility from a biological aging perspective.

Keywords: biological age; epigenetic clock; lung cancer.

Conflict of interest statement

Conflict of interest statement

The authors declare there are no potential conflicts of interest.

Figures

Figure 1
Figure 1
Smoking and age stratified barplots of standardized IEAA in cung cancer cases and controls.
Figure 2
Figure 2
Kaplan-Meier curves for 20-year lung cancer incidence.
Figure 3
Figure 3
Predicted 10-Year lung cancer incidence by age and IEAA
Figure 4
Figure 4
Baseline IEAA by smoking status and pack-years.

References

    1. Howlader N, Noone A, Krapcho M, Garshell J, Neyman N, Altekruse S, Kosary C, Yu M, Ruhl J, Tatalovich Z. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. [Based on the November 2012 SEER data submission, posted to the SEER web site, April 2013.]
    1. Group UCSW . United States Cancer Statistics: 1999–2011 incidence and mortality web-based report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2014.
    1. Bender E. Epidemiology: The dominant malignancy. Nature. 2014;513:S2–3.
    1. Warren GW, Alberg AJ, Kraft AS, Cummings KM. The 2014 Surgeon General's report: “The health consequences of smoking-50 years of progress”: a paradigm shift in cancer care. Cancer. 2014;120:1914–1916.
    1. Hecht SS. Lung carcinogenesis by tobacco smoke. Int J Cancer. 2012;131:2724–2732.
    1. National Lung Screening Trial Research T. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. Reduced lung-cancer mortality with low-dose computed tomographic screening. The New England journal of medicine. 2011;365:395–409.
    1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–1217.
    1. Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immun Ageing. 2008;5:11.
    1. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547–556.
    1. Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, van den Berg LH, Ophoff RA. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13:R97.
    1. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115.
    1. Cassidy A, Duffy SW, Myles JP, Liloglou T, Field JK. Lung cancer risk prediction: a tool for early detection. Int J Cancer. 2007;120:1–6.
    1. Yin D, Chen K. The essential mechanisms of aging: Irreparable damage accumulation of biochemical side-reactions. Experimental gerontology. 2005;40:455–465.
    1. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705.
    1. Akgun KM, Crothers K, Pisani M. Epidemiology and management of common pulmonary diseases in older persons. The journals of gerontology Series, A, Biological sciences and medical sciences. 2012;67:276–291.
    1. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010;31:89–98.
    1. Chang MY, Boulden J, Katz JB, Wang L, Meyer TJ, Soler AP, Muller AJ, Prendergast GC. Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer research. 2007;67:7605–7612.
    1. Anisimov VN, Zhukovskaya NV, Loktionov AS, Vasilyeva IA, Kaminskaya EV, Vakhtin YB. Influence of host age on lung colony forming capacity of injected rat rhabdomyosarcoma cells. Cancer Lett. 1988;40:77–82.
    1. Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, Mirabello L, Jacobs K, Wheeler W, Yeager M, Bergen AW, Li Q, Consonni D, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009;85:679–691.
    1. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature genetics. 2008;40:616–622.
    1. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008;452:633–637.
    1. Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen WV, Spitz MR, Eisen T, Amos CI, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nature genetics. 2008;40:1407–1409.
    1. Wu C, Hu Z, Yu D, Huang L, Jin G, Liang J, Guo H, Tan W, Zhang M, Qian J, Lu D, Wu T, Lin D, et al. Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer research. 2009;69:5065–5072.
    1. Truong T, Hung RJ, Amos CI, Wu X, Bickeboller H, Rosenberger A, Sauter W, Illig T, Wichmann HE, Risch A, Dienemann H, Kaaks R, Yang P, et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst. 2010;102:959–971.
    1. Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, Gibson J, Henders AK, Redmond P, Cox SR, Pattie A, Corley J, Murphy L, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25.
    1. Marioni RE, Shah S, McRae AF, Ritchie SJ, Muniz-Terrera G, Harris SE, Gibson J, Redmond P, Cox SR, Pattie A. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int J Epidemiol. 2015:dyu277.
    1. Horvath S, Garagnani P, Bacalini MG, Pirazzini C, Salvioli S, Gentilini D, Di Blasio AM, Giuliani C, Tung S, Vinters HV, Franceschi C. Accelerated epigenetic aging in Down syndrome. Aging cell. 2015;14:491–495.
    1. Horvath S, Mah V, Lu AT, Woo JS, Choi OW, Jasinska AJ, Riancho JA, Tung S, Coles NS, Braun J, Vinters HV, Coles LS. The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY) 2015;7:294–306.
    1. Walker RF, Liu JS, Peters BA, Ritz BR, Wu T, Ophoff RA, Horvath S. Epigenetic age analysis of children who seem to evade aging. Aging (Albany NY) 2015;7:334–339.
    1. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61–109.
    1. Curb JD, McTiernan A, Heckbert SR, Kooperberg C, Stanford J, Nevitt M, Johnson KC, Proulx-Burns L, Pastore L, Criqui M, Daugherty S, Morbidity WHI, Mortality C. Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Annals of epidemiology. 2003;13:S122–128.
    1. Cunningham J. The SEER program code manual: Cancer Statistics Branch, National Institutes of Health. National Cancer Institute; 1994.
    1. Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. Journal of statistical software. 2010;33:1.
    1. Fagnoni F, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, Franceschi C, Passeri M, Sansoni P. Expansion of cytotoxic CD8+ CD28-T cells in healthy ageing people, including centenarians. Immunology. 1996;88:501.
    1. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P. Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging. Blood. 2000;95:2860–2868.
    1. Gruver A, Hudson L, Sempowski G. Immunosenescence of ageing. The Journal of pathology. 2007;211:144–156.
    1. Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schächter F. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Experimental gerontology. 1994;29:601–609.
    1. Horvath S, Levine AJ. HIV-1 Infection Accelerates Age According to the Epigenetic Clock. J Infect Dis. 2015

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera