Acceleration of leukocytes’ epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer

// Danielle Fernandes Durso 1, 2, * , Maria Giulia Bacalini 3, * , Claudia Sala 4, 9 , Chiara Pirazzini 3 , Elena Marasco 1 , Massimiliano Bonafé 1 , Ítalo Faria do Valle 4 , Davide Gentilini 5 , Gastone Castellani 4, 9 , Ana Maria Caetano Faria 6 , Claudio Franceschi 3, * , Paolo Garagnani 1, 7, 8, 9, * , Christine Nardini 10, 11, * 1 Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy 2 National Counsel of Technological and Scientific Development (CNPq), Ministry of Science Technology and Innovation (MCTI), Brasilia, Brazil 3 IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy 4 Department of Physics and Astronomy, University of Bologna, Bologna, Italy 5 Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy 6 Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil 7 Applied Biomedical Research Center, S. Orsola-Malpighi Polyclinic, Bologna, Italy 8 Interdepartmental Center “L. Galvani”, University of Bologna, Bologna, Italy 9 Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden 10 Personal Genomics S.r.l., Verona, Italy 11 CNR IAC “Mauro Picone”, Rome, Italy * These authors contributed equally to this work Correspondence to: Christine Nardini, email: [email protected] Paolo Garagnani, email: [email protected] Claudio Franceschi, email: [email protected] Keywords: epigenetic clock(definition), ELOVL2, FHL2, cancer, blood Received: October 19, 2016      Accepted: February 12, 2017      Published: February 21, 2017 ABSTRACT Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.