DNA methylation marks in peripheral blood and the risk of developing mature B cell neoplasms

© 2018 Dr. Nicole Wong DooDysregulation of DNA methylation is a feature of mature B cell neoplasms (MBCN) but it is not known whether methylation changes can be detected in blood-derived DNA prior to MBCN diagnosis. In this prospective cohort study, peripheral blood was collected from healthy participants at recruitment (1990-1994). Participants who were subsequently diagnosed with MBCN (chronic lymphocytic lymphoma, B cell non-Hodgkin lymphoma and myeloma) up to 2012 were matched to the same number of controls based on age, sex, ethnicity, and type of blood sample (Guthrie cards, mononuclear cells, buffy coats). DNA methylation was measured using the Infinium®HumanMethylation450 BeadChip. Peripheral blood DNA was collected from 438 matched case-control pairs, a median of 10.6 years prior to diagnosis with MBCN. A series of analytical approaches was used in order to evaluate whether there was a distinct methylation profile associated with MBCN. First, global methylation analysis was performed, identifying increased methylation in CpG island and promoter-associated CpGs and widespread hypomethylation. Second, conditional logistic regression was used to identify differentially methylated CpG sites (DMPs) and kernel smoothing was used to identify differentially methylated regions (DMRs). Third, differential methylation variability, considered to be a distinctive feature in cancer, was assessed. In total, 1,338 DMPs were identified, of which 90 had gain of methylation in CpG sites associated with homeobox genes and 1,248 had loss of methylation in CpG sites associated with MAPK signaling pathway genes and genes involved in chemokine signaling pathways. There were 9,857 DMRs, with a cluster of 151 DMRs located in a 3.8kb region on 6p21.3, corresponding to the major histocompatibility locus. Differential methylation variability analysis identified 144 novel CpG sites distinctively located outside CpG islands. Conclusion: Distinctive changes in peripheral blood DNA methylation can be detected many years prior to diagnosis with MBCN, suggesting that changes in DNA methylation are an early epigenetic event. This contributes to our understanding of the timing of methylation changes in the development of MBCN