MicroRNA Processing Gene Methylation and Cancer Risk in the Normative Aging Study

Introduction: Epigenetic alterations of microRNA (miRNA) processing genes are a potentially useful cancer biomarker as they may affect tumor suppressive processes via miRNA levels. This analysis focuses on five genes in the primary miRNA processing complex previously linked to cancer in many different studies and 14 genes known to affect them. The objectives of this study are to examine associations between DNA methylation of these genes and: cancer incidence; cancer prevalence; intakes of green tea polyphenols and selenium; intakes and serum levels of folate and vitamin D; and levels of arsenic, cadmium, lead, and mercury. Methods: Data were collected for the Department of Veterans’ Affairs Normative Aging Study every 3-5 years from 1999-2013 via demographic/lifestyle interviews, medical record reviews, blood draws, toenail clippings, and X-rays from 686 consenting participants. Blood samples underwent whole-epigenome profiling using the Illumina 450K BeadChip array. Cox models and generalized estimating equations were used to model cancer incidence and prevalence, respectively. Nutrient and heavy metal analyses were conducted via penalized Least Absolute Shrinkage and Selection Operator models and supplemented with regional enrichment tests. Results: At three CpGs (DROSHA: cg23230564, TNRC6B: cg21034183, and TNRC6B: cg06751583), DNA methylation was associated with cancer development (inversely for cg23230564 and cg21034183, positively for cg06751583,). DNA methylation at one CpG (DROSHA: cg16131300) was positively associated with cancer prevalence while methylation at several hundred CpGs was associated with the micronutrients of interest. Patella and tibia lead were associated with methylation at relatively fewer (56 and six, respectively) CpGs. Other metals of interest were not associated with DNA methylation of miRNA processing genes. Regional analyses identified several nutrient- and metal-associated areas of methylation change. Discussion: This study identifies two miRNA processing genes that may be useful markers of cancer, one of which may also be a useful marker of cancer progression, which should be validated in future studies. The nutrients of interest and bone lead may also have substantial functional effects on miRNA processing, which may explain components of their health effects, and should also be explored in future studies of these exposures.