Epigenome-wide association study using prediagnostic bloods identifies a new genomic region (near TMEM204 and IFT140) associated with pancreatic cancer risk

Background: Epigenome-wide association studies (EWAS) using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design. Methods: Using a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in three prospective cohort studies (Nurses9 Health Study, Health Professionals Follow-up Study and Physicians9 Health Study). DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years. Results: A region in chromosome 16 near genes TMEM204 and IFT140 was identified as being differentially methylated in cases and controls. For some CpGs in the region, the associations were stronger with shorter time to diagnosis (e.g., OR= 5.95, 95% CI = 1.52-23.12, for top vs bottom quartile, for ≤5 years between blood draw and cancer diagnosis) but associations remained significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using GSEA analysis. Conclusions: Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways (potentially including alterations in immune subtypes) that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using EWAS approach could provide new opportunities for improving treatment and prevention.