Epigenome-Wide Association Study Using Prediagnostic Bloods Identifies New Genomic Regions Associated With Pancreatic Cancer Risk

BACKGROUND: Epigenome-wide association studies 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 3 prospective cohort studies. 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: Several new genomic regions were identified as being differentially methylated in cases and controls; the 5 strongest associations were observed for CpGs located in genes TMEM204/IFT140, MFSD6L, FAM134B/RETREG1, KCNQ1D, and C6orf227. For some CpGs located in chromosome 16p13.3 (near genes TMEM204 and IFT140), associations were stronger with shorter time to diagnosis (eg, odds ratio [OR] = 5.95, 95% confidence interval [CI] = 1.52 to 23.12, for top vs bottom quartile, for <5 years between blood draw and cancer diagnosis), but associations remained statistically 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 Gene Set Enrichment Analysis (GSEA) analysis. CONCLUSIONS: Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using epigenome-wide association studies approach could provide new opportunities for improving treatment and prevention.