Integration of genetics and epigenetics has emerged as a powerful approach to study cellular differentiation and tumourigenesis. The study of DNA methylation is of particular importance in cancer as causal involvement has been demonstrated and it is the most stable of all epigenetic modifications, making it a desirable marker for both early detection and treatment of tumours. Hypermethylation of CpG sites in gene promoter regions leads to decreased gene expression, if such a gene is a tumour suppressor this leads to carcinogenesis.
Ten fresh frozen sporadic pancreatic NET liver tumours (3 low grade, 3 intermediate grade and 4 high grade) were analysed using the Illumina HumMeth27 beadarray (interrogating 27 500 CpG sites relating to 14 000 genes) and the Affymetrix HumanGene 1.0 ST mRNA expression array (which has 26 probes covering the full coding region of 28 869 genes).
Integrated DNA methylation and mRNA expression analysis comparing tumour grade in sporadic pancreatic NETs identified the HIF/p53 hypoxia pathway to be differentially activated between low and intermediate grade tumours (P=4×10−4). JUN, EP300, HIF1-α and ARNT which are integral member s of HIF pathway were identified. The IGF1 pathway was also identified (P=3×10−3).
This study has highlighted the significance of the HIF/p53 hypoxia pathway in the development and progression of pancreatic NETs. This confirms previous work, which has utilised immunohistochemistry to study protein expression of HIF pathway members. Once validated this pathway would provide ideal novel therapeutic targets for pancreatic NETs.