Abstract
Aberrant DNA methylation is often involved in carcinogenesis. Our initial goal was to identify DNA methylation biomarkers associated with pancreatic cancer. A genomewide methylation study was performed on DNA from pancreatic ductal adenocarcinoma (PDAC) and endocrine pancreas tumors. Validation of DNA methylation patterns and concomitant alterations in expression of gene candidates was performed on patient samples and pancreatic cancer cell lines. Furthermore, validation was done on independent data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Finally, droplet digital PCR was employed to detect DNA methylation marks in cell‐free (cf) DNA isolated from plasma samples of PDAC patients and cancer‐free blood donors. Hypermethylation of the SST gene (encoding somatostatin) and concomitant downregulation of its expression were discovered in PDAC and endocrine tumor tissues while not being present in chronic pancreatitis (inflamed) tissues and normal pancreas. Fittingly, treatment with a somatostatin agonist (octreotide) reduced cell proliferation and migration of pancreatic cancer cells. Diagnostic performance of SST methylation in a receiver operating characteristic curve analysis was 100% and 89% for tissue and plasma samples, respectively. A large body of TCGA and GEO data confirmed SST hypermethylation and downregulation in PDAC and showed a similar effect in a broad spectrum of other tumor entities. SST promoter methylation represents a sensitive and promising molecular, pan‐cancer biomarker detectable in tumor tissue, and liquid biopsy samples.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the currently fourth leading cause of cancer-related death in developed countries, with a 5-year survival rate of about 6% (Rahib et al, 2014; Siegel et al, 2019)
Since the GenotypeTissue Expression (GTEx) project data showed that SST was highly expressed in different parts of brain and gastrointestinal tissues (Mele et al, 2015), we investigated the expression and methylation of the SST gene across other gastrointestinal cancer entities in the The Cancer Genome Atlas (TCGA) database: tumors and normal esophagus (TCGA-esophageal carcinoma (ESCA)), stomach (TCGA-stomach adenocarcinoma (STAD)), colon (TCGA-colon adenocarcinoma (COAD)) and rectum (TCGA-rectum adenocarcinoma (READ)) tissues
After performing a genomewide analysis of DNA methylation by assaying more than 450 000 CpG sites across the genome with the 450k Illumina microarray, principal component analysis (PCA) of the data was performed to compare different samples based on the b-values
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the currently fourth leading cause of cancer-related death in developed countries, with a 5-year survival rate of about 6% (Rahib et al, 2014; Siegel et al, 2019). It is predicted to rise and take second place only to lung cancer by year 2030. Abbreviations cfDNA, cell-free DNA; COAD, colon adenocarcinoma; COBRA, combined bisulfite restriction analysis; CP, chronic pancreatitis; CT, cystic tumors; ddPCR, droplet digital PCR; DMR, differentially methylated region; ESCA, esophageal carcinoma; FDR, false discovery rate; GEO, Gene Expression Omnibus; GTEx, Genotype-Tissue Expression; HNSC, head neck squamous cell carcinoma; IPA, ingenuity pathway analysis; N.PDAC, peritumoral tissue next to PDAC; NET, pancreatic neuroendocrine tumor; PDAC, pancreatic ductal adenocarcinoma; READ, rectum adenocarcinoma; ROC, receiver operating characteristic; STAD, stomach adenocarcinoma; TCGA, The Cancer Genome Atlas.
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