title: Aberrant methylation of the 5' CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs.
abstract: The recently identified tumor-suppressor gene TSLC1 on chromosome 11q23.2 is frequently inactivated in human non-small cell lung adenocarcinoma by DNA methylation-associated silencing. The aim of this study was to determine if TSLC1 is inactivated in adenocarcinoma of the pancreas. We analyzed 17 pancreatic cancer cell lines, 91 primary pancreatic adenocarcinoma, 46 pancreatic intraepithelial (PanIN) precursor lesions and 15 microscopically normal pancreata for methylation of the 5' CpG island of the TSLC1 gene through methylation-specific PCR. We observed 5' CpG methylation of TSLC1 in 4 of 17 cell lines (24%). In each cell line the aberrant methylation was associated with loss of TSLC1 expression by RT-PCR that was reversible after treatment with the DNA methyl-transferase inhibitor 5-aza-2'- deoxycytidine. Furthermore, we observed that TSLC1 was methylated in 25 of 91 primary pancreatic adenocarcinomas (27%), and in 2 of 7 highgrade PanIN-3 lesions (29%), but not in low-grade PanIN (0 of 9 PanlN-2 and 0 of 30 PanIN-1) lesions or in normal pancreata (n=15). We conclude that epigenetic silencing of TSLC1 expression through 5' CpG island associated methylation is common in pancreatic adenocarcinoma and is a late event in pancreatic neoplastic development.
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Fukushima
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Kim
authors.initials: K
authors.lastname: Walter
authors.forename: Renee
authors.initials: R
authors.lastname: Altink
authors.forename: Tjarda Van
authors.initials: TV
authors.lastname: Heek
authors.forename: Ralph
authors.initials: R
authors.lastname: Hruban
authors.forename: Johan G
authors.initials: JG
authors.lastname: Offerhaus
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D001374:Azacitidine / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007136:Immunoglobulins; D008565:Membrane Proteins; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D008565:Membrane Proteins; D011506:Proteins; D013447:Sulfites; D025521:Tumor Suppressor Proteins; D001374:Azacitidine; C009279:sodium bisulfite