title: Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis.
abstract: Well-differentiated neuroendocrine tumors including pancreatic endocrine tumors and carcinoid tumors are uncommon neoplasms that have site-specific differences in clinicopathological features, clinical course and genetic alterations. The epigenetic alterations in these tumors are not well characterized. We therefore compared methylation of the RAS-association domain family 1, isoform A (RASSF1A), p14, p16 and O6-methyl-guanine methyltransferase genes in neuroendocrine tumors from 47 patients including 16 pancreatic, 15 nonileal and 16 ileal neuroendocrine tumors. Methylation of the RASSF1A gene was present in 57% of tumors, p14 in 49%, p16 in 26% and O6-methyl-guanine methyltransferase in 13% of tumors. Ileal neuroendocrine tumors lacked methylation of O6-methyl-guanine methyltransferase gene (P = 0.04). RASSF1A methylation was associated with histopathologic type of tumors (P = 0.03) and lymph node metastasis (P = 0.004), and p16 methylation with older patient age (P = 0.002) and liver metastasis (P = 0.04). Two or more genes were methylated in 53% of tumors, one gene was methylated in 30% of tumors, and all four genes were unmethylated in 17% of tumors. Methylation of one or more gene was associated with older age of patients (P = 0.01), and methylation of two or more genes was associated with liver metastasis (P = 0.044). Our study shows that in neuroendocrine tumors epigenetic alterations vary by tumor subsite and clinicopathologic features, including age of onset, histopathologic type and metastasis status.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Liu
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.forename: Susu
authors.initials: S
authors.lastname: Xie
authors.forename: Jill A
authors.initials: JA
authors.lastname: White
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
mesh_terms: D000368:Aged; D002276:Carcinoid Tumor / Q000235:genetics* / Q000556:secondary; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D044127:Epigenesis, Genetic; D005260:Female; D019942:Genes, p16; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D020033:Protein Isoforms; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins