Epigenetic alterations in neuroendocrine tumors: Methylation of RAS-association domain family 1, isoform a and p16 genes are associated with metastasis

Lixia Liu, Russell R. Broaddus, James C. Yao, Susu Xie, Jill A. White, Tsung Teh Wu, Stanley R. Hamilton, Asif Rashid

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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 O 6-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, histopatholoic type and metastasis status.

Original languageEnglish (US)
Pages (from-to)1632-1640
Number of pages9
JournalModern Pathology
Volume18
Issue number12
DOIs
StatePublished - Dec 2005
Externally publishedYes

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p16 Genes
Neuroendocrine Tumors
Epigenomics
Methylation
Protein Isoforms
Neoplasm Metastasis
Neoplasms
Genes
Guanine
Methyltransferases
Neoplasms by Site
Liver
Carcinoid Tumor
Age of Onset
Lymph Nodes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Epigenetic alterations in neuroendocrine tumors : Methylation of RAS-association domain family 1, isoform a and p16 genes are associated with metastasis. / Liu, Lixia; Broaddus, Russell R.; Yao, James C.; Xie, Susu; White, Jill A.; Wu, Tsung Teh; Hamilton, Stanley R.; Rashid, Asif.

In: Modern Pathology, Vol. 18, No. 12, 12.2005, p. 1632-1640.

Research output: Contribution to journalArticle

Liu, Lixia ; Broaddus, Russell R. ; Yao, James C. ; Xie, Susu ; White, Jill A. ; Wu, Tsung Teh ; Hamilton, Stanley R. ; Rashid, Asif. / Epigenetic alterations in neuroendocrine tumors : Methylation of RAS-association domain family 1, isoform a and p16 genes are associated with metastasis. In: Modern Pathology. 2005 ; Vol. 18, No. 12. pp. 1632-1640.
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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 O 6-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, histopatholoic type and metastasis status.",
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