Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms

Michael House, James G. Herman, Ming Zhou Guo, Craig M. Hooker, Richard D. Schulick, Keith D. Lillemoe, John L. Cameron, Ralph H. Hruban, Anirban Maitra, Charles J. Yeo, Timothy J. Eberlein, Henry A. Pitt

Research output: Contribution to journalArticle

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Abstract

Objective: Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. Summary Background Data: Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. Methods: Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-β, p14ARF, GST-π, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. Results: Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87% of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75%), INK4a/p16 (40%), O6-MGMT (40%), RAR-β (25%), and hMLH1 (23%). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. Conclusions: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

Original languageEnglish (US)
Pages (from-to)423-432
Number of pages10
JournalAnnals of Surgery
Volume238
Issue number3
StatePublished - Sep 2003
Externally publishedYes

Fingerprint

Tumor Suppressor Genes
Pancreatic Neoplasms
Methylation
Neoplasms
Lymph Nodes
Recurrence
Genes
Survival
Tumor Suppressor Protein p14ARF
Neoplasm Metastasis
Liver
Cadherins
Polymerase Chain Reaction
Mutation

ASJC Scopus subject areas

  • Surgery

Cite this

House, M., Herman, J. G., Guo, M. Z., Hooker, C. M., Schulick, R. D., Lillemoe, K. D., ... Pitt, H. A. (2003). Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms. Annals of Surgery, 238(3), 423-432.

Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms. / House, Michael; Herman, James G.; Guo, Ming Zhou; Hooker, Craig M.; Schulick, Richard D.; Lillemoe, Keith D.; Cameron, John L.; Hruban, Ralph H.; Maitra, Anirban; Yeo, Charles J.; Eberlein, Timothy J.; Pitt, Henry A.

In: Annals of Surgery, Vol. 238, No. 3, 09.2003, p. 423-432.

Research output: Contribution to journalArticle

House, M, Herman, JG, Guo, MZ, Hooker, CM, Schulick, RD, Lillemoe, KD, Cameron, JL, Hruban, RH, Maitra, A, Yeo, CJ, Eberlein, TJ & Pitt, HA 2003, 'Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms', Annals of Surgery, vol. 238, no. 3, pp. 423-432.
House M, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD et al. Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms. Annals of Surgery. 2003 Sep;238(3):423-432.
House, Michael ; Herman, James G. ; Guo, Ming Zhou ; Hooker, Craig M. ; Schulick, Richard D. ; Lillemoe, Keith D. ; Cameron, John L. ; Hruban, Ralph H. ; Maitra, Anirban ; Yeo, Charles J. ; Eberlein, Timothy J. ; Pitt, Henry A. / Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms. In: Annals of Surgery. 2003 ; Vol. 238, No. 3. pp. 423-432.
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abstract = "Objective: Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. Summary Background Data: Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. Methods: Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-β, p14ARF, GST-π, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. Results: Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87{\%} of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75{\%}), INK4a/p16 (40{\%}), O6-MGMT (40{\%}), RAR-β (25{\%}), and hMLH1 (23{\%}). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. Conclusions: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.",
author = "Michael House and Herman, {James G.} and Guo, {Ming Zhou} and Hooker, {Craig M.} and Schulick, {Richard D.} and Lillemoe, {Keith D.} and Cameron, {John L.} and Hruban, {Ralph H.} and Anirban Maitra and Yeo, {Charles J.} and Eberlein, {Timothy J.} and Pitt, {Henry A.}",
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AU - House, Michael

AU - Herman, James G.

AU - Guo, Ming Zhou

AU - Hooker, Craig M.

AU - Schulick, Richard D.

AU - Lillemoe, Keith D.

AU - Cameron, John L.

AU - Hruban, Ralph H.

AU - Maitra, Anirban

AU - Yeo, Charles J.

AU - Eberlein, Timothy J.

AU - Pitt, Henry A.

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N2 - Objective: Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. Summary Background Data: Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. Methods: Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-β, p14ARF, GST-π, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. Results: Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87% of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75%), INK4a/p16 (40%), O6-MGMT (40%), RAR-β (25%), and hMLH1 (23%). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. Conclusions: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

AB - Objective: Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. Summary Background Data: Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. Methods: Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-β, p14ARF, GST-π, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. Results: Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87% of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75%), INK4a/p16 (40%), O6-MGMT (40%), RAR-β (25%), and hMLH1 (23%). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. Conclusions: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

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