Promoter Methylation and Response to Chemotherapy and Radiation in Esophageal Cancer

James Hamilton, Fumiaki Sato, Bruce D. Greenwald, Mohan Suntharalingam, Mark J. Krasna, Martin J. Edelman, Austin Doyle, Agnes T. Berki, John M. Abraham, Yuriko Mori, Takatsugu Kan, Carmit Mantzur, Bogdan Paun, Suna Wang, Tetsuo Ito, Zhe Jin, Stephen Meltzer

Research output: Contribution to journalArticle

Abstract

Background & Aims: Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation. Methods: Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment. Results: Thirteen (37%) of 35 patients were responders, and 22 (63%) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15% of responders vs 64% of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders. Conclusions: Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.

Original languageEnglish (US)
Pages (from-to)701-708
Number of pages8
JournalClinical Gastroenterology and Hepatology
Volume4
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

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Esophageal Neoplasms
Methylation
Radiation
Drug Therapy
Tumor Suppressor Genes
Genes
Tissue Inhibitor of Metalloproteinase-3
Students
Esophagectomy
Gene Silencing
Clinical Protocols
Neoplasms
Carcinogenesis
Biomarkers
Pathology
Polymerase Chain Reaction
Therapeutics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Promoter Methylation and Response to Chemotherapy and Radiation in Esophageal Cancer. / Hamilton, James; Sato, Fumiaki; Greenwald, Bruce D.; Suntharalingam, Mohan; Krasna, Mark J.; Edelman, Martin J.; Doyle, Austin; Berki, Agnes T.; Abraham, John M.; Mori, Yuriko; Kan, Takatsugu; Mantzur, Carmit; Paun, Bogdan; Wang, Suna; Ito, Tetsuo; Jin, Zhe; Meltzer, Stephen.

In: Clinical Gastroenterology and Hepatology, Vol. 4, No. 6, 06.2006, p. 701-708.

Research output: Contribution to journalArticle

Hamilton, J, Sato, F, Greenwald, BD, Suntharalingam, M, Krasna, MJ, Edelman, MJ, Doyle, A, Berki, AT, Abraham, JM, Mori, Y, Kan, T, Mantzur, C, Paun, B, Wang, S, Ito, T, Jin, Z & Meltzer, S 2006, 'Promoter Methylation and Response to Chemotherapy and Radiation in Esophageal Cancer', Clinical Gastroenterology and Hepatology, vol. 4, no. 6, pp. 701-708. https://doi.org/10.1016/j.cgh.2006.03.007
Hamilton, James ; Sato, Fumiaki ; Greenwald, Bruce D. ; Suntharalingam, Mohan ; Krasna, Mark J. ; Edelman, Martin J. ; Doyle, Austin ; Berki, Agnes T. ; Abraham, John M. ; Mori, Yuriko ; Kan, Takatsugu ; Mantzur, Carmit ; Paun, Bogdan ; Wang, Suna ; Ito, Tetsuo ; Jin, Zhe ; Meltzer, Stephen. / Promoter Methylation and Response to Chemotherapy and Radiation in Esophageal Cancer. In: Clinical Gastroenterology and Hepatology. 2006 ; Vol. 4, No. 6. pp. 701-708.
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abstract = "Background & Aims: Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation. Methods: Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment. Results: Thirteen (37{\%}) of 35 patients were responders, and 22 (63{\%}) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15{\%} of responders vs 64{\%} of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders. Conclusions: Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.",
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T1 - Promoter Methylation and Response to Chemotherapy and Radiation in Esophageal Cancer

AU - Hamilton, James

AU - Sato, Fumiaki

AU - Greenwald, Bruce D.

AU - Suntharalingam, Mohan

AU - Krasna, Mark J.

AU - Edelman, Martin J.

AU - Doyle, Austin

AU - Berki, Agnes T.

AU - Abraham, John M.

AU - Mori, Yuriko

AU - Kan, Takatsugu

AU - Mantzur, Carmit

AU - Paun, Bogdan

AU - Wang, Suna

AU - Ito, Tetsuo

AU - Jin, Zhe

AU - Meltzer, Stephen

PY - 2006/6

Y1 - 2006/6

N2 - Background & Aims: Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation. Methods: Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment. Results: Thirteen (37%) of 35 patients were responders, and 22 (63%) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15% of responders vs 64% of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders. Conclusions: Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.

AB - Background & Aims: Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation. Methods: Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment. Results: Thirteen (37%) of 35 patients were responders, and 22 (63%) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15% of responders vs 64% of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders. Conclusions: Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.

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