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J Thorac Cardiovasc Surg 2005;130:1371
© 2005 The American Association for Thoracic Surgery

General Thoracic Surgery

Promoter methylation of the hMLH1 gene and protein expression of human mutL homolog 1 and human mutS homolog 2 in resected esophageal squamous cell carcinoma

Ching Tzao, MD, PhD a , Han-Sui Hsu, MD b , Guang-Huan Sun, MD, PhD c , Hsiou-Lei Lai, BS a , Yi-Ching Wang, PhD d , Ho-Jui Tung, PhD e , Cheng-Ping Yu, MD, PhD f , Yeung-Leung Cheng, MD, PhD a , Shih-Chun Lee, MD a , *

a Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
c Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
f Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
b Division of Thoracic Surgery, Veterans General Hospital, Taipei, Taiwan, Republic of China.
d Department of Life Sciences, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
e Department of Humanity and Social Studies, National Defense Medical Center, Taipei, Taiwan, Republic of China.

Read at the Eighty-fifth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.

Received for publication March 25, 2005; revisions received May 15, 2005; accepted for publication June 7, 2005.

* Address for reprints: Shih-Chun Lee, MD, Division of Thoracic Surgery, National Defense Medical Center, 325, Section 2, Cheng Gong Road, Nei Hu, Taipei, Taiwan 114, Republic of China. (Email: ylc116{at}yahoo.com.tw).

OBJECTIVE: Aberrant expression of mismatch repair genes, such as human mutL homolog 1 (hMLH1) and human mutS homolog 2 (hMSH2), are common in some human cancers, and promoter methylation is believed to inactivate expression of hMLH1. We investigated whether promoter methylation is involved in loss of hMLH1 protein and whether aberrant expression of hMLH1 and hMSH2 protein is related to prognosis after resection for esophageal squamous cell cancer.

METHODS: We analyzed promoter methylation of hMLH1 using methylation-specific polymerase chain reaction and hMLH1 and hMSH2 protein by using immunohistochemistry in 60 resected tumor specimens. The Pearson {chi}2 test was used to compare expression of hMLH1 and hMSH2 protein among patients with different clinicopathologic parameters. Concordance analysis was performed between hMLH1 methylation and its protein expression.

RESULTS: Loss of hMLH1 and hMSH2 protein was found in 43 (72%) and 39 (65%, P = .06) of 60 resected specimens, respectively. hMLH1 protein correlated well with tumor staging (P < .0001), depth of tumor invasion (P = .008), and nodal involvement (P < .0001) but not with distant metastasis, whereas hMSH2 did not show correlation with any of these parameters. A concordance rate of 83.3% was present between expression of hMLH1 protein and its promoter methylation (P < .001).

CONCLUSIONS: Aberrant expression of hMLH1 and hMSH2 protein is frequently associated with the presence of esophageal squamous cell carcinoma, and expression of hMLH1 protein is a better prognostic predictor than is expression of hMSH2 protein. Promoter methylation is one of the mechanisms responsible for loss of hMLH1 protein in esophageal squamous cell cancer.

Abbreviations and Acronyms hMLH1 = human mutL homolog 1; hMSH2 = human mutS homolog 2; MMR = mismatch repair; PCR = polymerase chain reaction




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