Prognostic Value Of hMLH1 And hMSH2 Immunohistochemical Expression In Non-Small Cell Lung Cancer

摘要

The etiologic association and prognostic significance of mismatch repair gene/protein alterations have never been examined in lung cancer. We investigated protein expression of hMLH1 and hMSH2 genes in tumor specimens from 105 non-small cell lung cancer (NSCLC) patients. 60 of them were diagnosed with adenocarcinoma, 38 with squamous cell carcinoma and seven with large cell carcinoma. Out of the 105 patients 40 (20 adenocarcinomas and 20 squamous cell carcinomas) had already received neoadjuvant chemotherapy based on carboplatine and navelbine or carboplatine vepesid. Immunohistochemical staining was used to examine protein expression. Expression in each patient was compared with clinicopathologic variables as well as overall survival and cancer-specific survival rates. Results: Alteration of protein expression was observed in 30% of patients. Loss of hMLH1 and hMSH2 protein expression was associated with significantly shorter disease-free survival in patients who had received neoadjuvant chemotherapy (p=0.05). Conclusion: Loss of immunohistochemical expression of hMLH1 and hMSH2 markers in lung tumors indicates a poorer prognosis for NSCLC patients receiving neoadjuvant therapy. Introduction Lung cancer has become the leading cause of cancer death in many industrialized countries. In Taiwan, for example, lung cancer claims more than 7,000 lives annually [13]. Much attention has recently been focused on the rapidly increasing incidence of primary lung cancer in nonsmokers [14, 21, 28]. Gender differences in distribution, histological type, and exposure to tobacco have also been noted [4, 6, 8, 16, 18]. Although 80% of female lung cancer patients worldwide have smoked at some time, less than 10% of Taiwanese women with lung cancer have any smoking history. The low smoking status and high incidence rate of adenocarcinoma constitute distinctive characteristics of lung cancer in Taiwanese females. Ryberg et al. showed that susceptibility to DNA damage caused by environmental carcinogens such as polycyclic aromatic hydrocarbon–like compounds may be higher among women than among men. They concluded that women are at greater risk of tobacco and/or environmentally induced lung cancer [19]. Takagi et al. observed a distinct mutational spectrum for the p53 gene in lung cancer tissue from nonsmoking Chinese women in Hong Kong suggesting that environmental and/or genetic factors might be involved in the development of lung cancer in these women [23]. Molecular biological studies have shown that overt cancers carry multiple genetic and epigenetic alterations, which seem to indicate the involvement of tumor suppressor genes and dominant oncogene activation during the process of carcinogenesis and subsequent progression of cancer [20, 25]. Alteration analysis of genes controlling acquired somatic mutations, such as genes involved in DNA repair, may explain the observed susceptibility to various environmental factors seen in lung cancer in nonsmoking females. hMLH1 and hMSH2 are both known to play a role in DNA mismatch repair. Their inactivation by promoter hypermethylation has been reported to be associated with some human cancers [5, 7, 12, 15, 24]. Herman et al. have suggested that DNA methylation associated with transcriptional silencing of hMLH1 is the underlying cause of mismatch repair defects in most sporadic colorectal cancers [12]. Xinarianos et al. have shown that 58.6% and 57.8% of lung cancer tumor specimens had reduced expression levels of the hMLH1 and hMSH2 proteins, respectively [29]. The clinical significance of protein expression of hMLH1 and hMSH2 in lung cancers remains unclear. Recently, Brooks et al. reported that low protein expression of hMSH2 in positive mediastinal nodal specimens was associated with poor treatment response and cancer death in patients with stage III non–small cell lung cancer (NSCLC) [2]. In a previous study protein expression and status of promoter hypermethylation of hMLH1 and hMSH2 in 77 NSCLC