Association of epidermal growth factor receptor mutations with human papillomavirus 16/18 E6 oncoprotein expression in non–small cell lung cancer

Abstract

BACKGROUND: Lung cancers in women, in nonsmokers, and in patients with adenocarcinoma from Asia have more prevalent mutations in the epidermal growth factor receptor (EGFR) gene than their counterparts. However, the etiology of EGFR mutations in this population remains unclear. The authors hypothesized that the human papillomavirus (HPV) type 16=18 (HPV16=18) E6 oncoprotein may contribute to EGFR mutations in Taiwanese patients with lung cancer. METHODS: One hundred fifty-one tumors from patients with lung cancer were enrolled to determine HPV16=18 E6 and EGFR mutations using immunohistochemistry and direct sequencing, respectively. Levels of 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-oxo-dG) in lung tumors and cells were evaluated using immunohistochemistry and liquid chromatography-mass spectrometry=mass spectrometry. An supF mutagenesis assay was used to determine H 2 O 2 -induced mutation rates of lung cancer cells with or without E6 expression. RESULTS: Patients with E6-positive tumors had a greater frequency of EGFR mutations than those with E6-negative tumors (41% vs 20%; P 5.006). Levels of 8-oxo-dG were correlated with EGFR mutations (36% vs 16%; P 5.012). Two stable clones of E6-overexpressing H157 and CL-3 cells were established for the supF mutagenesis assay. The data indicated that the cells with high E6 overexpression had higher H 2 O 2 -induced SupF gene mutation rates compared with the cells that expressed lower levels of E6 and compared with vector control cells. CONCLUSIONS: HPV16=18 E6 may contribute in part to EGFR mutations in lung cancer, at least in the Taiwanese population. Cancer 2013;119:3367-76. V C 2013 American Cancer Society.KEYWORDS: epidermal growth factor receptor; mutation; 8-oxo-7; 8-dihydro-2& prime;-deoxyguanosine; human papillomavirus; lung cancer. INTRODUCTIONLung cancer is the leading cause of cancer death and predominantly is induced by tobacco smoke. However, approximately 25% of all lung cancer worldwide is not attributed to smoking. 1,2 In addition, nonsmokers with lung cancer are identified more often Asian women than among Caucasian women. 3,4 Lung cancer in nonsmokers has recently been recognized as a disease entity distinct from tobacco smoke-associated lung cancer. 5,6 The activation of epidermal growth factor receptor (EGFR) by its gene mutations, including exon 19 in-frame deletions and exon 21 L858R substitution, are currently recognized as the most potent biologic predictors of EGFR tyrosine kinase inhibitor (TKI) sensitivity. 7 These mutations are observed in approximately 40% to 60% of lung cancers in neversmokers, compared with approximately 10% to 20% of tobacco smoke-related lung cancers. 8,9 Therefore, an exploration of the etiologic factor(s) in EGFR mutations may be useful in the prevention of lung cancer in nonsmokers, particularly among women.A high frequency of EGFR mutations are common in nonsmoking women with lung adenocarcinoma in Asian populations, including Taiwanese. 3,4 Nonsmokers with lung cancer more prevalently present with an adenocarci...

Serum 25-hydroxyvitamin D levels correlate with EGFR mutational status in pulmonary adenocarcinoma

“…In a previous study that included squamous cell carcinomas, EGFR mutations were frequently observed in HPV-positive tumors (41 versus 20% in HPV-negative tumors, PZ0.006); however, the adjusted results did not remain significant (PZ0.111; Tung et al 2013). In another study including some non-classical EGFR-mutant tumors, old tuberculosis lesions were more frequently observed in EGFR-mutant tumors compared with wild-type tumors (80.6 versus 65.5%, PZ0.018).…”

“…Several Asian investigators have suggested the contribution of infection, including human papillomavirus (HPV) and tuberculosis, to EGFR-mutant tumors , Tung et al 2013. In a previous study that included squamous cell carcinomas, EGFR mutations were frequently observed in HPV-positive tumors (41 versus 20% in HPV-negative tumors, PZ0.006); however, the adjusted results did not remain significant (PZ0.111; Tung et al 2013).…”

“…Ethnic differences in the frequency of EGFR mutations have also been suggested because these mutations are predominantly found in Asians, including Koreans (Bell et al 2008). However, despite recent studies that have explored contributing factors , Tung et al 2013, an etiological explanation for EGFR mutations has not yet been proposed.…”

Human papillomavirus and lung cancinogenesis: an overview

“…ROS is a DNA-damaging agent that elevates the mutation rate and results in oncogenic transformation (Behrend et al 2003). The E6 oncoprotein causes oxidative stress in the cell leading to the DNA damage and giving rise to inactivation of the MMR pathway-responsible for controlling genetic stability by removing the bad base pairings-and thus increases the 8-OH-dG levels (Tung et al 2013). …”

Up-Regulation of FOXM1 by E6 Oncoprotein through the MZF1/NKX2-1 Axis Is Required for Human Papillomavirus–Associated Tumorigenesis

“…This leads to the accumulation of DNA damage and mutations that give rise to cell transformation and carcinoma development [9]. For example, the positive correlation of HPV 16/18 infection with the risk of epidermal growth factor receptor mutation occurrence has been shown in Taiwanese NSCLC patients [10]. Further insights into the mechanistic action of the E6 and E7 oncoproteins on tumor progression should be investigated.…”