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

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′‐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 H2O2‐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 = .006). Levels of 8‐oxo‐dG were correlated with EGFR mutations (36% vs 16%; P = .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 H2O2‐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. © 2013 American Cancer Society. The positive correlation of human papillomavirus type 16/18 E6 expression with the occurrence of epidermal growth factor receptor (EGFR) mutations in Taiwanese patients with lung cancer may be because EGFR mutations are more common among women, nonsmokers, and patients with adenocarcinoma in Taiwan.