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.