Human papillomavirus type 16 E6 and E7 gene variations in Indian cervical cancer

Objectives. Human papillomavirus type 16 is a causative factor for development of cervical cancer. The E6 and E7 genes of HPV 16 are critical to the process of immortalization and transformation of host cells. Recent reports suggest that variants of these two genes may contribute to the risk of malignant progression of cancer in the uterine cervix. However, no data exist on sequence variations of HPV 16 E6 and E7 genes that may exist in India. Therefore, we examined intratype variations in the E6 and E7 viral genes in DNA isolated from HPV 16-positive cervical scrapes and biopsies. Methods. The open reading frames of the E6 and E7 genes were amplified by PCR and then directly sequenced by the fluorescent dye dideoxy termination method. Results. In addition to the prototype E6 gene sequence, five sets of mutations of the E6 gene were identified. The European prototype (350T) was detected in 9.1% of the study group while the European variant (350G) was seen in 28% of patients. The remaining variants (a combination of the 350G mutation with 335T, 145T, or 419G) were significantly associated with cases compared to controls. The 350G + 145T variant was found at much higher incidence in cases in younger women, suggesting that this variant may be associated with aggressive tumor behavior. Interestingly the 350G + 419G combination was found only in controls. There was no significant association between the four genotypes of E7 and any stage of tumor progression or age. Conclusions. The results indicate that specific mutations in the E6 gene are found in young Indian women with high-grade squamous intraepithelial lesions and invasive cancer, suggesting that these mutations represent more oncogenically active HPV 16. Whether this increased oncogenecity is due to differences in p53 inactivation, ineffective keratinocyte differentiation, and/or altered response to the immune system by these oncogenic E6 mutants remains to be clarified.