Genetic basis of HPV mediated cervical cancer in Indian women

Cervical cancer is multi-factorial disease comprising both genetic and environmental components. Human papillomavirus is considered to be a major etiological factor for the development of cervical cancer. HPV type 16 is the most prevalent HPV accounting for more than 70% of cervical cancer cases in India, followed by HPV type 18 and other high-risk types. However, an infection with HPV is essential but it is not sufficient for the development of cervical cancer, which implies the involvement of host genetic factors. The primary cause in the development and progression of cervical neoplasia has been shown to be dependent on a series of cellular genetic and epigenetic events including mutation, deletion, polymorphism and or methylation of various tumor suppressor genes, checkpoint genes of cell cycle machinery etc. Little is known about whether genetic variation in tumor suppressor genes and cell cycle regulatory genes among Indian women associate with susceptibility to cervical cancer. We showed that promoter region of tumor suppressor genes FHIT and RASSF1A were aberrantly methylated in 28.3% and 35.0% respectively in cancer cases but both genes were methylated for 13.3% cases only. We identified a novel mutation at nucleotide position 655, at codon 98 from CAT→CGT with ultimate replacement of amino acid Histidine by Arginine in cervical cancer cases. Molecular modeling was performed to predict the effect of this mutation in disease pathology. We predict that this change, His to Arg substitution in substrate binding domain may generate catalytically inactive protein with loss of tumor suppressor activity. We also showed a novel association of cell cycle regulatory gene, cyclin D1 (CCND1) variation with cervical cancer cases in Indians. Strong evidence of CCND1G870A as risk factor and G1722C as protective factor for cervical cancer was observed. Therefore, presently studies are underway to examine the practical implications of these findings. This would give us important insights into genetic predisposition to cervical cancer in our population.