Abstract
Cancer of uterine cervix is the second most common cancer among women worldwide but it is the leading cancer in Indian women. Though high-risk human papillomavirus (HR-HPV) is the major etiological agent for the development of cervical carcinogenesis, HPV infection alone is not sufficient, but together with immunological, environmental or genetic cofactors might be responsible for cervical carcinogenesis. Therefore, we investigated the association of SNPs in TNF-LTA locus with susceptibility to cervical cancer/precancer in 400 subjects comprising 200 cases and 200 controls by PCR-RFLP followed by sequencing and TNF levels by ELISA. Significant association was established for TNFA -308 G/A (Pc =0.01) and LTA +252 A/G (Pc =0.02) polymorphisms with respect to cancer vs. controls. Interestingly, TNFA -857 C/T SNP and AGGCCT haplotype exhibited protective effect for cervical cancer (Pc =0.04), (Pc =0.02). Functional correlation was also established between TNF -308 G/A and elevated plasma levels (P= 0.03). Therefore, SNPs in TNF-LTA locus may play a critical role in cervical carcinogenesis.
Highlights
Cancer of the uterine cervix is the second most common cancer among women worldwide (Parkin and Bray 2006), but it is the leading cancer in Indian women with an annual incidence of about 130,000 cases and 70,000-75,000 deaths (Das et al 2008)
10% of the healthy women are found to harbour HPV infection (Das et al 2008), and among them 10%-30% women cannot clear HPV infection spontaneously, establishing the crucial role played by other factors including host-genetic, immunological and viral factors in HPV associated cervical carcinogenesis (Wang and Hildesheim 2003)
This genetic susceptibility can be attributed to the single nucleotide polymorphisms (SNPs) in the immunomodulatory Tumor Necrosis Factor α (TNF)-LTA
Summary
Cancer of the uterine cervix is the second most common cancer among women worldwide (Parkin and Bray 2006), but it is the leading cancer in Indian women with an annual incidence of about 130,000 cases and 70,000-75,000 deaths (Das et al 2008). Various clinico-epidemiological studies have established high-risk human papillomavirus (HR-HPV) as the major etiological agent in cervical carcinogenesis (Das et al 2008). In 70–90% of HPV-infected individuals, the virus is naturally cleared. A fraction of these individuals, with persistent infection of HR-HPV, develop cervical cancer after a long latent period (Zur 2002). HPV infection alone is not sufficient, but together with immunological, environmental or genetic cofactors might mediate cervical carcinogenesis (Zur 2002; Kohaar et al 2007). Among the host genetic factors, variations in effective host immune response may be an important determinant of persistence of HPV infection and susceptibility to cervical cancer
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