Down-regulation of FA-BRCA pathway in the molecular pathogenesis of uterine cervical carcinoma of Indian population: clinical and prognostic implications

Abstract

Objective: Our study was aimed to understand the importance of FA-BRCA pathway genes in cervical carcinogenesis and their association with the prognosis of the disease. Material and methods: we analysed the molecular profiles of the key regulatory genes of FA-BRCA pathway (BRCA1, BRCA2, FANCC, FANCD2) in 109 cervical lesions at different clinical stages and validated in different bioinformatical analysis as well. The results were next correlated with different clinicopathological parameters. Furthermore, the drug tolerance mechanism of the genes was characterized by treating two CACX cell lines (SiHa and HeLa) in presence of the chemotherapeutic drug cisplatin. Result: Our data showed that the expression pattern (mRNA/Protein) of the genes of FA-BRCA pathway was gradually decreased from normal cervical epithelium to the development of carcinogenesis, also validated in different GEO datasets. Further, in-depth look into the results revealed that genetic (deletion) and epigenetic alterations (promoter methylation) [30 to 55 %] of the genes was strongly correlated with their reduced expression and development of cervical cancer among the patients, resulting in worst 5-year overall survival trend. Incidentally, the prevalence of promoter methylation in both plasma and respective tumour DNA of invasive cervical carcinoma patients implicated its prognostic importance and association with disease recurrence in this study. In continuation of that, our in-vitro study revealed that cisplatin could upregulate the FA-BRCA pathway genes gradually with increasing drug concentrations in the CACX cell lines through promoter hypomethylation due to reduced expression of DNMT1, indicating the intrinsic mechanism of drug tolerance of residual tumour cells of the disease.Conclusion: Our data showed that the inactivation of FA-BRCA pathway was associated with the development and prognosis of CACX. Up-regulation of the pathway genes in presence of cisplatin in the CACX cell lines suggested a plausible mechanism of non-responsiveness to the therapy.