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Promoter Hypermethylation of FANCF: Disruption of Fanconi Anemia-BRCA Pathway in Cervical Cancer

Narayan, Gopeshwar; Arias-Pulido, Hugo; Nandula, Subhadra; Basso, Katia; Sugirtharaj, Dorcas D.; Vargas, Hernan; Mansukhani, Mahesh M.; Villella, Jeannine; Meyer, Larissa; Schneider, Achim; Gissmann, Lutz; Dürst, Matthias; Pothuri, Bhavana; Vundavalli, Murty V.

Patients with advanced stage invasive cervical cancer (CC) exhibit highly complex genomic alterations and respond poorly to conventional treatment protocols. In our efforts to understand the molecular genetic basis of CC, we examined the role of Fanconi Anemia (FA)-BRCA pathway. Here, we show that FANCF gene is disrupted by either promoter hypermethylation and/or deregulated gene expression in a majority of CC. Inhibition of DNA methy- lation and histone deacetylases induces FANCF gene re-expression in CC cell lines. FANCF-deregulated CC cell lines also exhibit a chromosomal hyper- sensitivity phenotype after exposure to an alkylating agent, a characteristic of FA patients. We also show the involvement of BRCA1 gene by promoter hypermethylation or down-regulated expression in a small subset of CC patients. Thus, we have found inactivation of genes in the FA-BRCA pathway by epigenetic alterations in a high proportion of CC patients, suggesting a major role for this pathway in the development of cervical cancer. Thus, these results have important implications in understanding the molecular basis of CC tumorigenesis and clinical management in designing targeted experimen- tal therapeutic protocols.

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