Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer.
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 methylation and histone deacetylases induces FANCF gene re-expression in CC cell lines. FANCF-deregulated CC cell lines also exhibit a chromosomal hypersensitivity 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 experimental therapeutic protocols.
Narayan
Gopeshwar
G
Department of Pathology, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Arias-Pulido
Hugo
H
Nandula
Subhadra V
SV
Basso
Katia
K
Sugirtharaj
Dorcas D
DD
Vargas
Hernan
H
Mansukhani
Mahesh
M
Villella
Jeannine
J
Meyer
Larissa
L
Schneider
Achim
A
Gissmann
Lutz
L
Dürst
Matthias
M
Pothuri
Bhavana
B
Murty
Vundavalli V V S
VV
D000477:Alkylating Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D052219:Fanconi Anemia Complementation Group F Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
D000477:Alkylating Agents; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; D016601:RNA-Binding Proteins; D016685:Mitomycin