Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers.
Loss of heterozygosity (LOH) at chromosome 3p21 is frequent in cervical cancers. The candidate tumor suppressor gene, RASSF1A located at 3p21.3, is found to be inactivated in several major human cancers, implicating its significance in carcinogenesis. We aimed to investigate the status of RASSF1A in cervical cancers. The mutation and methylation status of RASSF1A were analysed in 4 cervical cancer cell lines, 50 primary cervical cancers including 33 squamous cell carcinoma (SCC), 17 adenocarcinoma (AC) and 11 normal controls. The primary cancer samples were also detected for LOH at 3p21 and human papillomavirus (HPV). Hypermethylation of RASSF1A was detected in 30% of SCC, 12% of AC and in 1 of the 4 cancer cell lines but was absent in all normal cases. Methylation of the cancer cell line was associated with loss of gene expression, which was restored by demethylation. About 67% (8 of 12) of hypermethylated primary cancers showed concomitant LOH at 3p21. No somatic mutation was found in all primary cancer samples or cell lines but 2 cases showed germline polymorphism at codon 133. Oncogenic HPV DNAs were found in most cancer samples. No correlation was detected between RASSF1A-hypermethylation or LOH at 3p21 and age of patient, HPV genotype, tumor grade and stage. Hypermethylation of RASSF1A occurs in a subset of cervical cancers, among which concomitant LOH at 3p21 is common. The results supported that RASSF1A may be one of the cervical cancer-related tumor suppressor genes located at 3p21 regions.
Yu
Mei Y
MY
Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China.
Tong
Joanna H M
JH
Chan
Paul K S
PK
Lee
Tin L
TL
Chan
Michael W Y
MW
Chan
Anthony W H
AW
Lo
Kwok W
KW
To
Kai F
KF
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000473:pathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014412:Tumor Virus Infections / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology
D017931:DNA Primers; D004273:DNA, Neoplasm; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D001374:Azacitidine