Inactivation of RAS association domain family 1A gene in cervical carcinomas and the role of human papillomavirus infection.
Recently, we have identified a new putative tumor suppressor gene, RASSF1A (Ras association domain family 1A gene), located at human chromosome 3p21.3, the segment that is often lost in many types of human cancers. The RASSF1A promoter was shown to be frequently hypermethylated in various epithelial tumors, including small cell lung, breast, bladder, prostate, gastric, and renal cell carcinomas. In this study, we have analyzed the methylation status of the RASSF1A gene in primary human cervical cancers and in eight cervical cancer cell lines. The RASSF1A promoter is hypermethylated in 4 of 42 (= 10%) of squamous cell carcinomas, in 4 of 19 (= 21%) of adenosquamous carcinomas, and in 8 of 34 (= 24%) of cervical adenocarcinomas. Although in adenocarcinomas, methylation of RASSF1A and presence of human papillomavirus (HPV) type 16 or 18 sometimes coexisted, not a single case of HPV-16/18-positive squamous cell carcinomas had RASSF1A methylation. Similarly, in all eight analyzed cervical cell lines, RASSF1A inactivation and HPV infection were mutually exclusive (Fisher's exact test; P = 0.0357): two HPV-negative cervical cancer cell lines had a methylated and silenced RASSF1A promoter (C-33A and HT-3), whereas the other six HPV-positive lines expressed RASSF1A mRNA (ME 180, MS751, SiHa, C-4I, HeLa, and CaSki). For cervical tumors and cell lines combined, the Pearson's chi(2) test (chi(2) = 3.99; P <or= 0.05) indicates a borderline-significant reverse correlation between inactivation of RASSF1A and the presence of high-risk HPVs. Our data imply that the presence of HPVs in cervical carcinomas alleviates the requirement for RASSF1A inactivation and suggests that these two events may engage the same tumorigenic pathway.
Kuzmin
Igor
I
Basic Research Program, Science Applications International Corporation-Frederick, Inc., NCI Frederick, Frederick, Maryland, 21702, USA. kuzmin@mail.ncifcrf.gov
Liu
Limin
L
Dammann
Reinhard
R
Geil
Laura
L
Stanbridge
Eric J
EJ
Wilczynski
Sharon P
SP
Lerman
Michael I
MI
Pfeifer
Gerd P
GP
D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014412:Tumor Virus Infections / Q000150:complications / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology*
D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins