Alteration of p16 and p15 genes in common epithelial ovarian tumors.
We have examined the roles of 2 putative tumor-suppressor genes, the p16 and p15 inhibitor-of-cyclin-dependent-kinase genes, in the most commonly occurring epithelial tumors of the human ovary. Expression of p16 mRNA, examined by RT-PCR, was significantly reduced in 15 of the 48 tumors. Aberrant expression of p16 protein, detected by immunohistochemistry, occurred in 22 of 60 tumors, more frequently in low-grade tumors, and had significant correlation with low p16 mRNA expression. Hypermethylation of a site within the 5'-CpG island of the p16 gene was significantly associated with loss of p16 mRNA and protein expression. Homozygous gene deletion, evaluated by differential PCR analysis, was found in 2 tumors for the p16 gene and in 1 tumor for the p15 gene among 70 ovarian tumors examined. PCR-SSCP analysis detected point mutations in p16 in 4 tumors and in p15 in 1 tumor. One was a 38-bp deletion, from codons 48 to 60, in a mucinous tumor of low malignant potential; another was a non-sense mutation in codon 60 in a mucinous adenocarcinoma. The remaining 2 mutations were mis-sense mutations, one in codon 58 and the other in codon 60, in 2 endometrioid adenocarcinomas. We conclude that inactivation of p16, by loss of p16 mRNA and protein expression as a consequence of hypermethylation of the 5'-CpG island, rather than by gene deletion or point mutation, may play an important role in the genesis of human ovarian epithelial tumors.
Fujita
M
M
Department of Obstetrics and Gynecology, Osaka University Medical School, Suita, Japan.
Enomoto
T
T
Haba
T
T
Nakashima
R
R
Sasaki
M
M
Yoshino
K
K
Wada
H
H
Buzard
G S
GS
Matsuzaki
N
N
Wakasa
K
K
Murata
Y
Y
D000199:Actins / Q000235:genetics; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000199:Actins; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins