title: Inactivation of p16/CDKN2 and p15/MTS2 genes in different histological types and clinical stages of primary ovarian tumors.
abstract: To define the involvement of p16/CDKN2 and p15/MTS2 inactivation in ovarian tumorigenesis and the association of these inactivation events with histological types and clinical stages of ovarian tumors, we analyzed homozygous deletion and somatic mutation of p16/CDKN2 and p15/MTS2 genes, as well as hypermethylation of the 5'-CpG island of the p16/CDKN2 gene, in 49 primary ovarian tumors and 6 ovarian carcinoma cell lines. We found homozygous deletions of p16/CDKN2 and p15/MTS2 in 6 (12%) and 5 (10%) primary tumors, respectively. Somatic mutation of p16/CDKN2 was found in only 1 primary tumor, but mutation of p15/MTS2 was not detected in any sample. None of the 28 primary tumors or 6 cell lines was hypermethylated at the 5'-CpG island of p16/CDKN2. The incidence of inactivation of p16/CDKN2 in primary tumors was significantly higher in the advanced stages (7 of 29) than in the early stages (0 of 14). Seven of 9 alterations in p16/CDKN2 and p15/MTS2 were observed in serous (3 of 12), endometrioid (3 of 9) and clear-cell (1 of 4) carcinomas. However, only normal sequences of these genes were detected in mucinous carcinomas. Loss of heterozygosity (LOH) at the IFNA locus was detected in 1 of 19 (5%) tumors, but no change at the D9S171 locus was observed in 17 tumors. These results suggest that: (i) homozygous deletion is the main mechanism of inactivation of p16/CDKN2 and p15/MTS2 in ovarian tumorigenesis; (ii) inactivation of p16/CDKN2 and p15/MTS2 may be the histological type-specific events involved in ovarian tumorigenesis; and (iii) inactivation of p16/CDKN2 is potentially involved in the progression of ovarian tumors in advanced stages.
authors.affiliation: Department of Biochemistry and Molecular Oncology, Institute of Basic Medical Sciences, University of Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Koyama
authors.forename: M
authors.initials: M
authors.lastname: Hirai
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: M
authors.initials: M
authors.lastname: Nishida
authors.forename: H
authors.initials: H
authors.lastname: Tsunoda
authors.forename: T
authors.initials: T
authors.lastname: Kubo
authors.forename: M
authors.initials: M
authors.lastname: Miwa
authors.forename: K
authors.initials: K
authors.lastname: Uchida
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D013798:Thecoma / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins