A High Prevalence of Functional Inactivation by Methylation Modification of p16INK4A/CDKN2/MTS1 Gene in Primary Urothelial Cancers

• Published in: Japanese Journal of Cancer Research 1997-11, Vol.88 (11), p.1078-1086
• Main Authors: Akao, Toshiya, Kakehi, Yoshiyuki, Itoh, Noriyuki, Özdemir, Enver, Shimizu, Takashi, Tachibana, Akira, Sasaki, Masao S., Yoshida, Osamu
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hypermethylation; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Pelvis - pathology; Loss of Heterozygosity; Medical sciences; MTS1; Mutation; Nephrology. Urinary tract diseases; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Tumors of the urinary system; Ureteral Neoplasms - genetics; Ureteral Neoplasms - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary tract. Prostate gland; Urologic Neoplasms - genetics; Urologic Neoplasms - metabolism; Urothelial cancer
• ISSN: 0910-5050; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1997.tb00332.x

We analyzed the genetic and epigenetic alterations p16INK4A/CDKN2/MTSl gene (MTS1 gene) in 38 primary urothelial cancers. Genetic alterations of the MTS1 gene consisted of one base substitution mutation in exon 2(2.6%)and 6 homozygous deletions (16.2%). Hypermethylation of the 5’CpG island in exon 1 of theMTS1 genewas observed in 12 tumors (37.5%). Consequently, 19 of 38 tumors (50%) showed genetic alterations or epigenetic hypermethylation of the MTS1 gene. Retention of hypermethylated MTS1 gene(s) in 36% of the tumors showing loss of heterozygosity at the critical region indicates that the methylation modification could be an initial event followed by genomic rearrangements associated with total loss of MTS1 gene function. Immunohistochemical analysis of MTS1 expression revealed that all the tumors with genetic alterations of the MTS1 gene and 9 of 12 highly methylated tumors displayed an absence of MTS1 nuclear antigen. Genetic and epigenetic changes of theMTS1 gene were not correlated with the grade and stage of tumors, indicating that these alterations are early events in nrothelial carcinogenesis, in which functional inactivation by hypermethylation is a predominant mechanism.