A High Prevalence of Functional Inactivation by Methylation Modification of p16INK4A/CDKN2/MTS1Gene in Primary Urothelial Cancers

We analyzed the genetic and epigenetic alterations p16INK4A/CDKN2/MTSlgene (MTS1gene) in 38 primary urothelial cancers. Genetic alterations of the MTS1gene 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 theMTS1genewas observed in 12 tumors (37.5%). Consequently, 19 of 38 tumors (50%) showed genetic alterations or epigenetic hypermethylation of the MTS1gene. Retention of hypermethylated MTS1gene(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 MTS1gene function. Immunohistochemical analysis of MTS1expression revealed that all the tumors with genetic alterations of the MTS1gene and 9 of 12 highly methylated tumors displayed an absence of MTS1nuclear 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.