Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas

Genomic alterations of cyclin-dependent kinase inhibitors have been demonstrated in a variety of tumor types including brain tumors. Among them, the cyclin-dependent kinase inhibitor 2A (CDKN2A or p16(INK4a)) gene has been shown to be frequently deleted or inactivated in astrocytic tumors. The CDKN2C (p18(INK4c)) gene is functionally related to CDKN2A. Moreover, mice with targeted disruption of CDKN2C alone or combined CDKN2C and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27(Kip1)), or CDKN2C and TP53 gene disruption develop pituitary adenomas (PA) at high frequencies. The purpose of our study was to investigate genetic alterations of the CDKN2C gene by analysis of loss of heterozygosity (LOH), screening for mutations, analysis of promoter methylation, and protein expression in 38 PAs. In addition, genomic alterations and protein expression of the cell cycle genes CDKN2A and its alternatively spliced form, p14(ARF), as well as the retinoblastoma RB1 gene were investigated. LOH at the CDKN2C gene locus was detected in 25% of pituitary adenomas, whereas the RB1 and CDKN2A loci were altered in only 10%. No mutations were detected within the coding regions of the CDKN2C gene. However, 39.5% of adenomas displayed CDKN2C promoter methylation. The absence of CDKN2C protein was correlated with LOH of the CDKN2C locus on chromosome 1 and with methylation of the CDKN2C promoter. This is the first report to describe that the tumor suppressor gene CDKN2C is frequently targeted by genomic alterations in pituitary adenoma. The most common genetic alteration was promoter methylation suggesting that inactivation of CDKN2C by this mechanism may play an important role in pituitary adenoma development. Additional Supporting Information may be found in the online version of this article.