2403P - CDKN2A deletions are a mechanism for p16 inactivation in urothelial bladder carcinomas and are associated with an aggressive tumor phenotype

Background

Deletion of CDKN2A, encoded for the tumor suppressor protein p16, represents a common cause for reduced or absent of p16 expression in tumor cells. In this study, we analyzed the impact of CDKN2A deletion on tumor aggressiveness, patient prognosis, and p16 expression in patients with urothelial bladder carcinomas.

Methods

CDKN2A copy number status was analyzed by fluorescence in-situ hybridization (FISH) on more than 2,500 urothelial bladder carcinomas in a tissue microarray format. Data of CDKN2A deletion were compared with p16 expression data measured by immunohistochemistry in a previous study. The results were compared with parameters of tumor phenotype and patient outcome.

Results

CDKN2A deletions occurred in 28% of 1,880 analyzable carcinomas, including 9% heterozygous and 19% homozygous CDKN2A deletions. The CDKN2A deletion rate, especially for homozygous deletions, increased from pTa G2 low (14%), to pTa G2 high (35%) but slightly decreased in pTa G3 (20%) carcinomas (p<0.0001). In muscle-invasive urothelial carcinomas, especially homozygous CDKN2A deletions were associated with advanced pT stage (p<0.0001), but unrelated to patient prognosis. However, in the subset of pT4 urothelial bladder carcinomas, a tendency for shorter overall survival for patients with CDKN2A deleted tumors was found (p=0.0828). CDKN2A deletions were significantly associated with p16 immunostaining (p<0.0001). Cancers without p16 immunostaining harbored in 62% of all cases a CDKN2A deletion and 97% of 343 homozygous CDKN2A deleted cancers were p16 negative. Cancers with CDKN2A deletion and negative p16 immunostaining were associated with advanced stage (p<0.0001) but unrelated to patient prognosis in muscle-invasive urothelial carcinomas.

Conclusions

CDKN2A deletions were most commonly seen in p16-negative carcinomas, supporting their role for p16 inactivation in urothelial bladder carcinomas. The association of CDKN2A deletion – especially homozygous deletion – with advanced stage may reflect increasing genomic instability going along with stage progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.