Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Recent studies have shown that patients whose bladder cancer exhibit overex pression of RB protein as measured by immunohistochemical analysis do equal ly poorly as those with loss of RB function. We hypothesized that loss of p 16 protein function could be related to RB overexpression, since p16 can in duce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with hi gh p16 protein expression in several other tumor types, In the present stud y RB negative bladder tumors also exhibited strong nuclear p16 staining whi le each tumor with strong, homogeneous RB nuclear staining were p16 negativ e, supporting our hypothesis. To expand on these immunohistochemical studie s additional cases were selected in which the status of the p16 encoding ge ne had been determined at the molecular level. Absent p16 and high RB prote in expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 en coding gene allele, confirming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associa ted with poor prognosis in bladder cancer is also associated with toss of p 16 function and implies that loss of p16 function could be equally deleteri ous as RB loss in bladder and likely other cancers.