Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus–mediated (MCPyV+) and/or ultraviolet radiation–associated (MCPyV−) pathways. Advanced clinical stage and an MCPyV− status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV− status. p63 is a member of the p53 family of proteins among which complex interactions occur. It has two main isoforms (proapoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+ and 14 MCPyV−) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semiquantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed “wild-type” expression in 69%, with “aberrant” staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases) and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV− subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53 and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (ie, proapoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.