Mutation analysis of P73 and TP53 in Merkel cell carcinoma

Abstract

SummaryThe p73 gene has been mapped to 1p36.33, a region which is frequently deleted in a wide variety of neoplasms including tumours of neuroectodermal origin. The p73 protein shows structural and functional homology to p53. For these reasons, p73 was considered as a positional and functional candidate tumour suppressor gene. Thus far, mutation analysis has provided no evidence for involvement of p73 in oligodendrogliomas, lung carcinoma, oesophageal carcinoma, prostatic carcinoma and hepatocellular carcinoma. In neuroblastoma, two mutations have been observed in a series of 140 tumours. In view of the occurrence of 1p deletions in Merkel cell carcinoma (MCC) and the location of p73 we decided to search for mutations in the p73 gene in five MCC cell lines and ten MCC tumours to test potential tumour suppressor function for this gene in MCC. In view of the possible complementary functions of p73 and TP53 we also examined the status of the TP53 gene. Sequence analysis of the entire coding region of the p73 gene revealed previously reported polymorphisms in four MCCs. In one MCC tumour, a mis-sense mutation located in the NH 2 -terminal transactivation region of the p73 gene was found. These results show that p73, analogous to neuroblastoma, is infrequently mutated in MCC. This is also the first report in which the role of TP53 in MCC has been investigated by sequencing the entire coding region of TP53. TP53 mis-sense mutations and one non-sense mutation were detected in three of 15 examined MCCs, suggesting that TP53 mutations may play a role in the pathogenesis or progression of a subset of MCCs. Moreover, typical UVB induced C to T mutations were found in one MCC cell line thus providing further evidence for sun-exposure in the aetiology of this rare skin cancer.

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma

“…16 Moreover, UV-associated mutations in the tumor suppressor p53 have been documented in some cases of Merkel cell carcinoma. 63,64 Increased P53 protein detection seems to be more commonly found in Merkel cell polyomavirus- negative tumors. 4,5 Similarly, pure squamous cell carcinoma, a tumor known to express P53, and thought to be pathogenetically related to p53 alterations, is the archetypal UV-related cutaneous carcinoma, and for the most part, does not express Merkel cell polyomavirus.…”

Immunobiology of Merkel Cell Carcinoma: Implications for Immunotherapy of a Polyomavirus-Associated Cancer

“…For example, there is evidence that the binding of T-antigen to p53 in SV40 may not be sufficient to block p53 function and that other indirect mechanisms (involving small T-antigen and/or the J- and Rb-binding domains of the LT-antigen) are also important in functional suppression of p53 [52, 53]. Consistent with MCPyV somehow disabling p53 function in MCC tumors, inactivating mutations in TP53 gene and/or overexpression of p53 have been seen only in a small subset of MCC tumors [54, 55]. Moreover, recent studies have indicated an inverse relationship between p53 expression and MCPyV viral abundance in MCC tumors as well as p53 overexpression potentially being associated with poor outcome [56, 57].…”

Merkel Cell Carcinoma of the Head and Neck: A Single Institutional Experience

“…Furthermore, the authors noted that this change might also result from increased awareness and reporting of MCC [18]. A further risk factor for MCC is UVB exposure, as shown in epidemiological studies [23] and mutations analysis of TP53 [24]. Expression of p53 has been correlated to MCV-negative MCC [13, 14, 25], thus suggesting a different pathogenesis in MCV-positive and MCV-negative MCC.…”