Comprehensive analysis of the p53 status in mucosal and cutaneous melanomas

Abstract

The abrogation of the function of the ''gatekeeper of the genome'', p53, is the most prevalent molecular alteration in solid human tumors. Regarding melanomas the involvement of p53 alterations is discussed controversially to date. In order to evaluate the status of p53 in detail, primary tumors and metastases of 63 sporadic cutaneous (CM) and mucosal (MuM) melanomas were examined by immunohistochemistry and sequence analysis of the entire coding region of the p53 transcript, i.e., exons 2 to 11. In addition, loss of heterozygosity (LOH) and loss of allele-specific transcription (LOT) were determined. Accumulation of the p53 protein occurred in most of the CM and MuM specimens (71% and 58%, respectively). In contrast, protein stabilizing p53 mutations were observed in 14% of the CM and no mutation was found in MuM specimens. Two of the aberrations located outside the core domain. LOH was detected in 22% CM and 58% MuM, and LOT in 25% of the CM specimens. The genotype distribution at the polymorphic p53 codon 72 in melanoma patients differed significantly from control subjects. The calculation of odds ratios (OR) and 95% confidence intervals (CI) indicated an increased risk for developing cutaneous melanomas in individuals carrying the Procoding allele. Altogether, aberrant p53 expression appears to be a common event in both CM and MuM. ' 2005 Wiley-Liss, Inc.Key words: melanoma; p53; immunohistochemistry; transcript analysis; LOH; LOT Abrogation of normal p53 function appears to be the most prevalent molecular alteration in human cancers, which allows tumor cells to survive, proliferate and continue to progress despite the accumulation of other alterations. Currently, p53 mutations are believed to contribute to the manifestation of nearly 50% of solid tumors. The evidence implicating sun exposure as the main cause of most types of skin cancer is persuasive. Exposure to both UV-A and UV-B can cause genetic changes in many biological systems. 1Typical UV-triggered mutations have been identified in protooncogenes and tumor suppressor genes in both melanoma and nonmelanoma skin cancer (NMSC). Mutations found in the p53 gene in human NMSC are mainly C to T and CC to TT transitions at dipyrimidine sequences, termed UV-B molecular signature mutations.2,3 In addition, UV-A caused mutations occur, e.g., T to G and G to T transversions. P53 mutations have also been detected in normal sun exposed skin as well as in actinic keratoses and Bowens disease, which are considered to be precancerous lesions of cutaneous squamous cell carcinoma, suggesting p53 as an important target for UV-induced mutations in the skin.4-6 Furthermore, up to 90% of xeroderma pigmentosum patients characterized by an highly increased risk to skin cancer due to impaired DNA-repair mechanisms show p53 mutations in their malignancies, and most of these mutations are typically UV-induced ones. 7With regard to cutaneous melanomas, some early studies have determined the p53 protein expression by immunohistochemistry based on the findings that wild-type p5...

Molecular determinants of Akt-induced keratinocyte transformation

“…We also found positive staining for DNp63 in some samples showing reduced Akt activation, whereas low Akt activation is well correlated with low DNp63 levels. These results are in agreement with previous reports showing that DNp63 is overexpressed in the vast majority of HNSCC (Sniezek et al, 2004;Gwosdz et al, 2005;Thurfjell et al, 2005), and might indicate that, besides Akt, alternative pathways influence such overexpression. Although p53 may be actively involved in this process (Hildesheim et al, 2004), our data indicated that p53 is not relevant in the modulation of DNP63 expression (Figure 7).…”

MDM2 SNP309 and p53 Arg72Pro in cutaneous melanoma: association between SNP309 GG genotype and tumor Breslow thickness

“…[12][13][14] In our study, we found no association with risk of CM when the genotypes of the two SNPs were combined. The effect of p53 Arg72Pro on melanoma remains controversial, with some studies reporting associations between melanoma and the PP genotype 17,19 and others reporting associations between melanoma and the RR genotype. 18,20 Moreover, here we report that the distribution of p53 Arg72Pro genotypes do not vary by age, gender or Breslow thickness.…”

“…The results have shown positive associations between the proline/proline (PP) genotype and disease risk for some tumor types (for example esophageal squamous cell carcinoma, lung cancer, renal cell carcinoma [12][13][14] but no association for other tumor types (for example colorectal cancer, breast cancer 15,16 ). The association between the p53 Arg72Pro polymorphism itself and melanoma risk is controversial, [17][18][19][20] with some studies showing associations between melanoma risk and the PP genotype, 17,19 but others showing increased melanoma risk with the arginine/arginine (RR) genotype. 18,20 In light of these findings, we examined the MDM2 SNP309 and p53 Arg72Pro genotypes to determine whether they could be linked to an increased CM susceptibility, age of cancer diagnosis and clinical pathological variables in an Italian population composed of women and men.…”

Prognostic Significance of Regulators of Cell Cycle and Apoptosis, p16INK4a, p53, and bcl-2 in Primary Mucosal Melanomas of the Head and Neck

“…Gwosdz et al [33] reported p53 mutations in 57-58% of MM suggesting the role of non-UV related mechanisms. We found aberrant p53 protein expression in 21% of MM, and in contrast to cutaneous melanomas where p53 over-expression increases with disease progression and metastasis [32,[34][35][36][37], we found no significant difference between initial mucosal melanomas and recurrent/metastatic tumors.…”