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Purpose To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). Patients and Methods Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome. Results Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P ≤ .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). Conclusion The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.

To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their expression in melanoma lesions. Owing to the lack of sufficient material from fresh specimens, we employed short-term cell lines obtained from melanoma biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11 cutaneous and two visceral metastases from patients with sporadic (n=31), familial (n=4) and multiple melanoma (n=2) were analysed. The results revealed novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall, activating mutations of BRAF and loss of functional p16 and ARF were detected in the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41 and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss associated with mutated BRAFV599E was the most represented (n=15). In addition, TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN loss was found in association with CDKN2A or TP53 mutations in the absence of BRAF activation. The p16/ARFDelta+BRAF/RAS profile was significantly associated with a longer survival, while complex mutational profiles were detected in highly aggressive disease and poor survival. These data support the existence of several molecularly defined melanoma groups which likely reflect different clinical/biological behaviour, thus suggesting that a more extensive molecular classification of melanoma would significantly impact its clinical management.

BACKGROUND. Tobacco smoking, alcohol abuse, and high-risk human papillomavirus (HPV) are risk factors in the etiology of oropharyngeal squamous cell carcinomas (SCCs). The TP53 polymorphism, in which an arginine (R) is changed to proline (P) at codon 72, is functionally significant and could therefore be a predisposing genetic defect. METHODS. The aim of the study was to investigate the role of codon 72 polymorphism by means of double gradient-denaturing gel electrophoresis in 77 oropharyngeal SCC patients including 33 TP53 mutated and 16 HPV-16-positive cases. The controls consisted of 141 consecutive healthy blood donors. RESULTS. The cases and controls showed significantly different genotype distribution (P ¼ .0005): the frequencies of the RR, RP, and PP genotypes among the cases were, respectively, 81.8%, 10.4%, and 7.8%, as opposed to 59.6%, 33.3%, and 7.1% among the controls, in agreement with the Hardy-Weinberg equilibrium (P ¼ .35). The PP genotype was significantly overrepresented among females (22.2% vs 3.4%; P ¼ .0243) and in HPV-16-positive cases (25.0% vs 3.3%; P ¼ .0152). No segregation was found between either of the codon 72 genotypes and age or TP53 mutations. CONCLUSIONS. The significantly lower frequency of the RP genotype in the patients as a whole suggests that it has a protective effect on oropharyngeal SCCs. Moreover, the PP genotype may be a risk factor for the development of oropharyngeal SCC by females and the development of HPV-16-related SCC, although the findings need to be validated in a larger number of tumors. Cancer 2007;109:2461–5. � 2007 American Cancer Society.

In human tumors, p53 is often disabled by mutations in its DNA-binding domain and is thus inactive as a transcription factor. Alternatively, MDM2 gene amplification or up-regulation represents a mechanism of p53 wild-type inactivation, mainly reported in soft tissue sarcomas. In a previous TP53 analysis carried out on sporadic and NF1-related malignant peripheral nerve sheath tumors, in two cases, we observed the occurrence of C238Y missense mutation, leading to p53 stabilization unexpectedly coupled with immunophenotypic MDM2 overexpression. To investigate this TP53 missense mutation not yet functionally characterized in mammalian cell, we did MDM2 Southern blot and p53C238Y/MDM2 biochemical and functional analyses followed by molecular modeling. The results showed a lack of MDM2 gene amplification, evidence of p53-MDM2 protein complexes, and presence of a p53 that retains the ability to become phosphorylated on Ser15 and to induce the transcription of p21waf1. Additional molecular modeling data highlighted the structural similarities between p53C238Y and wild-type p53, further supporting that the p53C238Y mutant still retains functional wild-type p53 properties. [Mol Cancer Ther 2006;5(6):1467–73]

Objective: Since the p53 gene has been identified as a determinant of response to chemotherapy in ovarian carcinoma in previous studies, we investigated the significance of the p53 status in response to topotecan as second-line therapy. Methods: Twenty-eight patients with advanced ovarian carcinoma, pretreated with standard platinum/paclitaxel chemotherapy, received topotecan as single-agent second-line therapy. Tumors were investigated by molecular analysis for p53 mutations in tumor samples obtained at primary surgery (i.e. before first-line therapy). Results: Wild-type p53 tumors responsive to first-line therapy maintained substantial responsiveness to topotecan. In contrast, p53 mutation was associated with a low responsiveness to second-line therapy. Conclusions: The better outcome in relapsed patients with wild-type p53 suggests that the presence of a functional wild-type p53 confers stability of the drug-sensitive phenotype. This outcome is consistent with the clinical observation that the efficacy of topotecan in the treatment of relapsed ovarian carcinoma patients is dependent on platinum sensitivity, because platinum-sensitive tumors are expected to carry wild-type p53. Although untreated mutant p53 tumors may be responsive to first-line paclitaxel-containing therapy, it is likely that loss of p53 leads to genomic instability resulting in rapid progression to drug resistance.

Purpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers. Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18. Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN− SCRCs. All MIN− SCRCs showed β-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN− SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q. Conclusions: The APC-β-catenin pathway is inactivated in MIN− SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN− SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.

Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K-ras and H-ras gene mutations. The occurrence of TP53, p14(ARF) and p16(INK4a) deregulation and H-ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H-ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14(ARF) alterations accounted for 88% and the evidence of p16(INK4a) alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C--A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14(ARF)and p16(INK4a) promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust-exposed tumors with p16(INK4a) alterations shared TP53 or p14(ARF) deregulation. The present results show a close association of this occupational tumor with TP53, p14(ARF) and p16(INK4a) gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments.