The allele constitution at codon 72 of the p53 gene (CGC-arginine or CCC-proline) plays a major role in inducing apoptosis in p53 mutant cells. To verify this, we determined GC-status, p53-mutations, and p53-loss of heterozygosity (LOH) in a group of 54 squamous cell carcinomas of the head and neck (SCCHN). A novel approach, using a one-step real-time PCR analysis with fluorescent hybridization probes, was applied to detect the GC status in tumors and corresponding blood samples. p53 mutations in exons 4 to 8 were detected by PCR-SSCP-sequencing analysis. Apoptosis was determined immunohistochemically using antibodies against Fas, FasL, p53, Bcl2, and terminal deoxy-transferase-mediated dUTP nick end labeling (TUNEL) staining. The overall frequency of p53-LOH in SCCHN was 45.2%. In cases of LOH, there was a preferential loss of the proline allele, which was associated with an up-regulation of Bcl2 and lack of co-expression of Fas/FasL and, thus, impaired apoptosis (P < 0.001). Apoptosis was not observed in tumors carrying the arginine allele. p53 mutations were detected in 29.6% of SCCHN and preferentially occurred at the arginine allele (P = 0.01). p53 alterations were more frequently observed in tumors of the oral cavity, oropharynx and hypopharynx, whereas they were rare in larynx carcinomas (P = 0.07). The p53-LOH status was not found to be significantly correlated with sex, age, TNM-status, or tumor grading. We conclude that apoptosis is correlated with the allelic status of codon 72 in SCCHN. Homozygous proline 72 appears to be an important regulator of apoptosis via the Fas/FasL pathway in SCCHN.
Recent studies have shown that most Dutch families with atypical multiple-mole melanoma (FAMMM) have a 19bp germline deletion (p16-Leiden) in exon 2 of the p16 gene (p16 [MIM 600160]) (Gruis et al. 1995; van der Velden et al. 1999van der Velden et al. , 2001. Incomplete penetrance and variable clinical expression in p16-Leiden carriers point to the fact that other genetic mechanisms can compensate for the p16 loss of function (Gruis et al. 1995). Indeed, van der Velden et al. (2001) reported in the Journal that variants in the melanocortin-1 receptor modify the risk of melanoma in p16-Leiden carriers. It is interesting that, apart from reports on simultaneous pancreatic tumors, other cancer types have never been found in such families with p16- Leiden (Gruis et al. 1995).Recently, we found a hereditary heterozygous p16-Leiden mutation in a man who neither smoked more than five cigarettes daily nor abused alcohol, initially diagnosed at age 54 years, who simultaneously developed three carcinomas of the pharynx and oral cavity. The patient showed a familial accumulation of tumor diseases. Both of his parents and his only sister died of cancer very early (the mother of gynecologic cancer, the father of liver carcinoma, and the sister of leukemia). Dutch relatives are not known.DNA from tumors and blood was extracted according to a standard protocol (Sambrook et al. 1989). Mutation analysis of exon 1 and exon 2 of the p16 gene was done by PCR-SSCP sequencing as described by Schneider-Stock et al. (1998).The p16-Leiden mutation was found in the heterozygous constitution in all three tumors and in the blood of the patient. We investigated all DNA samples for p16 promotor methylation to check the status of the retained wild-type allele and, thus, to assess the real functional significance of this finding. The methylation status of the p16 promotor was determined by methylation-specific PCR (Herman et al. 1996). The primer sequences for the unmethylated reactions were (sense) 5 -TTA TTA
Cachexia of malignancy is a heterogenous and dynamic phenomenon. Thirty to fifty percent of all oncologic patients suffer from malnutrition. Patients with ENT carcinomas, from the clinical view-point, are clearly high-risk patients. Essentially, malnutrition in ENT carcinoma patients is attributable to reduced or even insufficient energy supply and intake of nutrients as a result of pain experienced in swallowing and constrictions of the upper swallowing tract. Malnutrition has turned out to be a factor entailing an unfavourable prognosis and, frequently, limiting a therapy. In a survey conducted by the Endoscopy Working Group of the German Society for Otorhinolaryngology, Head and Throat Surgery, 70% of the university ENT hospitals confirmed that their patients experienced a clinically relevant weight loss in the range from 3 to 10 kg during oncologic causal treatment. Tube feeding with liquid formula diets is the most efficient, least-risk approach to long term use, and should already be adopted prior to therapy irrespective of scheduled oncologic causal therapy. The feeding tube placed by percutaneous endoscopically controlled gastrostomy is increasingly becoming an alternative to a nasogastric tube. Two basic PEG techniques have been employed: 1. the transoral pull technique and 2. direct puncture. In direct puncture, as distinct from the pull technique, iatrogenic dispersal of tumour cells from the primary location of the tumour with subsequent implantation in the gastric or abdominal wall is definitely ruled out. In the ENT Clinic of Magdeburg University, we decided to adopt direct puncture and, since 1991, this technique has been used in interdisciplinary co-operation with the Magdeburg University Clinic of Gastroenterology and successfully employed in 660 patients with advanced carcinomas of the upper swallowing tract. Severe PEG-induced abdominal complications were extremely rare, observed in as little as 0.5% of the cases. For enteral feeding through PEG which maintained or even improved the nutritional status, good compliance was noted in 83% of the patients. Prior to PEG and oncologic causal therapy, 36% of the patients showed malnutrition (BMI < 20 kg/m2). At the stage of anamnesis half of the patients indicated that, for the past six months prior to diagnosis of the tumour, they had experienced a weight loss of more than 10% of the calculated ideal body weight. Prior to therapy, 97% of the patients complained of dysphagia-induced reduced or impaired food intake. The various PEG tube techniques, along with their pros and cons, as well as nutritional aspects in oncology are presented for the Magdeburg patients and discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.