title: Retention of the arginine allele in codon 72 of the p53 gene correlates with poor apoptosis in head and neck cancer.
abstract: 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.
authors.affiliation: Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany. Regine.Schneider-Stock@medizin.uni-magdeburg.de
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.forename: Christiane
authors.initials: C
authors.lastname: Motsch
authors.forename: Carsten
authors.initials: C
authors.lastname: Boltze
authors.forename: Brigitte
authors.initials: B
authors.lastname: Peters
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Peter
authors.initials: P
authors.lastname: Buhtz
authors.forename: Anja
authors.initials: A
authors.lastname: Giers
authors.forename: Astrid
authors.initials: A
authors.lastname: Rohrbeck
authors.forename: Bernd
authors.initials: B
authors.lastname: Freigang
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D017209:Apoptosis / Q000502:physiology*; D001120:Arginine / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D003062:Codon / Q000235:genetics; D053222:Fas Ligand Protein; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D019656:Loss of Heterozygosity; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D003062:Codon; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D001120:Arginine