High incidence of p53 alterations (mutation, deletion, overexpression) in head and neck primary tumors and metastases; absence of correlation with clinical outcome. Frequent protein overexpression in normal epithelium and in early non-invasive lesions.
We have analysed 78 head and neck carcinomas (50 node metastases and 28 primary tumors including 13 matched specimens) in 65 patients for p53 alterations. Mutations were found in 54 (69%) tumors. Of the 53 mutations within exons, 40 (76%) were missense, five (9%) nonsense and eight (15%) microdeletions or microinsertions. Twenty-five (47%) mutations were transitions mostly G-->A (40%) and 20 (38%) were transversions, mostly G-->T (25%), thus confirming the role of tobacco carcinogens in the induction of these mutations. The incidence of mutations was not different in primary tumors (68%) and node metastases (70%) indicating that this gene alteration was not related to the metastatic dissemination. For eight patients, mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. There was a good correlation between mutations and protein overexpression (Fisher's exact test P < 10(-4). Immunostaining was also observed in basal cells from normal epithelium and in early lesions adjacent to the primary tumor in 11/15 (73%) specimens irrespective of the presence of mutation in the corresponding tumors. These data confirm that p53 overexpression is an early event in the multistep process of epithelial cell carcinogenesis. Loss of heterozygosity for the TP53 locus was detected in 54% of tumors but no association was found with mutation (Fisher's exact test P = 0.14). No mdm-2 amplification was detected in any tumors. No correlation was found between mutation and clinical parameters, the 5-year survival rates were not different (log rank test P = 0.39) in patients with and without mutation. In conclusion, we have shown that p53 gene mutations and deletions and protein overexpression are frequent in the most aggressive head and neck carcinomas but are not associated with disease progression. The presence of protein in normal mucosa and in non-invasive lesions may constitute a biomarker for early stages of carcinogenesis.
Ahomadegbe
J C
JC
Laboratoire de Pharmacologie Clinique et Moléculaire, Institut Gustave Roussy, Villejuif, France.
Barrois
M
M
Fogel
S
S
Le Bihan
M L
ML
Douc-Rasy
S
S
Duvillard
P
P
Armand
J P
JP
Riou
G
G
D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005260:Female; D016158:Genes, p53; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D006579:Heterozygote; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D016896:Treatment Outcome
D017931:DNA Primers; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2