Loss of p53 gene mutation after irradiation is associated with increased aggressiveness in recurring head and neck cancer.
The p53 gene plays a pivotal role in the control of a checkpoint during G1 and in the apoptotic program. It has been postulated that alterations of p53 may influence radio-sensitivity and prognosis in several malignancies. We studied the p53 gene status of 35 consecutive head and neck cancer patients who failed primary radiotherapy (RT) in preirradiated and postirradiated tumor samples using DNA single-strand conformational polymorphism analysis. Sixteen of 35 (46%) preirradiated samples presented with band shifts suggestive of point mutations in one or two exons. Eleven of these tumors (69%) showed the same shift even in the postirradiated samples. Exons 5 and 8 were prevalently affected in this group. Five tumors (31%) lost the mutation following RT. The missed mutations clustered in exon 7. All mutations were confirmed by sequencing. Actuarial analysis demonstrated increased survival in patients with tumors bearing a p53 gene mutation in both preirradiated and postirradiated samples (P = 0.05 and P = 0.01, respectively). We also found that loss of p53 gene mutation in postirradiated cancers is associated with a significantly shorter disease-free interval (P < 0.02) and a worse prognosis (P < 0.05). A possible explanation in such cases is clonal selection by RT of more aggressive and radioresistant cell subpopulations, which are wild-type for the p53 gene. Taken together, our data suggest that not only p53 gene status but also the pattern of mutations could modulate the response of tumor cell to RT in vivo.
Gallo
O
O
Institute of Otolaryngology Head and Neck Surgery, Department of Clinical Physiopathology, Human Genetic Unit, University of Florence, Viale Morgagni 85, I-50134 Florence, Italy.
Chiarelli
I
I
Bianchi
S
S
Calzolari
A
A
Simonetti
L
L
Porfirio
B
B
D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics / Q000528:radiation effects; D016158:Genes, p53 / Q000235:genetics / Q000528:radiation effects*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000528:radiation effects; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D018807:Polymorphism, Single-Stranded Conformational; D016019:Survival Analysis
D004273:DNA, Neoplasm