O. Gallo et al., Multiple primary tumors of the upper aerodigestive tract: Is there a role for constitutional mutations in the p53 gene?, INT J CANC, 82(2), 1999, pp. 180-186
Head-and-neck cancer (HNC) patients have a high risk of developing second p
rimary tumors of the upper aerodigestive tract, the main cause of death. Al
though the roles of tobacco and diet in multiple head-and-neck carcinogenes
is have been thoroughly investigated, little is known about individual gene
tic susceptibility factors involved in this process. Genomic instability, r
eflecting the propensity and the susceptibility of the genome to acquire mu
ltiple alterations, could be considered a driving force behind multiple car
cinogenesis. Mutation of the p53 tumor-suppressor gene has been proposed to
play an important role in this process. Therefore, we evaluated the incide
nce of inherited p53 germ-line alteration(s) in a population of 24 consecut
ive HNC patients and their first-degree relatives affected by multiple mali
gnancies as well as the occurrence of p53 somatic acquired mutation(s) in 1
6 cancers, including first and second primaries from 5 HNCs of the same gro
up. Mutations in exons 4-11 of the p53 gene were investigated using SSCP-PC
R analysis and DNA sequencing. Analysis was extended to the peripheral bloo
d and cancer biopsies available from first-degree relatives of cancer-prone
families with p53 germ-line mutations. p53 germ-line mutations were identi
fied in the peripheral blood and corresponding cancers of 3 HNC patients wh
o had multiple malignancies. The only missense mutation detected was mapped
in exon 6; it is a GTG to GAC substitution with an amino acid change from
Val to Glu at codon 197, The remaining 2 p53 germ-line mutations were singl
e-nucleotide substitutions without amino acid change in exon 6 (codon 213,
CGA to CGG) and in exon 8 (codon 295, CCT to CCC), respectively. These muta
tions were found in HNC patients with a family history of cancer. Abnormal
expression of wild-type p53 protein in normal and pathological tissues from
patients with the same sense single-nucleotide substitutions was detected
by immuno-histochemistry. (C) 1999 Wiley-Liss, Inc.