Multiple primary tumors of the upper aerodigestive tract: Is there a role for constitutional mutations in the p53 gene?

Citation
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
Citations number
30
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
INTERNATIONAL JOURNAL OF CANCER
ISSN journal
00207136 → ACNP
Volume
82
Issue
2
Year of publication
1999
Pages
180 - 186
Database
ISI
SICI code
0020-7136(19990719)82:2<180:MPTOTU>2.0.ZU;2-O
Abstract
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.