P73 gene alterations and expression in primary oral and laryngeal squamous carcinomas

Abstract

p73, a recently identified gene, maps to chromosome region 1p36.3, which is frequently deleted in a variety of solid tumors. Although the gene shares sequence and functional homologies with p53, its suppressor function has not been proven. We investigated for the first time the genetic and expression status of the p73 gene and analyzed its flanking microsatellite loci on chromosome 1p36.3 in 67 primary oral and laryngeal squamous cell carcinomas to determine their association with these tumors. Our results reveal two missense mutations at codons 469 and 477 and a silent mutation at codon 349 in the C-terminal domain. Site-directed mutagenesis of p73 cDNA with these mutations and a p21 transactivation assay failed to show any significant functional consequences of these mutations. Microsatellite analysis of the flanking loci of p73 in region 1p36 showed overall alterations (loss of heterozygosity and instability) frequency of 39%, 16% at the proximal marker and 46% at the distal markers. Of the 21 cases for which we did protein expression analyses, 11 tumors had a >2-fold variation compared with matching histologically normal mucosa. Our study shows that: (i) intragenic alterations in this gene are rare and lack functional significance; (ii) its variable expression argues against a tumor suppressor function; (iii) this gene plays a minor role in head and neck squamous carcinoma; (iv) a distal site to this gene on 1p36 may harbor another suppressor gene.