ALLELIC LOSS AT CHROMOSOMES 3P, 8P, 13Q, AND 17P ASSOCIATED WITH POOR-PROGNOSIS IN HEAD AND NECK-CANCER

Background: Little is known about the molecular genetic events that co ntribute to the pathogenesis of squamous cell carcinoma of the upper a erodigestive tract. Previous molecular genetic studies have been limit ed to the identification of mutations of the p53 (also known as TP53) tumor suppressor gene, activation of a limited set of oncogenes, allel ic loss at 3p and other locations, and occasional association with hum an papillomavirus infection. Purpose: Our purpose was to screen tumor tissue and blood from patients with squamous cell carcinoma of the upp er aerodigestive tract for loss of heterozygosity at polymorphic loci corresponding to each of the autosomal chromosomes and to identify the locations of additional putative tumor suppresser genes, other than R B (also known as RB1) and p53, that may contribute to the pathogenesis of this disease. Methods: Tumor tissue and blood were obtained from 6 8 consecutive patients with squamous cell carcinoma of the upper aerod igestive tract. In all cases, tumor tissue was obtained from the cente r of the surgical specimen. The relative absence of non-neoplastic tis sue was confirmed by frozen-section histologic examination of immediat ely adjacent tissue. Initially, 30 paired tissue and blood samples wer e tested for loss of heterozygosity by polymerase chain reaction (PCR) to amplify 43 different highly polymorphic sequences containing small oligonucleotide repeats. After PCR amplification, with unique oligonu cleotides flanking the repeat, visualization and sizing of the alleles on DNA sequencing gels were performed. Specific loss of heterozygosit y was distinguished from random genetic loss due to generalized chromo somal instability if it occurred in more than 20% of specimens tested for a particular marker. Results: Significant loss of heterozygosity ( >20%) occurred at alleles at chromosome bands 3p21 (32%), 3p25-26 (56% ), 8pter-21.1 (31%), 13q14 (27%), and 17p12 (45%). Loss of heterozygos ity at more than two loci was significant with a poor prognosis (P = . 039). Conclusions: These findings demonstrate that squamous cell carci noma of the upper aerodigestive tract exhibits genetic alterations at multiple loci and that allelic loss at more than two locations is indi cative of a poor prognosis (the likelihood of the patient dying of dis ease). Implications: While tumor suppressor genes at 3p (VHL), 13q (RB ), and 17p (p53) have been identified, altered genes at other loci on 3p and on 8p have not yet been characterized. Furthermore, the genotyp e at these loci for squamous cell carcinoma of the upper aerodigestive tract has prognostic importance and may identify the patients who sho uld receive the most aggressive treatment.