DNA studies underestimate the major role of CDKN2A inactivation in oral and oropharyngeal squamous cell carcinomas

Citation
Cl. Wu et al., DNA studies underestimate the major role of CDKN2A inactivation in oral and oropharyngeal squamous cell carcinomas, GENE CHROM, 25(1), 1999, pp. 16-25
Citations number
39
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
GENES CHROMOSOMES & CANCER
ISSN journal
10452257 → ACNP
Volume
25
Issue
1
Year of publication
1999
Pages
16 - 25
Database
ISI
SICI code
1045-2257(199905)25:1<16:DSUTMR>2.0.ZU;2-H
Abstract
Loss of CDKN2A expression was demonstrated by immunohistochemistry in 87% o f oral and oropharyngeal squamous cell carcinoma (OSCC) primary tumor sampl es. By contrast, DNA studies showed a much lower frequency of loss of the C DKN2A gene. Point mutations and promoter methylation of CDKN2A were seen in 7% and 23%, respectively, of primary tumors. Loss of heterozygosity analys is using a dense set of 9p markers showed allelic imbalance that included C DKN2A in only 31% of samples, but a further 47% showed loss at loci near CD KN2A with apparent retention of CDKN2A. No tumor with any allelic imbalance expressed CDKN2A, whether or not the imbalance appeared to involve the CDK N2A locus. We interpret these data as showing partially overlapping deletio ns on the two 9p homologues, with homozygous deletion of CDKN2A masked by a mplification of contaminating stromal material. Our data show that inactiva tion of the CDKN2A gene products is a near-universal step in the developmen t of oral and oropharyngeal squamous cell carcinomas, and we suggest that h omozygous deletion is the most common mechanism of inactivation. The CDKN2A locus may be particularly prone to deletion because it encodes two unrelat ed tumor suppressor proteins, CDKN2A (p16(INK4a)) and p19(ARF), and deletio n, but not point mutation or methylation, would inactivate both gene produc ts. However, our results also suggest that complex patterns of allelic imba lance in primary squamous carcinomas in general may not provide reliable ev idence for the existence of multiple tumor suppressor genes within a single chromosomal region. Genes Chromosomes Cancer 25:16-25, 1999. (C) 1999 Wile y-Liss, Inc.