title: DNA studies underestimate the major role of CDKN2A inactivation in oral and oropharyngeal squamous cell carcinomas.
abstract: Loss of CDKN2A expression was demonstrated by immunohistochemistry in 87% of oral and oropharyngeal squamous cell carcinoma (OSCC) primary tumor samples. By contrast, DNA studies showed a much lower frequency of loss of the CDKN2A gene. Point mutations and promoter methylation of CDKN2A were seen in 7% and 23%, respectively, of primary tumors. Loss of heterozygosity analysis using a dense set of 9p markers showed allelic imbalance that included CDKN2A in only 31% of samples, but a further 47% showed loss at loci near CDKN2A with apparent retention of CDKN2A. No tumor with any allelic imbalance expressed CDKN2A, whether or not the imbalance appeared to involve the CDKN2A locus. We interpret these data as showing partially overlapping deletions on the two 9p homologues, with homozygous deletion of CDKN2A masked by amplification of contaminating stromal material. Our data show that inactivation of the CDKN2A gene products is a near-universal step in the development of oral and oropharyngeal squamous cell carcinomas, and we suggest that homozygous deletion is the most common mechanism of inactivation. The CDKN2A locus may be particularly prone to deletion because it encodes two unrelated tumor suppressor proteins, CDKN2A (p16INK4a) and p19ARF, and deletion, but not point mutation or methylation, would inactivate both gene products. However, our results also suggest that complex patterns of allelic imbalance in primary squamous carcinomas in general may not provide reliable evidence for the existence of multiple tumor suppressor genes within a single chromosomal region.
authors.affiliation: University Department of Medical Genetics, St Mary's Hospital, Manchester, United Kingdom.
authors.forename: C L
authors.initials: CL
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Roz
authors.forename: S
authors.initials: S
authors.lastname: McKown
authors.forename: P
authors.initials: P
authors.lastname: Sloan
authors.forename: A P
authors.initials: AP
authors.lastname: Read
authors.forename: S
authors.initials: S
authors.lastname: Holland
authors.forename: S
authors.initials: S
authors.lastname: Porter
authors.forename: C
authors.initials: C
authors.lastname: Scully
authors.forename: I
authors.initials: I
authors.lastname: Paterson
authors.forename: M
authors.initials: M
authors.lastname: Tavassoli
authors.forename: N
authors.initials: N
authors.lastname: Thakker
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D019942:Genes, p16 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D019656:Loss of Heterozygosity; D009062:Mouth Neoplasms / Q000235:genetics*; D009959:Oropharyngeal Neoplasms / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D004273:DNA, Neoplasm