p16(MTS1/CDK4I) mutations and concomitant loss of heterozygosity at 9p21-23 are frequent events in squamous cell carcinoma of the larynx

P. Jares, P.L. Fernández, A. Nadal, M. Cazorla, L. Hernández, M. Pinyol, S. Hernández, J. Traserra, A. Cardesa, E. Campo

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Abstract

We have examined the presence of p16(MTS1/CDK4I) gene deletions, mutations and methylation status, and 9p21-23 deletions in a series of 46 squamous cell carcinomas of the larynx and paired normal mucosa previously characterized for cyclin D1 gene amplification and overexpression. pRb expression was also examined by immunohistochemistry. p16(MTS1/CDK4I) mutations were found in 10/46 (22%) carcinomas and hypermethylation in 2/31 (7%). Loss of heterozygosity at 9p21-23 was found in 24 out of 42 (57%) carcinomas examined. All p16(MTS1/CDK4I) mutated cases and the two hypermethylated carcinomas showed 9p21-23 loss of heterozygosity. The loss of heterozygosity correlated with advanced local invasion (P = 0.0045), lymph node metastases (P = 0.0326), stage IV of the tumors (P = 0.0058), and existence of cyclin D1 amplification/overexpression (P <0.03). Only one out of 37 carcinomas was negative for pRb expression. No alterations in p16 gene or 9p21-23 loss of heterozygosity were detected in this case. These findings indicate that p16(MTS1/CDK4I) is frequently inactivated by gene mutation, hypermethylation, and allelic deletions in a significant subset of squamous cell carcinomas of larynx. Since 9p21-233 loss of heterozygosity was more frequently detected than p16(MTS1/CDK4I) mutations, and mutated carcinomas invariably had loss of heterozygosity, allelic losses probably precede the p16(MTS1/CDK4I) mutations. Their association with cyclin D1 deregulation in advanced carcinomas could indicate a possible cooperative effect in the progression of these neoplasms.

Original languageEnglish
Pages (from-to)1445-1453
Number of pages9
JournalOncogene
Volume15
Issue number12
DOIs
Publication statusPublished - 18 Sep 1997

Keywords

  • p16(MTS1/CDK4I)
  • LOH 9p21-23
  • larynx
  • squamous cell carcinoma
  • KINASE-4 INHIBITOR GENE
  • CYCLIN D1 FUNCTION
  • HUMAN CANCERS
  • SOMATIC MUTATIONS
  • NONSMALL CELL
  • GEL-ELECTROPHORESIS
  • ALTERED EXPRESSION
  • PRIMARY TUMORS
  • LUNG CANCERS
  • CDKN2 GENE

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