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Biallelic inactivation of the p16-Gen in a metachronous triple carcinoma in the oropharyngeal region

, : Biallelic inactivation of the p16-Gen in a metachronous triple carcinoma in the oropharyngeal region. Laryngo- Rhino- Otologie 83(1): 55-60

Recent studies have shown that most Dutch families with atypical multiple-mole melanoma (FAMMM) have a 19-bp deletion (p16-Leiden) in exon 2 of the p16 gene. Apart from reports on metachronous pancreatic tumors, other cancer types have never been described in such families. Due to heterozygous p16-Leiden constitution, our proband with multiple head and neck carcinomas was a suitable model for studying the type of p16 inactivation according to the Knudson-two-hit model. p16 mutations in exons 1 and 2 were determined using PCR-SSCP-Sequencing analysis. p16 methylation was assessed by methylation-specific PCR. All three metachronous (larynx, pharynx, oral cavity) tumors had a methylated p16 promotor. The p16 protein loss detected by immunohistochemistry clearly confirmed a complete loss of p16 tumor suppressor function. Thus, all three tumors exhibited biallelic inactivation of p16, caused by aberrant methylation of the p16 promotor. This is the first report on p16-Leiden mutation in head and neck cancer. We provide evidence that the somatic methylation of p16 promotor is associated with the germline transmission of p16-Leiden mutation. This is an example for the rare event of in which aberrant methylation acting as the 'second hit' in a familial cancer syndrome. Our results show that this epigenetic event is equivalent to genetic alterations (mutation/LOH) confirming the Knudson's hypothesis for tumor suppressor gene inactivation.


PMID: 14740307

DOI: 10.1055/s-2004-814111

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