[Biallelic inactivation of the p16-Gen in a metachronous triple carcinoma in the oropharyngeal region].
OBJECTIVE
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.


METHODS
p16 mutations in exons 1 and 2 were determined using PCR-SSCP-Sequencing analysis. p16 methylation was assessed by methylation-specific PCR.


RESULTS
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.


CONCLUSIONS
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.
Motsch
C
C
Otto-von-Guericke Universität, Klinik für Hals-, Nasen- und Ohrenheilkunde, Magdeburg, Germany. Christiane.Motsch@medizin.uni-magdeburg.de
Giers
A
A
Boltze
C
C
Evert
M
M
Freigang
B
B
Roessner
A
A
Schneider-Stock
R
R
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017567:Karnofsky Performance Status; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000601:surgery; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics*; D010610:Pharyngeal Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011879:Radiotherapy Dosage; D013997:Time Factors
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm