Mutations of the cell cycle regulatory genes p16INK4A and p21WAF1 and the metastasis-inducing gene S100A4 are infrequent and unrelated to p53 tumour suppressor gene status and data on survival in oropharyngeal squamous cell carcinomas.
BACKGROUND
Oropharyngeal squamous cell carcinoma (SCC) is probably the most serious cancer to be encountered in the clinic.


METHODS
Exons 1-3 of the p16 and exon 2 of the p21 genes were examined for mutations by polymerase chain reaction (PCR)/direct DNA sequencing methods in 21 fresh-frozen tissue specimens of oropharyngeal SCCs previously studied for expression and mutation (exons 5-9) of the p53 gene. Mutations in exons 2 and 3 of the S100A4 gene were studied in 10 cases. Findings were examined for correlations with patients' clinicopathological parameters and data on survival.


RESULTS
No p16 gene mutations were found in any of the cases examined. Only one tumour, which previously had shown expression and mutation in the p53, had a point mutation at codon 117 of exon 2 of the p21 gene with a resulting Cys-->Tyr amino acid substitution. Exons 2 and 3 of the S100A4 gene were not found mutated in the cases studied. Analysis of survival data showed that, among the 60% (12 out of 20) of patients who died, 50% (6 out of 12) had mutations in p53 while the remaining 50% had no mutations. Of the 50% with mutated p53, 17% (1 out of 6) also had mutation in p21. For the 40% (8 out of 20) who are alive, 63% (5 out of 8) had mutations in p53 and 37% (3 out of 8) had no mutations.


CONCLUSIONS
These findings demonstrate that: (i) mutations of the cell cycle regulatory genes p16 and p21 and the S100A4 gene are infrequent and might be unnecessary in development and/or progression of oropharyngeal SCCs, (ii) the results were not found to relate to previous results of p53, (iii) loss of p21 and/or p53 might not predict for prognosis in these cancers, (iv) the absence of mutations of the three genes examined in the cases previously found mutated for p53 might suggest that these mutations are complementary to p53 mutations in the development of these cancers, but the lack of these mutations in the cases with no mutations in p53 might suggest that the pathogenesis of these cancers may follow other independent pathways. Since p53 and pRb (p16/pRb/cyclin-D1) pathways represent the two main mechanisms for cell cycle control at the G1-S checkpoint, further studies are necessary to examine the possible alterations in the pRb (p16/pRb/cyclin-D1) and the p53 pathways in oropharyngeal SCCs.
Ibrahim
Salah Osman
SO
Department of Biomedicine, Section for Biochemistry and Molecular Biology, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway. sosman@ibmb.uib.no
Lillehaug
Johan Rikard
JR
Vasstrand
Endre Normann
EN
D000428:Alcohol Drinking; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics*; D012907:Smoking; D016019:Survival Analysis
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human