We investigated whether there is a relationship between loss of p16(INK4a) protein expression and p53 alterations in head and neck squamous cell carcinomas (HNSCCs). For this purpose, immunohistochemistry was performed on tissue microarrays of 664 tumours; this represents the largest HNSCC cohort studied for molecular biomarkers. Loss of p16(INK4a) protein expression was associated with aberrant p53 expression (negative or overexpressed) in the total cohort, and with TP53 mutations in 200 tumours analysed (p < 0.0001 each). Both loss of p16(INK4a) expression and p53 alterations differed significantly across both tumour sites and stages, being more prevalent in the hypopharynx than in the other tumour sites and in advanced tumour stages. As a possible link between p53 status and p16(INK4a) loss, we found that increased DNA methyltransferase 1 protein levels occurred preferentially in tumours with aberrant p53 (p = 0.001) and negative p16(INK4a) expression (p = 0.0004). In the total cohort, there was a borderline significant difference in patient survival across three p16(INK4a) expression levels (negative, positive, high), with loss of p16(INK4a) expression showing shortest survival. It is suggested that loss of p16(INK4a) expression and p53 alterations should be viewed as related events involved in the early carcinogenic process.
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