signature=4bfbf257ebc393e8ee3071d531b76778,Epigenetic silencing of CDKN2A, p14(ARF) and CDKN2B and T...

Abstract

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The aim of this study was to determine the association between methylation status of multiple tumor suppressor genes, p16(INK4A), p14(ARF), p15 (INK4B) in a HNSCCs and clinicopathological parameters. Aberrant methylation of p16(INK4A), is common gene silencing mechanism in HNSCC. However, aberrant methylation of p15 (INK4B) appears to be important and recently we demonstrated that TRβI is silencing by aberrant methylation. We investigated CpG island methylation of p16(INK4A), p14(ARF), p15 (INK4B) in a series of 55 primary HNSCCs and on healthy tissue to assess specificity of aberrant methylation. The samples were tested by methylation specific PCR (MSP) while gene expression was detected with real time RT-PC. Of the 55 HNSCCs examined, 34 (62%) tumors showed aberrant methylation at least on one of the genes tested and 15 % had two genes hypermethylated and 5% had three genes hypermethylated. Methylation frequencies varied with p16(INK4A) the most methylated and p14(ARF) the least. Aberrantly methylated genes were detected at early states (I and II) and at late stages (III and IV). No association between p16 (INK4A), p14 (ARF). p15 (INK4B) methylation and conventional clinicopathological parameters was observed. The presence of p14 (ARF) methylation was associated with shorter patient survival. In summary, we have identified a set of aberrant methylation signatures of the 9p21 locus tumor suppressor genes CDKN2A/p14(ARF)/CDKN2B that may be useful as tumor markers for the early identification of HNSCC patients.