Transcriptional silencing of Chfr predicts clinical outcome to chemoradiotherapy in head and neck cancer

2159 Several genes encode proteins which function as mitotic stress checkpoints, including Chfr (checkpoint with forkhead associated and ring finger). Chfr is subject to methylation-dependent silencing in a number of human cancers. Here, we show that RNAi-dependent silencing of Chfr confers increased in vitro cellular sensitivity to cisplatin and irradiation, in addition to taxanes, whereas sensitivity to anthracyclines is unaffected. To investigate the potential clinical significance of this observation, we examined promoter methylation of Chfr in 79 cases of locally advanced head and neck squamous cell carcinomas (HNSCC) treated with chemoradiation. Using methylation specific PCR and bisulphite sequencing, we detected CpG methylation in the transcriptional regulatory elements of Chfr in 47/79 cases. Methylation of Chfr was also detectable in pre-malignant dysplasias, implying that methylation-dependent silencing is an early event in tumourigenesis in subset of HNSCC. Silencing of Chfr occurred irrespective of HPV and p53 status. Complete response (CR) to chemoradiotherapy was higher in cases with methylation of Chfr (p=