Koos Boeve

20 Chapter 1 be complementary in regulating tumour processes such as metastasis [45]. Moreover, hypermethylation is more common earlier in the carcinogenesis compared to DNA mutations [45]. In addition, hypermethylation of certain genes (MGMT, DAPK1 ) has been reported to be associated with lymph node status [67]. Recently, using a global genome- wide screening approach, three new markers were identified to be differently methylated comparing OSCC with and without lymph node metastasis ( WISP1, RAB25 and S100A9 ) [68,69] [Clausen, S100A9, in prep]. Because of the clear association with lymph node status, a panel of these methylation markers might contribute to the detection of lymph node metastasis, however the accuracy in detecting occult metastasis in early stage OSCC has not been validated yet. Figure 5. DNAmethylation in cancer. Methylation of CpG sites (red lollipops) in the promotor region of a cancer-related gene induces silencing of gene expression and might contribute to carcinogenesis [45]. Methylation of CpG sites throughout the genome outside the coding domains of genes (GRAY boxes) decreases (hypomethylation) in cancer [45]. [Adapted from the Atlas of genetics and cytogenetics in oncology and haematology in 2013[70]]. CHALLENGE 2: DETECTION OF LOCAL RECURRENCES AND SECOND PRIMARY TUMOURS Local recurrences and second primary tumours are reported in up to 10-30% percent of the cases in OSCC [71]. Local recurrence is defined as tumour growth within the same area (maximal distance of 20 mm) and within three years after diagnosis of the initial tumour, while second primary disease is defined as intra-oral tumour growth not fitting to one of the criteria of local recurrence. Causes for local recurrences and second primary tumors of OSCC are residual tumor cells after treatment and field cancerization of the oral mucosa (Figure 6) [42].