Koos Boeve

205 English summary Another technique to assess OSCC patients without clinical and radiological neck involvement is selection using molecular tumour markers. The advantage of such markers is the non-invasive character. Chromosomal region 11q13, including genes CCND1 , Fas-associated death domain ( FADD) and CTTN , is often amplified in OSCC with nodal metastases. However, evidence in predicting occult nodal metastases is limited. In chapter 6 we used 158 patients with early tongue and floor of mouth (FOM) squamous cell carcinomas to correlate the molecular markers CCND1 amplification, cyclin D1, FADD and cortactin protein expression with occult nodal metastases. CCND1 amplification and cyclin D1 expression correlated with occult nodal metastases. Cyclin D1 expression was validated in an independent multicenter cohort, confirming the correlation with occult nodal metastases in early FOM cancers. Therefore, cyclin D1 is a predictive biomarker for occult nodal metastases in early FOM cancers. Preoperative selection of patients at risk for occult metastasis using molecular tumour markers might lead to a more individualized neck strategy with a watchful waiting strategy for low risk patients, a SLNB for intermediate risk patients and an elective neck dissection for patients with a high risk. The additional and more detailed information on individual drainage patterns, micrometastasis and isolated tumour cells provided by the SLNB might have impact on the clinical value of molecular biomarkers that have previously been associated with nodal status. In chapter 7 associations between molecular tumour markers (cortactin, cyclin D1, FADD, RAB25 and S100A9) and lymph node metastasis was investigated in 87 early stage OSCC patients who underwent SLNB neck staging. Cortactin was associated with lymph node status in patients with a pT1 tumour and infiltration depth <4 mm with a negative predictive value of 92%. Therefore, cortactin is a promising tumour marker to select early stage OSCC patients for a watchful waiting strategy instead of a SLNB. Not only the detection of occult lymph node metastasis is challenging in OSCC, also the early detection of local recurrences and second primary tumours is a major challenge. The high local recurrence rate of 20-30% in patients with oral squamous cell carcinoma (OSCC) is partly caused by residual tumour cells of the first primary tumour and the presence of precancerous epithelium (field cancerization) that has not (yet) clinically manifested. Due to this field cancerization, the risk for a second primary tumour is about 20%. Since OSCC cells are shed into the oral cavity, the detection of tumour-specific DNA methylation markers in saliva could be a tool for the early detection of local recurrences or second primary tumours of OSCC. In chapter 8 we selected seven genomic locations representing six genes ( C11orf85 , CMTM2 , FERMT3 , KCNA5 , SIPA1 and TBX4 ) that are methylated in OSCC and not in normal cells from a genome-wide methylation screening analysis using MethylCap- Seq analysis of 12 OSCCs compared to controls. In addition, we selected 4 markers reported to be methylated in saliva of OSCC patients by others ( EDNRB, HOXA9, NID2 and TIMP3).