General discussion 509 13 accordance with previous literature but requires further validation in larger, prospective trials before any recommendation can be made for clinical practice [39, 309, 455, 480, 485]. In Chapters 11 and 12 of this thesis, we showed that oncocytic thyroid neoplasms have a different molecular profile than nononcocytic thyroid neoplasms, with copy number alterations (CNA) and near-whole genome haploidization as a consequence of whole-chromosome instability as a main characteristic of tumorigenesis, and in addition possibly specific point mutations, such as TERT, PTEN, and TP53 [695, 725]. Various commercial MD panels are reported to underperform in oncocytic lesions, perhaps because CNA are only assessed in a part of the genome [491, 683, 751-753]. In Chapter 11 we proposed an assessment method based on a whole-genome 1,500 SNP NGS panel, that distinguishes genome-haploidization type CNA and loss of heterozygosity (CNALOH) from reciprocal chromosomal imbalance type CNA and additionally assesses the number of affected chromosomes, the possible presence of genome doubling and/or heterogenicity, in order to categorize nodules as molecularly (likely) benign, uncertain malignant, or malignant. This NGS panel is applied in addition to somatic mutation and gene fusion panels. Subsequently, in Chapter 12, we validated this assessment method for the first time in the 31 different oncocytic nodules in the EfFECTS trial cohort and showed that it may be an accurate rule-out test, provided that nondiagnostic MD results may be minimized and that future larger validation studies may confirm this diagnostic accuracy [725]. Altogether, we are likely just at the start of developing an accurate diagnostic workup for oncocytic thyroid nodules, and both semi-quantitative [18F]FDG-PET/CT and MD including CNA-LOH analysis may be useful diagnostics. A lot of research to validate the results of the EfFECTS trial and other studies still lies ahead of us. Pathophysiology of [18F]FDG-positivity: from genotype to phenotype In the current thesis, we also aimed to raise our understanding of the [18F]FDG false-positivity of benign thyroid nodules. In Chapter 8, we demonstrated that [18F]FDG positive benign thyroid nodules and [18F]FDG positive thyroid carcinomas with indeterminate cytology showed increased expression of GLUT1, HK2, and MCT4 as compared to the expression in [18F]FDG negative benign nodules [708]. The uptake of [18F]FDG in thyroid carcinomas is considered the result of intracellular metabolic alterations caused by mutations in oncogenes, such as BRAF and RAS [633, 645, 754]. This likely also holds true for [18F]FDG-false positive benign nodules, as in Chapter 12, we showed that [18F]FDG positive benign nodules more frequently carried a driver mutation than [18F]FDG negative benign nodules. These were most frequently isolated RAS mutations [725]. These results suggest that [18F]FDG positive benign nodules may undergo metabolic changes similar to those in [18F]FDG positive thyroid carcinoma, initiated by pathogenic driver mutations. Although mere suggestions, these findings are another link in the chain towards understanding the cellular processes from genotype to phenotype in indeterminate thyroid nodules and thyroid carcinoma.
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