65 Diagnostic utility of molecular and imaging biomarkers 2 Recent developments and future prospects The cancer genome atlas Papillary thyroid cancer was one of the cancers targeted by the cancer genome atlas (TCGA) research network, a large collaborative project by the National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI). The incentive of the project is to map genomic alterations occurring in 33 types of cancer in 11.000 patients and improve the understanding, classification and extending possibilities for targeted therapy of these cancers [332]. Genetic alterations of all kinds were detected in nearly five hundred clinically non-aggressive PTCs (classical, follicular and tall cell variants) using one proteomic and six genomic platforms. PTC harboured fewer somatic mutations than other human cancer types, but if they were present, driver mutations were detected in the majority of the cancer cells. As expected, the known driver mutations in the MAPK/ERK pathway were dominant, confirming the mutually exclusive relation for BRAF and RAS point mutations and RET/PTC rearrangements. Other detected genetic alterations included genetic variations of the TERT promoter, PI3K and PPARy pathways, as well as new alterations of known and new drivers, such as EIF1AX, PPM1D and CHEK2. Moreover, molecular subtypes of for example BRAF-mutated PTC were identified and linked to different clinical subtypes. The role of microRNA in determining cancer phenotype was elaborated, allowing better understanding of clinical behaviour of various genetic variants of PTC. Somatic copy number alterations were mostly linked to FVPTC. Ultimately, the TCGA Research Network envisions a reclassification of thyroid carcinoma, abandoning the discrimination between PTC and FTC, and classifying according to molecular subtypes instead of by histopathological subtype first [333]. The identified markers may not just have an application in the diagnosis of thyroid carcinoma, but also in better risk-stratification of the different cancers and in targeted therapies. The plurality of applications is best known for the BRAFV600E mutation, which has an association with clinically more aggressive tumour behaviour on several fronts. Also, non-thyroid malignancies carrying a BRAF mutation are now (experimentally) treated with RAF inhibitors [334, 335]. There is little doubt that molecular classification systems are the future of oncology diagnostics in all types of human cancers. The position of histopathological assessment is changing, but cannot be renounced. With the current knowledge of thyroid genomics, the need to distinguish the mutated malignant from the mutated benign – premalignant – neoplasms remains, with all due consequences for the surgical and postoperative treatment strategy. Cytological application of the TCGA set was also already investigated in a recent study. Pagan et al. validated a panel containing the genomic alterations identified by the TCGA in 88 FNAC samples selected from a previous cohort study, including 22 indeterminate thyroid nodules [164, 336]. In the latter, 33% sensitivity and 84% specificity were demonstrated. In the same set of patients, Pagan
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