Context: Somatic mutations at residue R132 of isocitrate dehydrogenase 1 (IDH1) were recently discovered in gliomas and leukaemia at a high frequency. IDH1 is a metabolic gene, and the R132 mutations create a new enzymatic activity.
Objectives: To determine whether IDH1 had somatically acquired mutations in thyroid carcinomas.
Design: Exons 4 and 6 of IDH1 were sequenced in a large panel of thyroid tumours (n=138) and compared with the patients normal DNA (n=26). We also correlated IDH1 mutations with clinical-pathological data and BRAF and RAS mutational status.
Results: We identified four novel and two previously described non-synonymous variants in thyroid carcinomas, which were absent in benign tumours and paired normal thyroid. Although IDH1 variants occurred at higher frequency in follicular thyroid carcinomas, follicular variant of papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinomas than the observed variants in classical PTC (15/72 vs 3/37), it was not significant (P=0.1). Sequence alignment across several species shows that all IDH1 genetic alterations occurred at evolutionarily conserved residues located within the active site, and therefore, are likely to affect protein function. Unlike other tumours, IDH1 and BRAF or RAS mutations are not mutually exclusive. There was no association between IDH1 mutational status and clinical characteristics.
Conclusion: IDH1-acquired genetic alterations are highly prevalent in thyroid carcinomas (16%). Our findings not only extend our understanding of the molecular mechanism underlying pathogenesis of thyroid tumours, but also emphasize the biological differences between tumour types. Those tumours with IDH1 mutations might benefit from therapies that exploit this alteration.