Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma

Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies. [Display omitted] •HCC is driven by unique alterations of the nuclear and mitochondrial genomes•Early widespread loss of chromosomes leads to a stable near-haploid state in HCC•mtDNA mutations in complex I of the electron transport chain are enriched in HCC•DAXX, TERT, TP53, NRAS, NF1, CDKN1A, and ARHGAP35 are recurrently altered in HCC Gopal et al. identify recurrent alterations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter, as well as in mtDNA-encoding complex I of the electron transport chain, in Hürthle cell carcinomas (HCC). Many HCCs harbor widespread chromosomal loss culminating in a near-haploid state.