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

Cancer Cell. 2018 Aug 13;34(2):242-255.e5. doi: 10.1016/j.ccell.2018.06.013.


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.

Keywords: Hürthle cell; chromosomal losses; complex I; haploid; loss of heterozygosity; metastasis; mitochondria; mtDNA; oncocytic; thyroid cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Chromosome Aberrations*
  • DNA Copy Number Variations
  • DNA, Mitochondrial / genetics*
  • Exome Sequencing
  • Haploidy
  • Humans
  • Mutation*
  • Neoplasm Metastasis
  • Telomerase / genetics
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology


  • DNA, Mitochondrial
  • TERT protein, human
  • Telomerase