Gopal RK*,
Kübler K*, Calvo SE,
Polak P,
Livitz D,
Rosebrock D, Sadow PM, Campbell B, Donovan SE, Amin S, Gigliotti BJ, Grabarek Z,
Hess JM,
Stewart C, Braunstein LZ, Arndt PF, Mordecai S, Shih AR, Chaves F, Zhan T, Lubitz CC,
Kim J, Iafrate AJ, Wirth L, Parangi S,
Leshchiner I, Daniels GH, Mootha VK, Dias-Santagata D,
Getz G#^, McFadden DG
#^
Cancer Cell
34
(2)
:242-255.e5
(2018)
Abstract
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.