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

Raj K Gopal; Kirsten Kübler; Sarah E Calvo; Paz Polak; Dimitri Livitz; Daniel Rosebrock; Peter M Sadow; Braidie Campbell; Samuel E Donovan; Salma Amin; Benjamin J Gigliotti; Zenon Grabarek; Julian M Hess; Chip Stewart; Lior Z Braunstein; Peter F Arndt; Scott Mordecai; Angela R Shih; Frances Chaves; Tiannan Zhan; Carrie C Lubitz; Jiwoong Kim; A John Iafrate; Lori Wirth; Sareh Parangi; Ignaty Leshchiner; Gilbert H Daniels; Vamsi K Mootha; Dora Dias-Santagata; Gad Getz; David G McFadden

doi:10.1016/j.ccell.2018.06.013

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.

Authors

Raj K Gopal¹, Kirsten Kübler², Sarah E Calvo³, Paz Polak⁴, Dimitri Livitz⁵, Daniel Rosebrock⁵, Peter M Sadow⁶, Braidie Campbell⁷, Samuel E Donovan⁷, Salma Amin⁸, Benjamin J Gigliotti⁹, Zenon Grabarek³, Julian M Hess⁵, Chip Stewart⁵, Lior Z Braunstein⁵, Peter F Arndt⁵, Scott Mordecai¹⁰, Angela R Shih¹¹, Frances Chaves¹⁰, Tiannan Zhan¹², Carrie C Lubitz¹³, Jiwoong Kim¹⁴, A John Iafrate¹¹, Lori Wirth¹⁵, Sareh Parangi¹⁶, Ignaty Leshchiner⁵, Gilbert H Daniels¹⁷, Vamsi K Mootha¹⁸, Dora Dias-Santagata¹¹, Gad Getz¹⁹, David G McFadden²⁰

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Harvard Medical School, Boston, MA 02115, USA.
² Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁴ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA 02114, USA.
¹³ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁴ Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁷ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Thyroid Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁸ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
¹⁹ Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: gadgetz@broadinstitute.org.
²⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Thyroid Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: david.mcfadden@utsouthwestern.edu.

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.

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

Substances

DNA, Mitochondrial
TERT protein, human
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding