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

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

Author information

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

PMID:
30107175
PMCID:
PMC6121811
[Available on 2019-08-13]
DOI:
10.1016/j.ccell.2018.06.013

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