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 ZhanCarrie 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

Research output: Contribution to journalArticle

31 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)242-255.e5
JournalCancer Cell
Volume34
Issue number2
DOIs
StatePublished - Aug 13 2018

Keywords

  • chromosomal losses
  • complex I
  • haploid
  • Hürthle cell
  • loss of heterozygosity
  • metastasis
  • mitochondria
  • mtDNA
  • oncocytic
  • thyroid cancer

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Gopal, R. K., Kübler, K., Calvo, S. E., Polak, P., Livitz, D., Rosebrock, D., Sadow, P. M., Campbell, B., Donovan, S. E., Amin, S., Gigliotti, B. J., Grabarek, Z., Hess, J. M., Stewart, C., Braunstein, L. Z., Arndt, P. F., Mordecai, S., Shih, A. R., Chaves, F., ... McFadden, D. G. (2018). Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma. Cancer Cell, 34(2), 242-255.e5. https://doi.org/10.1016/j.ccell.2018.06.013