Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes

Ian Ganly; Vladimir Makarov; Shyamprasad Deraje; YiYu Dong; Ed Reznik; Venkatraman Seshan; Gouri Nanjangud; Stephanie Eng; Promita Bose; Fengshen Kuo; Luc G T Morris; Inigo Landa; Pedro Blecua Carrillo Albornoz; Nadeem Riaz; Yuri E Nikiforov; Kepal Patel; Christopher Umbricht; Martha Zeiger; Electron Kebebew; Eric Sherman; Ronald Ghossein; James A Fagin; Timothy A Chan

doi:10.1016/j.ccell.2018.07.002

Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes

Cancer Cell. 2018 Aug 13;34(2):256-270.e5. doi: 10.1016/j.ccell.2018.07.002.

Authors

Ian Ganly¹, Vladimir Makarov², Shyamprasad Deraje³, YiYu Dong³, Ed Reznik⁴, Venkatraman Seshan⁵, Gouri Nanjangud⁶, Stephanie Eng³, Promita Bose³, Fengshen Kuo³, Luc G T Morris⁷, Inigo Landa³, Pedro Blecua Carrillo Albornoz², Nadeem Riaz², Yuri E Nikiforov⁸, Kepal Patel⁹, Christopher Umbricht¹⁰, Martha Zeiger¹⁰, Electron Kebebew¹¹, Eric Sherman¹², Ronald Ghossein¹³, James A Fagin³, Timothy A Chan¹⁴

Affiliations

¹ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Surgery, Head and Neck Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].
² Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Surgery, Head and Neck Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁹ Department of Surgery, Division of Endocrine Surgery, New York University Langone Medical Center, New York, NY, USA.
¹⁰ Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Endocrine Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
¹² Department of Medicine, Head and Neck Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹³ Department of Pathology, Head and Neck Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁴ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].

Abstract

The molecular foundations of Hürthle cell carcinoma (HCC) are poorly understood. Here we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor behavior. We elucidate the mutational profile and driver mutations and show that these tumors exhibit a wide range of recurrent mutations. Notably, we report a high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy-number-neutral uniparental disomy. We also identify fusion genes and disrupted signaling pathways that may drive disease pathogenesis.

Keywords: Hurthle cell carcinoma; copy-number alterations; fusion genes; genomics; mitochondrial mutations; transcriptome.

Publication types

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

MeSH terms

Chromosome Aberrations*
DNA Repair
DNA, Mitochondrial / genetics*
Haploidy
Humans
Loss of Heterozygosity
Mutation*
Signal Transduction
TOR Serine-Threonine Kinases / physiology
Telomerase / genetics
Thyroid Neoplasms / genetics*

Substances

DNA, Mitochondrial
MTOR protein, human
TOR Serine-Threonine Kinases
TERT protein, human
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding