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Radha Gopal , Kirsten Kübler , Sarah E. Calvo , Paz Polak , Bernard Campbell , Sharon M. Donovan , Salma Amin , Benjamin J. Gigliotti , Zenon Grabarek , Carrie C. Lubitz , Peter M. Sadow , Gilbert H. Daniels , Sareh Parangi , Lori J. Wirth , V. Vinod Mootha , Dora Dias‐Santagata , Gad Getz , David G. McFadden , Julika Lietzow , Mengwei Xu , J Golchert , Georg Homuth , J Ko ̈hrle , R Liu , Mingzhao Xing , David L. Steward , Sally E. Carty , Rebecca S. Sippel , Priscilla L. Yang , J Sosa , Jennifer A. Sipos , James Figge , S. J. Mandel , Bryan R. Haugen , Kenneth D. Burman , Zubair Baloch , R Lloyd , R Seethala , Jennifer L. Poehls , Marina N. Nikiforova , William E. Gooding , Yuri E. Nikiforov , Quan‐Yang Duh , Trevor E. Angell , Joshua Babiarz , Neil M. Barth , Thomas Blevins , Ronald Ghossein , Ruth Harrell , Jing Huang , Su Yeon Kim , Richard T. Kloos , Paul W. Ladenson , Virginia A. LiVolsi , Kepal N. Patel , G.W. Randolph , Michael H. Shanik , S. Thomas Traweek , P Walsh , Michael W. Yeh , Gwen Kennedy ·

YOU? · · 2017 · Open Access · · DOI: https://doi.org/10.1089/thy.2017.29050.sc.abstracts

Hu ¨rthle cell (oncocytic) carcinoma is an uncommon form of thyroid cancer exhibiting follicular patterned growth, radioactive iodine resistance, and an accumulation of mitochondria.Focused DNA sequencing of small numbers of tumors has revealed an absence of alterations in known thyroid cancer driver genes.We performed whole exome sequencing on 71 samples obtained from 41 patients (34 primary tumors, 24 locoregional recurrences, and 13 distant metastases) with joint analysis of the nuclear and mitochondrial DNA for somatic mutations and DNA copy number alterations.SNaPshot genotyping and anchored multiplex PCR-sequencing was performed to validate point mutations and identify fusion oncogenes, respectively.Fluorescence in situ hybridization and flow cytometry confirmed DNA copy number in a subset of samples.In the nuclear genome, we found recurrent mutations in DAXX, TP53, NRAS, NF1, and the TERT promoter.Analysis of the mitochondrial genome revealed frequent, high variant allele fraction, disruptive mutations in complex I of the mitochondrial electron transport chain.DNA copy number analysis showed widespread chromosomal losses, culminating in a near-haploid state in a subset of tumors.Characterization of recurrent and metastatic genomes suggested that complex I mitochondrial DNA mutations are early, clonal events maintained during tumor evolution.Furthermore, primary tumors, recurrences, and metastases from individual patients exhibited closely related DNA copy number profiles, including stability of the near-haploid state over time.Recurrent somatic mutations in DAXX, NF1, TP53, NRAS, the TERT promoter, and complex I mitochondrial DNA genes are candidate driver events in Hu ¨rthle cell carcinoma.A large fraction of tumors showed a copy number signature of widespread chromosomal losses, including a near-haploid state.Evaluation of tumor evolution predicts complex I mitochondrial DNA mutations arise early during tumorigenesis and that widespread chromosomal loss is tolerated during metastatic outgrowth.We propose that the description of altered genes and chromosomes in Hu ¨rthle cell carcinoma will facilitate the development of clinical stratification and therapeutic strategies.

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Type: article
Language: en
Landing Page: https://doi.org/10.1089/thy.2017.29050.sc.abstracts
PDF: https://www.liebertpub.com/doi/pdf/10.1089/thy.2017.29050.sc.abstracts
OA Status: bronze
Cited By: 2
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DOI: https://doi.org/10.1089/thy.2017.29050.sc.abstracts

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Publication year: 2017

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Publication date: 2017-10-01

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Authors: Radha Gopal, Kirsten Kübler, Sarah E. Calvo, Paz Polak, Bernard Campbell, Sharon M. Donovan, Salma Amin, Benjamin J. Gigliotti, Zenon Grabarek, Carrie C. Lubitz, Peter M. Sadow, Gilbert H. Daniels, Sareh Parangi, Lori J. Wirth, V. Vinod Mootha, Dora Dias‐Santagata, Gad Getz, David G. McFadden, Julika Lietzow, Mengwei Xu, J Golchert, Georg Homuth, J Ko ̈hrle, R Liu, Mingzhao Xing, David L. Steward, Sally E. Carty, Rebecca S. Sippel, Priscilla L. Yang, J Sosa, Jennifer A. Sipos, James Figge, S. J. Mandel, Bryan R. Haugen, Kenneth D. Burman, Zubair Baloch, R Lloyd, R Seethala, Jennifer L. Poehls, Marina N. Nikiforova, William E. Gooding, Yuri E. Nikiforov, Quan‐Yang Duh, Trevor E. Angell, Joshua Babiarz, Neil M. Barth, Thomas Blevins, Ronald Ghossein, Ruth Harrell, Jing Huang, Su Yeon Kim, Richard T. Kloos, Paul W. Ladenson, Virginia A. LiVolsi, Kepal N. Patel, G.W. Randolph, Michael H. Shanik, S. Thomas Traweek, P Walsh, Michael W. Yeh, Gwen Kennedy

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Landing page: https://doi.org/10.1089/thy.2017.29050.sc.abstracts

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