@article{1e086bcc7e11447f87a8c4a525dfc0cb,
title = "Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in H{\"u}rthle Cell Carcinoma",
abstract = "H{\"u}rthle 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 H{\"u}rthle cell carcinomas (HCC). Many HCCs harbor widespread chromosomal loss culminating in a near-haploid state.",
keywords = "H{\"u}rthle cell, chromosomal losses, complex I, haploid, loss of heterozygosity, metastasis, mitochondria, mtDNA, oncocytic, thyroid cancer",
author = "Gopal, {Raj K.} and Kirsten K{\"u}bler and Calvo, {Sarah E.} and Paz Polak and Dimitri Livitz and Daniel Rosebrock and Sadow, {Peter M.} and Braidie Campbell and Donovan, {Samuel E.} and Salma Amin and Gigliotti, {Benjamin J.} and Zenon Grabarek and Hess, {Julian M.} and Chip Stewart and Braunstein, {Lior Z.} and Arndt, {Peter F.} and Scott Mordecai and Shih, {Angela R.} and Frances Chaves and Tiannan Zhan and Lubitz, {Carrie C.} and Jiwoong Kim and Iafrate, {A. John} and Lori Wirth and Sareh Parangi and Ignaty Leshchiner and Daniels, {Gilbert H.} and Mootha, {Vamsi K.} and Dora Dias-Santagata and Gad Getz and McFadden, {David G.}",
note = "Funding Information: We thank Anita Hawkins and the Cytogenomics Core Laboratory at Brigham and Women's Hospital for isolation of nuclei from tissue blocks. This work was supported by a generous gift from the Ruane family and an Ellison Foundation award. The ImageStream MarkII located in the MGH Department of Pathology Flow and Image Cytometry Core was purchased using an NIH Shared Instrumentation Grant 1S10OD012027-01A1 . K.K. and P.P. were partially supported by G.G.{\textquoteright}s startup funds from MGH . R.K.G. was supported by NIH grant P50 CA101942-13 . C.L. was supported by NIH grant R01CA149738 . We thank Carissa Desilus and Ryan Frazier for technical assistance with FISH. V.K.M. is an Investigator of the Howard Hughes Medical Institute. G.G. was supported by the Paul C. Zamecnik Chair in Oncology at the MGH Cancer Center. J.K. was supported by a Cancer Prevention and Research Institute of Texas award ( RP150596 ). D.G.M. was supported by a Career Development Award from the NCI ( K08CA160658 ), a Scholar Award from the Cancer Prevention & Research Institute of Texas ( RR140084 ), a Disease-Oriented Clinical Scholar Award (DOCS) from UT Southwestern Medical Center, and a St. Baldrick's Foundation Scholar Award ( 524523 ). Funding Information: We thank Anita Hawkins and the Cytogenomics Core Laboratory at Brigham and Women's Hospital for isolation of nuclei from tissue blocks. This work was supported by a generous gift from the Ruane family and an Ellison Foundation award. The ImageStream MarkII located in the MGH Department of Pathology Flow and Image Cytometry Core was purchased using an NIH Shared Instrumentation Grant 1S10OD012027-01A1. K.K. and P.P. were partially supported by G.G.?s startup funds from MGH. R.K.G. was supported by NIH grant P50 CA101942-13. C.L. was supported by NIH grant R01CA149738. We thank Carissa Desilus and Ryan Frazier for technical assistance with FISH. V.K.M. is an Investigator of the Howard Hughes Medical Institute. G.G. was supported by the Paul C. Zamecnik Chair in Oncology at the MGH Cancer Center. J.K. was supported by a Cancer Prevention and Research Institute of Texas award (RP150596). D.G.M. was supported by a Career Development Award from the NCI (K08CA160658), a Scholar Award from the Cancer Prevention & Research Institute of Texas (RR140084), a Disease-Oriented Clinical Scholar Award (DOCS) from UT Southwestern Medical Center, and a St. Baldrick's Foundation Scholar Award (524523). Funding Information: We thank Anita Hawkins and the Cytogenomics Core Laboratory at Brigham and Women's Hospital for isolation of nuclei from tissue blocks. This work was supported by a generous gift from the Ruane family and an Ellison Foundation award. The ImageStream MarkII located in the MGH Department of Pathology Flow and Image Cytometry Core was purchased using an NIH Shared Instrumentation Grant 1S10OD012027-01A1. K.K. and P.P. were partially supported by G.G.{\textquoteright}s startup funds from MGH. R.K.G. was supported by NIH grant P50 CA101942-13. C.L. was supported by NIH grant R01CA149738. We thank Carissa Desilus and Ryan Frazier for technical assistance with FISH. V.K.M. is an Investigator of the Howard Hughes Medical Institute. G.G. was supported by the Paul C. Zamecnik Chair in Oncology at the MGH Cancer Center. J.K. was supported by a Cancer Prevention and Research Institute of Texas award (RP150596). D.G.M. was supported by a Career Development Award from the NCI (K08CA160658), a Scholar Award from the Cancer Prevention & Research Institute of Texas (RR140084), a Disease-Oriented Clinical Scholar Award (DOCS) from UT Southwestern Medical Center, and a St. Baldrick's Foundation Scholar Award (524523). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = aug,
day = "13",
doi = "10.1016/j.ccell.2018.06.013",
language = "English (US)",
volume = "34",
pages = "242--255.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}