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 Zhan; Carrie 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

doi:10.1016/j.ccell.2018.06.013

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 journal › Article › peer-review

166 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 language	English (US)
Pages (from-to)	242-255.e5
Journal	Cancer Cell
Volume	34
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2018.06.013
State	Published - Aug 13 2018

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2018.06.013

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

Gopal, RK, Kübler, K, Calvo, SE, Polak, P, Livitz, D, Rosebrock, D, Sadow, PM, Campbell, B, Donovan, SE, Amin, S, Gigliotti, BJ, Grabarek, Z, Hess, JM, Stewart, C, Braunstein, LZ, Arndt, PF, Mordecai, S, Shih, AR, Chaves, F, Zhan, T, Lubitz, CC, Kim, J, Iafrate, AJ, Wirth, L, Parangi, S, Leshchiner, I, Daniels, GH, Mootha, VK, Dias-Santagata, D, Getz, G & McFadden, DG 2018, 'Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma', Cancer Cell, vol. 34, no. 2, pp. 242-255.e5. https://doi.org/10.1016/j.ccell.2018.06.013

@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 = "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",

}

TY - JOUR

T1 - Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma

AU - Gopal, Raj K.

AU - Kübler, Kirsten

AU - Calvo, Sarah E.

AU - Polak, Paz

AU - Livitz, Dimitri

AU - Rosebrock, Daniel

AU - Sadow, Peter M.

AU - Campbell, Braidie

AU - Donovan, Samuel E.

AU - Amin, Salma

AU - Gigliotti, Benjamin J.

AU - Grabarek, Zenon

AU - Hess, Julian M.

AU - Stewart, Chip

AU - Braunstein, Lior Z.

AU - Arndt, Peter F.

AU - Mordecai, Scott

AU - Shih, Angela R.

AU - Chaves, Frances

AU - Zhan, Tiannan

AU - Lubitz, Carrie C.

AU - Kim, Jiwoong

AU - Iafrate, A. John

AU - Wirth, Lori

AU - Parangi, Sareh

AU - Leshchiner, Ignaty

AU - Daniels, Gilbert H.

AU - Mootha, Vamsi K.

AU - Dias-Santagata, Dora

AU - Getz, Gad

AU - McFadden, David G.

PY - 2018/8/13

Y1 - 2018/8/13

N2 - 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.

AB - 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.

KW - Hürthle cell

KW - chromosomal losses

KW - complex I

KW - haploid

KW - loss of heterozygosity

KW - metastasis

KW - mitochondria

KW - mtDNA

KW - oncocytic

KW - thyroid cancer

UR - http://www.scopus.com/inward/record.url?scp=85049891350&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049891350&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.06.013

DO - 10.1016/j.ccell.2018.06.013

M3 - Article

C2 - 30107175

AN - SCOPUS:85049891350

SN - 1535-6108

VL - 34

SP - 242-255.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this