Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS

Nishant Agrawal, Yuchen Jiao, Mark Sausen, Rebecca Leary, Chetan Bettegowda, Nicholas J. Roberts, Sheetal Bhan, Allen S. Ho, Zubair Khan, Justin Bishop, William H. Westra, Laura D. Wood, Ralph H. Hruban, Ralph P. Tufano, Bruce Robinson, Henning Dralle, Sergio P A Toledo, Rodrigo A. Toledo, Luc G T Morris, Ronald A. Ghossein & 8 others James A. Fagin, Timothy A. Chan, Victor E. Velculescu, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Barry D. Nelkin, Douglas W. Ball

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume98
Issue number2
DOIs
StatePublished - Feb 1 2013

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Genes
Tumors
Mutation
Exons
Exome
Proteins
Repair
Medullary Thyroid cancer
DNA
Spliceosomes
Neoplasms
Thyroid Neoplasms
DNA Repair

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. / Agrawal, Nishant; Jiao, Yuchen; Sausen, Mark; Leary, Rebecca; Bettegowda, Chetan; Roberts, Nicholas J.; Bhan, Sheetal; Ho, Allen S.; Khan, Zubair; Bishop, Justin; Westra, William H.; Wood, Laura D.; Hruban, Ralph H.; Tufano, Ralph P.; Robinson, Bruce; Dralle, Henning; Toledo, Sergio P A; Toledo, Rodrigo A.; Morris, Luc G T; Ghossein, Ronald A.; Fagin, James A.; Chan, Timothy A.; Velculescu, Victor E.; Vogelstein, Bert; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Nelkin, Barry D.; Ball, Douglas W.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 98, No. 2, 01.02.2013.

Research output: Contribution to journalArticle

Agrawal, N, Jiao, Y, Sausen, M, Leary, R, Bettegowda, C, Roberts, NJ, Bhan, S, Ho, AS, Khan, Z, Bishop, J, Westra, WH, Wood, LD, Hruban, RH, Tufano, RP, Robinson, B, Dralle, H, Toledo, SPA, Toledo, RA, Morris, LGT, Ghossein, RA, Fagin, JA, Chan, TA, Velculescu, VE, Vogelstein, B, Kinzler, KW, Papadopoulos, N, Nelkin, BD & Ball, DW 2013, 'Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS', Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 2. https://doi.org/10.1210/jc.2012-2703
Agrawal, Nishant ; Jiao, Yuchen ; Sausen, Mark ; Leary, Rebecca ; Bettegowda, Chetan ; Roberts, Nicholas J. ; Bhan, Sheetal ; Ho, Allen S. ; Khan, Zubair ; Bishop, Justin ; Westra, William H. ; Wood, Laura D. ; Hruban, Ralph H. ; Tufano, Ralph P. ; Robinson, Bruce ; Dralle, Henning ; Toledo, Sergio P A ; Toledo, Rodrigo A. ; Morris, Luc G T ; Ghossein, Ronald A. ; Fagin, James A. ; Chan, Timothy A. ; Velculescu, Victor E. ; Vogelstein, Bert ; Kinzler, Kenneth W. ; Papadopoulos, Nickolas ; Nelkin, Barry D. ; Ball, Douglas W. / Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. In: Journal of Clinical Endocrinology and Metabolism. 2013 ; Vol. 98, No. 2.
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abstract = "Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90{\%} of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.",
author = "Nishant Agrawal and Yuchen Jiao and Mark Sausen and Rebecca Leary and Chetan Bettegowda and Roberts, {Nicholas J.} and Sheetal Bhan and Ho, {Allen S.} and Zubair Khan and Justin Bishop and Westra, {William H.} and Wood, {Laura D.} and Hruban, {Ralph H.} and Tufano, {Ralph P.} and Bruce Robinson and Henning Dralle and Toledo, {Sergio P A} and Toledo, {Rodrigo A.} and Morris, {Luc G T} and Ghossein, {Ronald A.} and Fagin, {James A.} and Chan, {Timothy A.} and Velculescu, {Victor E.} and Bert Vogelstein and Kinzler, {Kenneth W.} and Nickolas Papadopoulos and Nelkin, {Barry D.} and Ball, {Douglas W.}",
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T1 - Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS

AU - Agrawal, Nishant

AU - Jiao, Yuchen

AU - Sausen, Mark

AU - Leary, Rebecca

AU - Bettegowda, Chetan

AU - Roberts, Nicholas J.

AU - Bhan, Sheetal

AU - Ho, Allen S.

AU - Khan, Zubair

AU - Bishop, Justin

AU - Westra, William H.

AU - Wood, Laura D.

AU - Hruban, Ralph H.

AU - Tufano, Ralph P.

AU - Robinson, Bruce

AU - Dralle, Henning

AU - Toledo, Sergio P A

AU - Toledo, Rodrigo A.

AU - Morris, Luc G T

AU - Ghossein, Ronald A.

AU - Fagin, James A.

AU - Chan, Timothy A.

AU - Velculescu, Victor E.

AU - Vogelstein, Bert

AU - Kinzler, Kenneth W.

AU - Papadopoulos, Nickolas

AU - Nelkin, Barry D.

AU - Ball, Douglas W.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

AB - Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

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DO - 10.1210/jc.2012-2703

M3 - Article

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JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

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ER -