title: Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Baltimore, Maryland 21287, USA. nagrawal@jhmi.edu
authors.forename: Nishant
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authors.lastname: Agrawal
authors.forename: Yuchen
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authors.lastname: Jiao
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authors.lastname: Sausen
authors.forename: Rebecca
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authors.forename: Chetan
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authors.forename: Zubair
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authors.lastname: Khan
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authors.forename: William H
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authors.lastname: Westra
authors.forename: Laura D
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authors.lastname: Hruban
authors.forename: Ralph P
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authors.lastname: Tufano
authors.forename: Bruce
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authors.lastname: Robinson
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authors.lastname: Dralle
authors.forename: Sergio P A
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authors.lastname: Toledo
authors.forename: Rodrigo A
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authors.lastname: Toledo
authors.forename: Luc G T
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authors.lastname: Morris
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authors.forename: James A
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authors.lastname: Chan
authors.forename: Victor E
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authors.lastname: Velculescu
authors.forename: Bert
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authors.lastname: Vogelstein
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Nickolas
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authors.lastname: Papadopoulos
authors.forename: Barry D
authors.initials: BD
authors.lastname: Nelkin
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Ball
mesh_terms: D018276:Carcinoma, Medullary / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D006801:Humans; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)