Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

Author(s):Show less -

Agrawal, Nishant ^{[1, 2, 3, 4]} ; Jiao, Yuchen ^{[2, 3]} ; Sausen, Mark ^{[2, 3]} ; Leary, Rebecca ^{[2, 3]} ; Bettegowda, Chetan ^{[2, 3, 5]} ; Roberts, Nicholas J. ^{[2, 3]} ; Bhan, Sheetal ^[4] ; Ho, Allen S. ^[6] ; Khan, Zubair ^[1] ; Bishop, Justin ^[7] ; Westra, William H. ^{[4, 7]} ; Wood, Laura D. ^[7] ; Hruban, Ralph H. ^[7] ; Tufano, Ralph P. ^{[1, 4]} ; Robinson, Bruce ^[8] ; Dralle, Henning ^[9] ; Toledo, Sergio P. A. ^[10] ; Toledo, Rodrigo A. ^[10] ; Morris, Luc G. T. ^[11] ; Ghossein, Ronald A. ^[12] ; Fagin, James A. ^[13] ; Chan, Timothy A. ^{[6, 14, 15]} ; Velculescu, Victor E. ^{[2, 3, 4]} ; Vogelstein, Bert ^{[2, 3, 4]} ; Kinzler, Kenneth W. ^{[2, 3, 4]} ; Papadopoulos, Nickolas ^{[2, 3, 4]} ; Nelkin, Barry D. ^[4] ; Ball, Douglas W. ^{[4, 16]}

Affiliation:Show less -

^[1] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 - USA

^[2] Ludwig Ctr Canc Genet, Baltimore, MD 21287 - USA

^[3] Howard Hughes Med Inst, Baltimore, MD 21287 - USA

^[4] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 - USA

^[5] Johns Hopkins Med Inst, Dept Neurosurg, Baltimore, MD 21287 - USA

^[6] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 - USA

^[7] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 - USA

^[8] Univ Sydney, Sydney, NSW 2006 - Australia

^[9] Univ Halle Wittenberg, D-06099 Halle - Germany

^[10] Univ Sao Paulo, Sch Med, Div Endocrinol, BR-05403900 Sao Paulo - Brazil

^[11] Mem Sloan Kettering Canc Ctr, Head & Neck Serv, New York, NY 10021 - USA

^[12] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 - USA

^[13] Mem Sloan Kettering Canc Ctr, Dept Endocrinol, New York, NY 10021 - USA

^[14] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 - USA

^[15] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 - USA

^[16] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21287 - USA

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 98, n. 2, p. E364-E369, FEB 2013.
• Web of Science Citations: 96

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. (J Clin Endocrinol Metab 98: E364-E369, 2013) (AU)

• FAPESP's process: 09/15386-6 - Analysis of the CDKN1A, CDKN1B, CDKN2B and CDKN2C genes in multiple endocrine neoplasias type 1 and 2.
• Grantee: Rodrigo de Almeida Toledo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral