Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
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Charny Park1,*, Sang Yun Ha1,*, Seung Tae Kim2,*, Hee Cheol Kim3, Jin Seok Heo3, Young Suk Park2, Gregory Lauwers4, Jeeyun Lee2, Kyoung-Mee Kim1
1Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
*These authors contributed equally to this work
Jeeyun Lee, e-mail: [email protected]
Kyoung-Mee Kim, e-mail: [email protected]
Keywords: neuroendocrine tumors, BRAFV600E mutation, pazopanib
Received: August 03, 2015 Accepted: November 22, 2015 Published: December 14, 2015
Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.
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