Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors

Oncotarget. 2016 Jan 26;7(4):4024-35. doi: 10.18632/oncotarget.6602.

Abstract

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.

Keywords: BRAFV600E mutation; neuroendocrine tumors; pazopanib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Cohort Studies
  • Exome / genetics*
  • Female
  • Genome, Human
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Indazoles
  • Intestinal Neoplasms / drug therapy
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neuroendocrine Tumors / drug therapy
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyrimidines / therapeutic use
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Sulfonamides / therapeutic use

Substances

  • Biomarkers, Tumor
  • Indazoles
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor