ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Tirosh, A., Killian, J. K., Zhu, Y. J., Petersen, D., Walling, J., Mor-Cohen, R., Neychev, V., Stevenson, H., Keutgen, X. M., Patel, D., Nilubol, N., Meltzer, P., Kebebew, E. 2019


Purpose to report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET) and of other genetic alterations that may be associated with tumorigenesis Methods A phase II mutation targeted therapy trial was conducted in patients with advanced well differentiated G1/G2 GEP-NETs. Mutations found in mTOR pathway associated genes, led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor DNA from GEP-NETs were sequenced and compared with germline DNA, using the OncoVar-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called, and copy-number (CN) variant analysis was performed. Results Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NETs and 5 of other primary sites), harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n=26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chr 18 (p<0.05), and CN gain of chr 5, and loss of chr 13. CN losses in chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesion sequenced. Conclusions Wide DNA sequencing may identify candidate actionable genes, and lead to the identification of novel target genes for advanced well-differentiated GEP-NETs.

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