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Assessment of pancreatic neuroendocrine tumor cytologic genotype diversity to guide personalized medicine using a custom gastroenteropancreatic next-generation sequencing panel.

ABSTRACT: Recent genetic studies have highlighted that alterations in MEN1, chromatin remodeling genes, and mammalian target of rapamycin (mTOR) pathway genes are the most frequent molecular events identified in pancreas neuroendocrine tumors (pNETs). The prognostic or predictive impact of these biomarkers and other less frequently observed aberrations, i.e. PTEN, TSC2 and PIK3CA are relatively unknown. The aims of this targeted next generation sequencing (NGS) study were to assess tumor cytology genotype diversity, to survey for potential adverse prognostic biomarkers and the prevalence of mTOR pathway variants.Using a custom 15 gene gastroenteropancreatic neuroendocrine tumor panel, targeted NGS of archived (2002-2013) primary pNETs (n=90) and pNET liver metastasis (n=32) cytology smears was performed.The genetic variant landscape revealed that 21% and 28% of primary and metastatic liver pNETs harbored ? 2 variants per tumor, respectively. The most prevalent primary tumor variants were in the MEN1 (42%), DAXX (11%), ATRX (10%), and TSC2 (8%) genes. Patients harboring aberrations in TSC2, KRAS or TP53 were more likely to experience disease progression and reduced overall survival, when compared to individuals who were wild-type. The prevalence of these potential prognostic biomarkers in early disease was observed in 3.3% of the primary tumor cohort. mTOR pathway variants including alterations in PTEN, TSC2 and PIK3CA were identified in 10% and 12.5% of primary tumors and pNET liver metastasis, respectively.Cytology based tumor genotyping revealed a broad spectrum of genetic variants including possible adverse prognostic biomarkers, reflective of an aggressive phenotype. It also demonstrated the prevalence of potential predictive biomarkers for mTOR pathway inhibitor sensitivity.

SUBMITTER: Gleeson FC

PROVIDER: S-EPMC5706811 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Assessment of pancreatic neuroendocrine tumor cytologic genotype diversity to guide personalized medicine using a custom gastroenteropancreatic next-generation sequencing panel.

Gleeson Ferga C FC Voss Jesse S JS Kipp Benjamin R BR Kerr Sarah E SE Van Arnam John S JS Mills John R JR Marcou Cherisse A CA Schneider Amber R AR Tu Zheng Jin ZJ Henry Michael R MR Levy Michael J MJ

Oncotarget 20170628 55

<h4>Background</h4>Recent genetic studies have highlighted that alterations in MEN1, chromatin remodeling genes, and mammalian target of rapamycin (mTOR) pathway genes are the most frequent molecular events identified in pancreas neuroendocrine tumors (pNETs). The prognostic or predictive impact of these biomarkers and other less frequently observed aberrations, i.e. PTEN, TSC2 and PIK3CA are relatively unknown. The aims of this targeted next generation sequencing (NGS) study were to assess tumo ...[more]

PMID: 29212165

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Project description:Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (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-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET 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 NET, 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 chromosome (Chr) 18 (P<.05), 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 lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.

Project description:Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

Dataset Information

Assessment of pancreatic neuroendocrine tumor cytologic genotype diversity to guide personalized medicine using a custom gastroenteropancreatic next-generation sequencing panel.

Publications

Assessment of pancreatic neuroendocrine tumor cytologic genotype diversity to guide personalized medicine using a custom gastroenteropancreatic next-generation sequencing panel.

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