Abstract
BackgroundRecent 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.MethodsUsing 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.ResultsThe 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.ConclusionCytology 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.
Highlights
Pancreas neuroendocrine tumors are a heterogeneous collection of rare tumors with a distinct gene mutation spectrum when compared to pancreatic ductal adenocarcinomas (PDAC), with an overall 10year survival of 47%. [1, 2] A recent whole exome sequencing study of sporadic Pancreas Neuroendocrine Tumor (pNET) identified key molecular alterations at a low frequency, presumably reflecting the indolent nature of this tumor type. [3] The relatively unique genetic variant landscape revealed that 44% of pancreas neuroendocrine tumors (pNETs) harbored a Menin 1 gene (MEN1) alteration and 43% either a Death-Domain Associated Protein (DAXX) or Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene aberration
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 Tuberous sclerosis 2 gene (TSC2) (8%) genes
Summary
Pancreas neuroendocrine tumors (pNETs) are a heterogeneous collection of rare tumors with a distinct gene mutation spectrum when compared to pancreatic ductal adenocarcinomas (PDAC), with an overall 10year survival of 47%. [1, 2] A recent whole exome sequencing study of sporadic pNETs identified key molecular alterations at a low frequency, presumably reflecting the indolent nature of this tumor type. [3] The relatively unique genetic variant landscape revealed that 44% of pNETs harbored a MEN1 (a tumor suppressor gene) alteration and 43% either a DAXX or ATRX gene (chromatin remodeling complex) aberration. [12,13,14,15,16,17,18] Collectively, this work has highlighted the potential role of EUS to provide personalized patient care, due to the enhanced ability to identify prognostic and predictive disease biomarkers, in the field of targeted gene therapy. 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 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
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