Genomic landscape of pancreatic neuroendocrine tumors

Abstract

AIM:To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs). METHODS:A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalinfixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed. RESULTS:Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis. CONCLUSION:This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of Pan-NET. Gebauer N et al . Chromosomal aberrations in PanNETs (PanNETs). Analysis of recurrent genomic amplifications delineated two independent clusters of genomic aberrations as well as two patient groups characterized by significantly overlapping cytogenetic features. Copy number alterations affecting chromosomes 6, 8, 9 and 17 were shown to be associated with survival. A high degree of genomic heterogeneity between primary tumor samples and metastatic lesions demonstrates the need for a more focused molecular and cytogenetic characterization in the light of upcoming targeted therapy approaches. PanNETs appear to be genetically distinct from other types of neuroendocrine tumors.

Molecular Signatures and Their Clinical Utility in Pancreatic Neuroendocrine Tumors

“…Various studies have identified non-mutational biomarkers associated with tumor progression/metastasis that could potentially assist with management. Copy-number alterations at certain chromosomal loci, such as 6p22.2-p22.1, 8q24.3, 9q34.11, and 17p13.1 have been associated with poorer prognosis ( 65 ). This is an important area of ongoing research, though the prognostic implications of other copy-number alterations and chromosomal translocations are poorly defined at this time.…”