Published online Dec 14, 2014. doi: 10.3748/wjg.v20.i46.17498
Revised: May 3, 2014
Accepted: July 24, 2014
Published online: December 14, 2014
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 formalin-fixed 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 PanNET.
Core tip: In the current study, we characterized the genomic landscape of pancreatic neuroendocrine tumors (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.