Gene Expression Profiling of Pancreas Neuroendocrine Tumors with Different Ki67-Based Grades

SIMPLE SUMMARY: Ki67-based grading is a major prognostic parameter for pancreatic neuroendocrine tumors. Gene expression profiles of these tumors have been explored, yet their relationship with Ki67-based tumor grade has only been superficially investigated. To fill this gap, we analyzed differentially expressed genes across 29 cases of different grades. Our data provided the first proof that the switch from lower to higher grades is associated with a profound change in the transcriptome. The comparison of multiple samples from the same patients, including primaries and metastasis, showed that the major determinant of difference was tumor grade, irrespective of the anatomic location or patient of origin. These data call for further investigation of this association and of the role of Ki67 in affecting chromosomal stability in neuroendocrine tumors of different grades, which may clarify the basis of tumor progression and provide clues on how to interfere with it. ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) display variable aggressive behavior. A major predictor of survival is tumor grade based on the Ki67 proliferation index. As information on transcriptomic profiles of PanNETs with different tumor grades is limited, we investigated 29 PanNETs (17 G1, 7 G2, 5 G3) for their expression profiles, mutations in 16 PanNET relevant genes and LINE-1 DNA methylation profiles. A total of 3050 genes were differentially expressed between tumors with different grades (p < 0.05): 1279 in G3 vs. G2; 2757 in G3 vs. G1; and 203 in G2 vs. G1. Mutational analysis showed 57 alterations in 11 genes, the most frequent being MEN1 (18/29), DAXX (7/29), ATRX (6/29) and MUTYH (5/29). The presence and type of mutations did not correlate with the specific expression profiles associated with different grades. LINE-1 showed significantly lower methylation in G2/G3 versus G1 tumors (p = 0.007). The expression profiles of matched primaries and metastasis (nodal, hepatic and colorectal wall) of three cases confirmed the role of Ki67 in defining specific expression profiles, which clustered according to tumor grades, independently from anatomic location or patient of origin. Such data call for future exploration of the role of Ki67 in tumor progression, given its involvement in chromosomal stability.