The Genomic Patterns of Well-Differentiated Pancreatic Neuroendocrine Tumors (NETs) Identify Sub-Sets for Rational...

The natural history of pancreatic neuroendocrine tumors (NETs) can span decades of slow progression, but it is unpredictable, with a more aggressive course also being common. The two clinical biomarkers currently used to define the grade of a tumor, the Ki67 index and the mitotic index, are not able to fully capture the course of individual patients. This creates an unmet need to discover better prognostic biomarkers to inform therapeutic decisions, as well as therapies with overall survival benefit. Two genomic series of pancreatic NETs were examined to discover sub-sets with divergent characteristics. Primary data were downloaded from the cBioportal cancer genomics portal and analyzed at the individual sample level. Pancreatic NET patients without MEN1/DAXX/ATRX mutations were younger than NET patients with any of these mutations. Pancreatic NETs had consistently low tumor mutation burden but were heterogeneous in their Fraction Genome Altered (FGA), a metric of chromosomal instability (CIN), with one group presenting high FGA and another possessing low to intermediate FGA. FGA did not correlate with Ki67, but high FGA was most prevalent in cases with mutations in MEN1 and DAXX or ATRX. TSC2 mutations were significantly more prevalent in the group with high FGA.