Next-generation sequencing (NGS) in pancreatic neuroendocrine tumors (panNETs): Defining differentiation and grade genetically.

Abstract

291 Background: Advances in tumor sequencing technology have improved our understanding of the genetic basis of panNETs. Whole exome sequencing of well differentiated (WD) panNETs demonstrated changes in chromatin remodeling genes; in poorly differentiated (PD) neuroendocrine carcinomas, changes along the TP53/RB signaling pathways have been observed. We sought to validate these observations in clinical practice. Methods: This prospective study (NCT01775072) used the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay to do NGS on panNETs in the routine practice setting. MSK-IMPACT is an assay providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number changes, and select gene rearrangements. Results: Results are available in 89 tumor samples from 78 patients (mean patient age 53, 58% female); 31 tumors (35%) low grade, 35 tumors (39%) intermediate grade, and 23 tumors (26%) high grade; 5 patients (6%) with PD tumors and 73 patients (94%) with WD tumors. Changes in chromatin remodeling genes were observed only in WD tumors; DAXX alterations in 24 tumors (27%), ATRX alterations in 15 tumors (17%), and SETD2 alterations in 10 tumors (11%). RB1 alterations were identified in 3 tumors (3%); all of these tumors were PD/high grade. TP53 alterations were seen in 9 tumors (10%); 4/9 tumors (44%) PD/high grade, 3/9 tumors (33%) WD/intermediate grade, 2/9 tumors (22%) WD/low grade. All WD, TP53-altered tumors also had DAXX/ATRX changes. Conclusions: In line with prior work, using an institutional NGS assay, we demonstrated tumor differentiation and grade genetically. Changes in chromatin remodeling genes were exclusive to WD tumors. Only PD tumors had RB1 changes. While TP53 was altered in both WD and PD tumors, TP53-altered WD tumors also harbored changes in the chromatin remodeling genes.