Growth factor signaling in pancreatic neuroendocrine tumor metastases.

Abstract

256 Background: Pancreatic neuroendocrine tumors (PanNETs) are among one of the fastest growing cancer diagnoses, yet clinical management for patients with metastatic disease is largely empirically based. Currently, surgical resection remains the only curative option; however, surgical resection of metastatic disease may not be feasible. Preliminary genomic analysis of primary PanNETs revealed a complex mutational landscape with four common oncogenic events; but, critical activation pathways of metastatic lesions have yet to be elucidated. Therefore, pan-genomic analysis of metastatic PanNETs is necessary to understand which genes/pathways are deregulated in PanNET metastases for potential therapeutic exploitation. Methods: We initiated a preliminary genomic sequencing study to evaluate mutations in a set of matched primary and metastatic PanNETs to determine genetic variants involved in metastasis to the liver. De-identified FFPE tumor samples were analyzed from patients who underwent surgical resection without receiving preoperative therapy. DNA was isolated and whole exome sequencing was performed using the Nextera Rapid Capture Exome Kit by Illumina on an Illumina HiSeq 2000/2500. The following criteria were used to define genetic variants: bidirectional, non-synonymous, clean mapping in IGV, ≥ 15X coverage, and an alternate allele frequency of 0.3 ≤ x ≤ 0.7. Results: All metastatic PanNETs were classified as WHO grade G2/G3 based on their KI-67 proliferation index. Each primary PanNET contained an average of 102 genetic variants while liver metastases showed an average of 124 genetic variants. MUFFINN and string analysis revealed that primary PanNETs contained enrichment for mutations involved in the PI3K/Akt and Ras signaling pathways while liver metastases showed enrichment for mutations involved in the MAPK and ErbB signaling pathways. Additionally, two-thirds of liver metastases contained somatic mutations in FGFR3. Conclusions: We have discovered novel pathways that have the potential to regulate pancreatic neuroendocrine tumor metastasis along with an innovative signaling pathway that may sustain metastatic growth and survival as well as exploitation for therapeutic potential.