Authors: Georgios Andrea Zenonos, MD; Ahmed Jorge, MS; Andrew Venteicher, MD, PhD; Benita Valappil, MS; Juan Fernandez-Miranda, MD; Carl Snyderman, MD; Eric Wang, MD; William LaFramboise, PhD; Paul Gardner, MD (Miami, FL)

Introduction: The genetic aberrancies driving recurrent skull base chordomas after surgery and radiation are poorly understood. Deciphering these processes may be key in developing targeted therapies for tumors that fail the standard of care. Methods: To minimize the background genetic noise of inter-subject variability, we sought to study the progression of genetic signatures in the same patients with skull base chordomas, each undergoing the sequence of primary tumor resection, radiation, tumor progression, and recurrent tumor resection.Whole-exome sequencing was performed on 16 samples: five primary tumors and their six recurrences (one patient had two recurrences), along with matched peripheral blood. Germline and tumor-specific mutations (single nucleotide variations, insertions/deletions, and copy number variations) were called using established pipelines for each patient's blood, primary and recurrent tumor(s) samples. The data were then curated for potentially deleterious mutations employing a battery of algorithms (ACMG designation and effect,and 14-Variant Effect Predictor scores). The genetic aberrancies unique to the transition of primary to recurrent tumors were determined, and studied using a series of gene set enrichment analysis tools (GSEA, DAVID, IPA, CPDB, and Reactome). Results: Three-hundred and ninety-eight genes were exclusively affected in recurrent tumors, either by copy number variations, or potentially deleterious point mutations and insertions/deletions. Gene set enrichment analysis integrated these results into several potentially actionable pathways, such as Neurotrophin-signaling(FDR=1.52e -4 ), EGF-signaling (FDR=1.01e -3 ), mTOR-signaling (FDR=2.74e -3 ), ErbB-signaling (FDR=3.76e -3 ), Jak2-signaling (FDR=7.57e- 3 ), and ATF2-signaling (FDR=7.57 e -3 ). Additionally, a number of other cancer-related and immunologic signatures, as well as cytoskeleton-related processes were enriched with an FDR<0.01. Conclusion: We have identified genetic signatures uniquely characterizing the progression of primary skull base chordomas to recurrent tumors after surgery and radiation. Many of the affected pathways are potentially actionable, and could guide targeted therapy investigations for these challenging tumors.