# Genomic Characterization of Chordoma: Insights from the AACR Project GENIE Database

## TL;DR

This study uses genomic data to identify key mutations in chordoma tumors, revealing potential targets for treatment and highlighting differences in pediatric and adult cases.

## Contribution

The study provides a comprehensive genomic profile of chordoma, identifying novel mutation patterns and potential therapeutic targets.

## Key findings

- Frequent mutations in genes like PBRM1, ARID1A, and SETD2 were linked to chromatin remodeling pathways.
- TERT promoter mutations and CDKN2A alterations were common, with CDKN2A/B deletions enriched in metastatic tumors.
- Pediatric chordoma cases showed distinct mutation profiles compared to adult cases.

## Abstract

Chordoma is a rare, slow-growing tumor arising from remnants of the embryonic notochord. This study investigates genomic alterations in chordoma using a large national patient-level repository, the AACR Project GENIE. The goal was to identify mutations in key genes such as PBRM1, ARID1A, TERT, and TP53, which may influence tumor behavior, treatment response, and clinical outcomes. These findings contribute to an improved understanding of chordoma biology, highlighting potential biomarkers and therapeutic targets.

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.