Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

SIMPLE SUMMARY: Chordoma is an extremely rare bone cancer that has not been fully characterized and few risk factors have been identified, highlighting the need for improving our understanding of the disease biology. Our study aims to identify chordoma susceptibility genes by investigating 265 genes involved in chordoma-related signaling pathways and other biological processes on germline DNA of 138 chordoma patients of European ancestry compared to internal control datasets and general population databases. Results were intersected with whole genome sequencing data from 80 skull-base chordoma patients of Chinese ancestry. Several rare loss-of-function and predicted deleterious missense variants were enriched in chordoma cases in both datasets, suggesting a complex model of pathways potentially involved in chordoma development and susceptibility, warranting further investigation in larger studies. ABSTRACT: Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.