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Published on: August 15, 2019
Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility
Sally Yepes1, Nirav N Shah1, Jiwei Bai2
1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
Researchers identified rare genetic variants in chordoma patients, suggesting a complex genetic susceptibility beyond the known TBXT gene. These findings in North American and Chinese populations highlight potential new pathways for chordoma predisposition.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Chordoma is a rare bone cancer with largely unknown genetic causes.
- The TBXT gene is the only known chordoma susceptibility gene, with variants linked to familial and sporadic cases.
- Genetic susceptibility beyond TBXT remains largely unexplored.
Purpose of the Study:
- To investigate rare germline genetic variants in genes related to TBXT/chordoma signaling pathways.
- To explore genetic susceptibility in chordoma patients from North America and China.
- To identify novel genes and pathways involved in chordoma development.
Main Methods:
- Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed on 138 European ancestry and 80 Chinese chordoma patients.
- Identified very rare and potentially pathogenic variants in 265 genes.
- Focused on genes involved in notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex, and mesoderm development pathways.
Main Results:
- Rare and likely pathogenic variants were found in 23% of European ancestry patients.
- Variants were identified in genes associated with notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex, and mesoderm development.
- Pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT, and TSC2 were observed in Chinese patients.
Conclusions:
- Several rare loss-of-function and predicted deleterious missense variants were identified in germline DNA of chordoma patients.
- These variants may contribute to chordoma predisposition.
- The findings suggest a complex genetic susceptibility for chordoma, requiring further large-scale studies.
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