Exome-wide analysis of rare deleterious variants in 3,569 sarcoma cases and 21,788 controls from multiple international data sources reveals no novel susceptibility genes.

PURPOSE: Sarcoma is a cancer of tissues of mesenchymal origin, constituting ∼1% of cancer diagnoses and comprising >70 subtypes. Phenotype low frequency and poor prognosis have previously limited sarcoma susceptibility gene investigation.

METHODS

We used germline exome/genome sequencing data from six case and four control datasets for case-control gene-burden testing using SAIGE-GENE in 3,569 cases and 21,788 controls in total. We analysed 92 autosomal dominant cancer susceptibility genes for loss-of-function and/or likely pathogenic/pathogenic variants. We performed exome-wide association study (ExWAS) for "Tier 1": loss-of-function variants and "Tier 2": loss-of-function and protein-altering variants.

RESULTS

TP53 and NF1, both established sarcoma susceptibility genes, demonstrated significantly increased burden of loss-of-function and pathogenic/likely pathogenic variants amongst cases. After exclusion of known sarcoma susceptibility genes, there was residual increased burden of qualifying variants amongst remaining cancer susceptibility genes combined. TP53 had significantly increased burden of qualifying variants in ExWAS in cases for Tier 1 only. Despite ∼80% power to detect novel sarcoma susceptibility genes with relative risk of ≥5 to population frequency of ≥0.17%, no novel gene-sarcoma associations were identified.

CONCLUSION

Undiscovered sarcoma susceptibility genes likely have small effect size and/or occur at low frequency and/or association is limited to specific rare subtypes.