Integrated case-control and somatic-germline interaction analyses of soft-tissue sarcoma.

PURPOSE

The contribution of rare genetic variation in the development of soft-tissue sarcoma (STS) remains underexplored. To address this gap, we conducted a whole-exome case-control and somatic-germline interaction study to identify and characterise STS susceptible genes.

METHODS

The study involved 219 STS cases from The Cancer Genome Atlas and 3507 controls. All cases and controls were matched genetically onEuropean ancestry based on the 1000 Genomes project. Cross-platform technological stratification was performed with XPAT and gene-based association tests with VAAST 2.

RESULTS

exhibited the strongest genome-wide signal across the six subtypes, with p=1×10. We also observed nominally significant association signals for three additional genes of interest, (p=0.0025), (p=0.0281), and (p=0.0085). , which has not previously been implicated in STS, exhibited the strongest genome-wide signal after , with p=6×10. The association signals for and were driven primarily by truncating variants, with ORs of 39 (95% CI: 7.1 to 220) for and 33 (95% CI: 2.4 to 460) for . In contrast, the association signals for and were driven primarily by predicted damaging missense variants, with estimated ORs of 12 (95% CI: 2.4 to 59) for and 20 (95% CI: 1.4 to 300) for .

CONCLUSIONS

Our results confirm that pathogenic variants in , and confer large increases in the risk of developing multiple STS subtypes, provide support for the role of in STS susceptibility and identify as a novel candidate STS risk gene.