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 NF1 exhibited the strongest genome-wide signal across the six subtypes, with p=1×10−5. We also observed nominally significant association signals for three additional genes of interest, TP53 (p=0.0025), RB1 (p=0.0281), and MSH2 (p=0.0085). BAG1, which has not previously been implicated in STS, exhibited the strongest genome-wide signal after NF1, with p=6×10−5. The association signals for NF1 and MSH2 were driven primarily by truncating variants, with ORs of 39 (95% CI: 7.1 to 220) for NF1 and 33 (95% CI: 2.4 to 460) for MSH2. In contrast, the association signals for RB1 and BAG1 were driven primarily by predicted damaging missense variants, with estimated ORs of 12 (95% CI: 2.4 to 59) for RB1 and 20 (95% CI: 1.4 to 300) for BAG1.
Conclusions Our results confirm that pathogenic variants in NF1, RB1 and TP53 confer large increases in the risk of developing multiple STS subtypes, provide support for the role of MSH2 in STS susceptibility and identify BAG1 as a novel candidate STS risk gene.
- clinical genetics
- molecular genetics
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Contributors CH conceived of the study. FH, YY, J-SC, HH and CH conducted association analyses. PS, FH, YY and CH conducted copy number alteration analyses. CH, FH, YY and PS interpreted results. FH prepared tables and figures. FH and CH prepared and wrote the manuscript. All authors approved submission of the manuscript in its present form.
Funding US National Institutes of Health grants R01 CA195614, R01 GM104390, R01 HG005859 US National Cancer Institutes Cancer Center Support Grant P30CA016672.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. Data are available in The Cancer Genome Atlas (TCGA) and the National Database for Autism Research (NDAR).
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