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

Abstract

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. 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. <i>NF1</i> 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, <i>TP53</i> (p=0.0025), <i>RB1</i> (p=0.0281), and <i>MSH2</i> (p=0.0085). <i>BAG1</i>, which has not previously been implicated in STS, exhibited the strongest genome-wide signal after <i>NF1</i>, with p=6×10^-5. The association signals for <i>NF1</i> and <i>MSH2</i> were driven primarily by truncating variants, with ORs of 39 (95% CI: 7.1 to 220) for <i>NF1</i> and 33 (95% CI: 2.4 to 460) for <i>MSH2</i>. In contrast, the association signals for <i>RB1</i> and <i>BAG1</i> were driven primarily by predicted damaging missense variants, with estimated ORs of 12 (95% CI: 2.4 to 59) for <i>RB1</i> and 20 (95% CI: 1.4 to 300) for <i>BAG1</i>. Our results confirm that pathogenic variants in <i>NF1</i>, <i>RB1</i> and <i>TP53</i> confer large increases in the risk of developing multiple STS subtypes, provide support for the role of <i>MSH2</i> in STS susceptibility and identify <i>BAG1</i> as a novel candidate STS risk gene.