Abstract 4345: Evaluation of the prevalence and impact of molecular variation in the three-prime repair exonuclease 1 TREX1 across mammalian species and in human malignancies
Authors: Konate Mariam M. , Shekfeh Marwa , Krushkal Julia 
Published: March 2024

Abstract
The three-prime repair exonuclease 1, TREX1, degrades cytosolic DNA to prevent aberrant immune activation. Inactivation of TREX1 results in DNA accumulation in the cytosol and subsequent induction of the cGAS-STING DNA sensing pathway, downstream interferon-mediated innate immune signaling, and inflammation. Correspondingly, germline pathogenic mutational defects in the TREX1 gene lead to hereditary autoimmune and autoinflammatory disorders. While TREX1 mutations are also reported in some tumors, their consequences in cancer remain poorly understood. To assess the functional importance of amino acid residues in TREX1, we analyzed protein sequences of the functional TREX1 isoform, TREX1b, from 168 mammalian species. We also conducted a survey of genomic variant databases COSMIC, ClinVar, TCGA, LOVD, Decipher, and gnomAD for disease-associated TREX1 mutations. Finally, we modeled TREX1 mutations occurring in human tumors to evaluate predicted impact on protein stability and function using structure-based approaches FoldX and INPS-3D, and compared results to available predictions from AlphaMissense and COSMIC-3D. In the Cancer Genome Atlas (TCGA), 16 out of 32 cancer histologies have tumor samples bearing protein-altering TREX1 variants, with bladder cancer and melanoma having the highest frequency of TREX1 variants at 2.7% of tumor samples. Moreover, all 32 cancer types have some samples with loss of one or both copies of TREX1; frequencies of heterozygous loss range from 0.6% (thymoma) to 86% (kidney clear cell and lung squamous cell carcinomas). We also observed TREX1 copy gain with lower frequency than instances of copy loss, but also occurring in 31 out of 32 studies. Multiple tumors have a combination of a TREX1 protein sequence variant and copy number gain or loss, suggesting that their potential interplay may increase functional impact of TREX1 variants. Out of 15 cancer-associated TREX1 variants, 5 (33%) were predicted to be pathogenic by AlphaMissense. For FoldX and INPS-3D mutagenesis modeling, we used the published experimental 3D crystal structure of the wild type (WT) human TREX1 (PDB: 7TQQ). The changes in Gibbs free energy of folding ΔΔG between WT and mutant predicted by FoldX and INPS-3D both correlated strongly with the AlphaMissense pathogenic probability scores (Pearson r=0.69 and 0.73, respectively). We will discuss implications of TREX1 variation and conservation across mammalian species and potential effects of germline TREX1 variants in hereditary autoimmune and autoinflammatory disorders and on somatic and germline TREX1 variants in human cancer cells and tumor samples.
Citation Format: Mariam M. Konate, Marwa Shekfeh, Julia Krushkal. Evaluation of the prevalence and impact of molecular variation in the three-prime repair exonuclease 1 TREX1 across mammalian species and in human malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4345.