Gene alterations in inborn errors of immunity and their presence in cancers: implications for oncogenesis, progression, and outcomes

Inborn Errors of Immunity (IEI) are genetic disorders impairing the immune system, increasing susceptibility to infections, autoimmunity, inflammation, and malignancies. Mutations in over 500 genes have been shown to cause IEI. This study investigated IEI-related differential gene expression by examining the somatic transcriptomes of cancers. RNA-sequencing data from cancers were obtained from TCGA and TARGET databases, alongside healthy tissue data from GTEx, and the differentially expressed gene set was filtered for 592 IEI-related genes. To examine the differential expression of genes across cancers, odds ratios were computed for enrichment of IEI-related genes. Pathway analysis on the differentially expressed IEI-related genes identified immune pathways that are significantly represented. IEI-genes that were significantly dysregulated include TMPRSS15, SEMA3E, ANGPT1, CFH, F5, CFB, CFD, CFH, and CR2. Interestingly, complement-related pathways were the most altered in our analysis. Furthermore, IEI-related genes are more likely to be differentially expressed compared to non-IEI genes in certain cancers. This study presents bioinformatic analyses of pan-cancer genomic datasets, identifying distinct IEI-associated gene expression changes. The findings provide insights into the role of immunological pathways, specifically the complement system, in cancer. Further investigation into the identified gene alterations could advance the care of a vulnerable group of cancer patients.