Mapping inherited genetic variation with opposite effects on autoimmune disease and cancer identifies candidate drug targets associated with the anti-tumor immune response.

Autor: Chen J; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Epstein MP; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA., Schildkraut JM; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Kar SP; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.; Ovarian Cancer Programme, Cancer Research UK Cambridge Centre, Cambridge, UK.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Dec 28. Date of Electronic Publication: 2023 Dec 28.
DOI: 10.1101/2023.12.23.23300491
Abstrakt: Background: Germline alleles near genes that encode certain immune checkpoints ( CTLA4, CD200 ) are associated with autoimmune/autoinflammatory disease and cancer but in opposite directions. This motivates a systematic search for additional germline alleles which demonstrate this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetic evidence.
Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. To ensure detection of alleles with opposite effects on cancer and autoimmune/autoinflammatory disease, the signs on the beta coefficients in the autoimmune/autoinflammatory GWAS were reversed prior to meta-analyses.
Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with P meta <5x10 -8 associated with at least one of the cancer types at P cancer <10 -3 and one of the autoimmune/autoinflammatory diseases at P auto <10 -3 . At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping each lead variant to its nearest gene as its putative functional target and focusing on genes with established immunological effects implicated 32 of the nearest genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes ( IRF1, IKZF1, SPI1, SH2B3, LAT ) were each strongly correlated (Spearman's ρ>0.5) with at least one intra-tumor T/myeloid cell infiltration marker ( CD4, CD8A, CD11B, CD45 ) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via expression quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable.
Conclusion: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 , and LAT as possible targets for cancer immunotherapy.
Databáze: MEDLINE
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