Chen Junyu, Epstein Michael P, Schildkraut Joellen M, Kar Siddhartha P
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Genes (Basel). 2025 May 14;16(5):575. doi: 10.3390/genes16050575.
: Germline alleles near genes encoding certain immune checkpoints (, ) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. : 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. : Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with < 5 × 10 associated with at least one of the cancer types at < 10 and one of the autoimmune/autoinflammatory diseases at < 10. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (, , , , ) was each strongly correlated (Spearman's ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (, , , ) 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 the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. : We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by , , , and as possible targets for cancer immunotherapy.
编码某些免疫检查点（……）的基因附近的种系等位基因与自身免疫性/自身炎症性疾病和癌症相关，但方式相反。这促使我们系统地寻找具有这种模式的其他种系等位基因，目的是利用人类遗传学确定潜在的癌症免疫治疗靶点。：将乳腺癌、前列腺癌、卵巢癌和子宫内膜癌（240,540例/317,000例对照）以及七种自身免疫性/自身炎症性疾病（112,631例/895,386例对照）的全基因组关联研究（GWAS）进行成对固定效应跨疾病荟萃分析，并进行计算机后续分析。：荟萃分析后进行连锁不平衡聚类，确定了312个独特的、独立的领先变异，其P值<5×10⁻⁸，与至少一种癌症类型在P<10⁻⁸时相关，与至少一种自身免疫性/自身炎症性疾病在P<10⁻⁸时相关。在每个领先变异处，赋予自身免疫性/自身炎症性疾病风险的等位基因对癌症具有保护作用。将领先变异映射到最接近的基因作为假定的功能靶点，并聚焦于免疫相关基因，涉及32个基因。肿瘤大量RNA测序数据突出显示，在每种癌症类型中，5/32个基因（……）的肿瘤表达与至少一种肿瘤内T/髓样细胞浸润标志物（……）均呈强相关（斯皮尔曼ρ>0.5）。来自所有癌症类型的肿瘤单细胞RNA测序数据表明，这五个基因在肿瘤内免疫细胞与恶性细胞中更有可能表达。与这些基因相对应的五个领先单核苷酸多态性通过数量性状基因座机制的表达以及至少一条额外的功能证据线与它们相关联。这些基因编码的蛋白质预计是可成药的。：我们提供了群体规模的种系遗传和功能基因组证据，以支持进一步评估由……编码的蛋白质作为癌症免疫治疗的可能靶点。
