Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany.
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
Clin Cancer Res. 2022 Aug 2;28(15):3342-3355. doi: 10.1158/1078-0432.CCR-20-4774.
To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).
A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes.
One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE.
Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.
通过全基因组关联研究（GWAS）确定化疗后出现 3/4 级中性粒细胞减少或白细胞减少事件（NLE）的分子预测因子。
对 III 期化疗研究 SUCCESS-A 中的患者（n = 3322）进行了 GWAS。使用 Illumina HumanOmniExpress-12v1 阵列进行基因分型。使用细胞培养模型对发现进行了功能验证，并将可能的致病基因的基因型和基因表达与临床治疗反应和预后结果相关联。
在染色体 16 上发现了一个位点（rs4784750；NLRC5；P = 1.56E-8）和染色体 13 上的另一个位点（rs16972207；TNFSF13B；P = 3.42E-8），达到了全基因组显著水平。功能验证表明，这两个基因的表达受两种转录因子的基因型依赖性和化疗依赖性活性改变。基因型与 NLE 患者的无病生存也有关联。
NLRC5 和 TNFSF13B 中的两个位点与 NLE 相关。MHC I 调节剂 NLRC5 的参与暗示了免疫肿瘤学途径的可能参与。
