Svedberg Anna, Björn Niclas, Sigurgeirsson Benjamín, Pradhananga Sailendra, Brandén Eva, Koyi Hirsh, Lewensohn Rolf, De Petris Luigi, Apellániz-Ruiz María, Rodríguez-Antona Cristina, Lundeberg Joakim, Gréen Henrik
Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
Lung Cancer. 2020 Sep;147:106-114. doi: 10.1016/j.lungcan.2020.07.005. Epub 2020 Jul 12.
Gemcitabine/carboplatin treatment is known to cause severe adverse drug reactions which can lead to the need for reduction or cessation of chemotherapy. It would be beneficial to identify patients at risk of severe hematological toxicity in advance before treatment start. This study aims to identify genetic markers for gemcitabine/carboplatin-induced leukopenia and neutropenia in non-small cell lung cancer patients.
Whole-exome sequencing was performed on 215 patients. Association analysis was performed on single-nucleotide variants (SNVs) and genes, and the validation was based on an independent genome-wide association study (GWAS). Based on the association and validation analyses the genetic variants were then selected for and used in weighted genetic risk score (wGRS) prediction models for leukopenia and neutropenia.
Association analysis identified 50 and 111 SNVs, and 12 and 20 genes, for leukopenia and neutropenia, respectively. Of these SNVS 20 and 19 were partially validated for leukopenia and neutropenia, respectively. The genes SVIL (p = 2.48E-06) and EFCAB2 (p = 4.63E-06) were significantly associated with leukopenia contain the partially validated SNVs rs3740003, rs10160013, rs1547169, rs10927386 and rs10927387. The wGRS prediction models showed significantly different risk scores for high and low toxicity patients.
We have identified and partially validated genetic biomarkers in SNVs and genes correlated to gemcitabine/carboplatin-induced leukopenia and neutropenia and created wGRS models for predicting the risk of chemotherapy-induced hematological toxicity. These results provide a strong foundation for further studies of chemotherapy-induced toxicity.
已知吉西他滨/卡铂治疗会引起严重的药物不良反应，这可能导致化疗需要减量或停药。在治疗开始前提前识别有严重血液学毒性风险的患者将大有裨益。本研究旨在识别非小细胞肺癌患者中吉西他滨/卡铂诱导的白细胞减少和中性粒细胞减少的遗传标志物。
对215例患者进行全外显子组测序。对单核苷酸变异（SNV）和基因进行关联分析，并基于独立的全基因组关联研究（GWAS）进行验证。基于关联分析和验证分析，然后选择遗传变异并将其用于白细胞减少和中性粒细胞减少的加权遗传风险评分（wGRS）预测模型。
关联分析分别识别出50个和111个与白细胞减少和中性粒细胞减少相关的SNV，以及12个和20个相关基因。在这些SNV中，分别有20个和19个在白细胞减少和中性粒细胞减少方面得到部分验证。基因SVIL（p = 2.48E-06）和EFCAB2（p = 4.63E-06）与白细胞减少显著相关，包含部分验证的SNV rs3740003、rs10160013、rs1547169、rs10927386和rs10927387。wGRS预测模型显示高毒性和低毒性患者的风险评分有显著差异。
我们已经识别并部分验证了与吉西他滨/卡铂诱导的白细胞减少和中性粒细胞减少相关的SNV和基因中的遗传生物标志物，并创建了用于预测化疗诱导血液学毒性风险的wGRS模型。这些结果为进一步研究化疗诱导的毒性提供了坚实的基础。
