Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10⁻⁵), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10⁻⁴), rs6118 in SERPINA5 (P-value = 5.83 × 10⁻⁴), and rs5877 in SERPINC1 (P-value = 1.07 × 10⁻³), and the genes CAPZA2 (P-value = 4.03 × 10⁻⁴) and SERPINC1 (P-value = 1.55 × 10⁻³). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10⁻⁴) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10⁻⁸), and decrease (OR = 66.82, P-value = 5.92 × 10⁻⁹). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

化疗引起的骨髓抑制，包括血小板减少症，是癌症治疗期间的一个经常出现的问题，可能需要改变剂量或停止治疗，才能影响治疗的抗肿瘤作用。为了鉴定与治疗性血小板减少症相关的遗传标记，我们对215名接受吉西他滨/卡铂均匀治疗的非小细胞肺癌患者进行了全外显子测序。血小板的减少（定义为最低点/基线）用于评估治疗引起的血小板减少症。在单核苷酸变异体（SNV）（基于最佳的错误发现率，预期后果的严重性和影响），基因和途径水平上分析了生殖系遗传变异体与血小板减少症之间的关联。这些分析确定了130个SNV / INDEL和25个与血小板减少症（P值<0.002）。在一项独立的全基因组关联研究（GWAS）中验证了23个SNV。最高的关联包括JMJD1C中的rs34491125（P-值= 9.07×10 ^-5），DOCK8中经过验证的变体rs10491684（P-值= 1.95×10 ^-4），SERPINA5中的rs6118（P-值= 5.83×10 ^-4）和SERPINC1中的rs5877（P-值= 1.07×10 ^-3），以及基因CAPZA2（P -value = 4.03×10 ^-4）和SERPINC1（P-值= 1.55×10 ^-3）。得分最高的途径“参与巨核细胞发育和血小板生成的因素”（P值= 3.34×10 ^-4）中的SNV用于构建加权遗传风险评分（wGRS）和预测血小板减少症的逻辑回归模型。wGRS预测哪些患者处于CTCAE的高或低毒性风险水平（几率（OR）= 22.35，P值= 1.55×10 ^-8），并降低（OR = 66.82，P值= 5.92×10 ⁻⁹）。逻辑回归模型预测CTCAE为3-4级（曲线下的接收者操作员特征（ROC）面积（AUC）= 0.79），而下降幅度较大（ROC AUC = 0.86）。我们在造血相关途径中鉴定并验证了遗传变异，为使用遗传标记预测化疗引起的血小板减少和个性化治疗的未来研究奠定了坚实的基础。