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.