Genetic association of gemcitabine/carboplatin-induced leukopenia and neutropenia in non-small cell lung cancer patients using whole-exome sequencing

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 147; pp. 106 - 114
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2020
• Subjects: Adverse drug reactions; Carboplatin; Chemotherapy; Gemcitabine; Hematological toxicity; Non-small cell lung cancer; Toxicity; Whole-exome sequencing; Chemotherapy; Gemcitabine; Toxicity; Whole-exome sequencing; Non-small cell lung cancer; Carboplatin; Hematological toxicity; Adverse drug reactions
• ISSN: 0169-5002; 1872-8332; 1872-8332
• DOI: 10.1016/j.lungcan.2020.07.005

•The severity of gemcitabine/carboplatin-induced hematological toxicities varies extensively.•Severe hematological toxicities can lead to the need for postponed treatment, reduced doses and treatment discontinuation.•Genetic variability may explain and predict the variation in severe leukopenia and neutropenia. 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.