Purpose: Chemotherapy induced myelosuppression is a recurrent problem in cancer treatment, both for the patients’ quality of life and response. Severe hematological toxicities lead to dose reduction, postponed or ceased treatment, affecting the treatment effect. Identifying genetic markers associated with toxicity is an important factor for individualized chemotherapy and might increase the overall effect of the treatment.
Material and methods: Non-small cell lung cancer patients undergoing gemcitabine/carboplatin chemotherapy were included and their exomes were sequenced. Genetic variants from 212 exomes were correlated to thrombocytopenia, leukopenia, and neutropenia on single nucleotide and gene level. Results were processed through enrichment analysis and variants were validated using externally available datasets.
Results: SNV analysis identified 103, 131 and 112 variants to be associated with thrombocytopenia, leukopenia and neutropenia, respectively. Gene based analysis identified 21, 54 and 31 genes to be associated with thrombocytopenia, leukopenia and neutropenia, respectively. Using external data sets 8, 26 and 9 SNVs were validated through linkage disequilibrium for thrombocytopenia, leukopenia and neutropenia, respectively.
The variant rs61739531 (CADD = 25.7) in the gene MYO1G was identified to be associated with high toxicity in all forms of myelosuppression. Validated variants include rs6118 (CADD = 22.3) in SERPINA5, rs16910526 (CADD = 35.0) in CLEC7A and rs79350244 (CADD = 24.2) in DNAH2. Enrichment analysis of associated genes identified the pathways hemostasis, HIF-1 alpha transcription factor network and vitamin B12 metabolism to be involved in thrombocytopenia, leukopenia and neutropenia, respectively.
Factors involved in megakaryocyte development and platelet production, was also associated with thrombocytopenia for three genes JMJD1C with the variant rs34491125 (CADD = 22.1), DOCK8 with the variant rs10491684 (CADD = 11.7) and CAPZA2 based on three variants in the gene based analysis.
Conclusion: The results highlight genetic markers and relevant pathways associated with chemotherapy induced myelosuppression and form a strong foundation for further investigation into toxicity induced myelosuppression.
chemotherapy, adverse drug reaction, exome sequencing, lung cancer, myelosuppression