Abstract
Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.
Highlights
Lung cancer is a common and deadly form of cancer
The raw VCF file included a total of 17,934,566 single-nucleotide variants (SNVs) and insertions/deletions (INDELs), after filtering 15,751,023 bi-allelic loci remained on chromosomes 1–22, X, and Y
The present study is, to the best of our knowledge, the most comprehensive whole-genome sequencing (WGS) study focused on myelosuppressive toxicity induced by gemcitabine/carboplatin treatment
Summary
Lung cancer is a common and deadly form of cancer. It represents close to a fifth (18.4%) of all cancer deaths worldwide[1]. The primary treatment of non-small cell lung cancer (NSCLC) includes the use of PD-1 inhibitors or targeted therapies. Depending on their success, the continuation of the treatment using a classical combination chemotherapy consisting of gemcitabine and carboplatin is common. It is well known that the use of classical chemotherapeutic agents is associated with the induction of considerable adverse drug reactions (ADRs) This is the case for gemcitabine/carboplatin treatment, which commonly induces severe myelosuppression (mainly expressed in the form of neutropenia, leukopenia, and thrombocytopenia) that may lead to non-optimal treatments in terms of postponements, reduction, or discontinuation[2,3,4,5,6]. The underlying germline genetic variation is thought to be a contributing factor to the vast inter-individual differences in ADRs5–9
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