Dataset Information

Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients.

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?

SUBMITTER: Bjorn N

PROVIDER: S-EPMC7445166 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients.

Björn Niclas N Badam Tejaswi Venkata Satya TVS Spalinskas Rapolas R Brandén Eva E Koyi Hirsh H Lewensohn Rolf R De Petris Luigi L Lubovac-Pilav Zelmina Z Sahlén Pelin P Lundeberg Joakim J Gustafsson Mika M Gréen Henrik H

NPJ systems biology and applications 20200824 1

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 g ...[more]

PMID: 32839457

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Project description:Background: Lung cancers represent the main cause of cancer related-death in the world. Recently, immunotherapy alone or in combination with chemotherapies have deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatments so far. The development of new therapies based on comprehension of mechanisms of resistance is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hampers to clearly understand the consequence of these molecules on tumor cells and then, to identify adapted second line therapies. Methods: To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts (Human Foreskin Fibroblasts-2, HFF2). MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinic schedule of administration consisting on three repetitions of treatments (one combination and two single treatments (paclitaxel or gemcitabine)). The impact of treatments was studied using cell viability assay, histology, 3’RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. Results: We showed that treatments induced a decrease of cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damages repair and the cell cycle. Interestingly, we also observed a modification of the expression of genes considered as hallmarks of response/resistance to immune check point inhibitors and immunogenicity and particularly an increase of CD274 gene expression, coding for PD-L1. This result was validated at the protein level and showed to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed on an additional cell line, expressing low basal level of CD274. These results are consistent with previous observations on patients showing higher PD-L1 tumoral expression after chemotherapy exposure. Conclusions: This study shows that MCTS could be interesting models to study the impact of first line therapies using conditions close to the clinical practice and then, to identify more adapted second line or concomitant therapies for the treatment of lung cancers.

Dataset Information

Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients.

Publications

Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients.

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