Key Takeaways & Executive Findings
- •• A genome-wide association study identified rs6856089 and linked SNPs as significantly associated with platinum-based chemotherapy-induced myelosuppression in NSCLC patients. • Patients carrying the A allele of rs6856089 had a markedly lower risk of myelosuppression (OR = 0.1300, P = 7.59 × 10–8). • Gene-based analysis implicated EMCN, encoding endomucin, a hematopoietic stem cell marker, as a potential mediator of myelosuppression. • These findings provide a scientific basis for personalized therapeutic approaches to reduce myelosuppression in NSCLC patients receiving platinum-based chemotherapy.
Abstract
Platinum-based chemotherapy remains the mainstay for non-small cell lung cancer (NSCLC), but it frequently causes dose-limiting myelosuppression, with significant individual variability in susceptibility. However, the genetic basis of myelosuppression side effects remains elusive, greatly hindering personalized therapeutic approaches. In this study, we perform a comprehensive genome-wide association analysis on 491 NSCLC patients receiving platinum-based chemotherapy, examining 4,690,998 single-nucleotide polymorphisms (SNPs) to identify relevant genetic variants. LDBlockShow, FUMA, and MAGMA are utilized to explore linkage disequilibrium, expression quantitative trait loci (eQTLs), chromatin interaction, and conduct gene-based and gene set-based analysis of candidate SNPs. The GWAS results reveal that rs6856089 and its linked SNPs are significantly associated with platinum-based chemotherapy-induced myelosuppression. Specifically, patients with the A allele of rs6856089 have a significantly lower risk of myelosuppression [odds ratio (OR) = 0.1300, P = 7.59 × 10–8]. Furthermore, gene-based analysis reveals that EMCN (P = 2.47 × 10–5), which encodes endomucin, a marker for hematopoietic stem cells, might mediate myelosuppression. This study provides a scientific basis for the individual differences in platinum-based chemotherapy-induced myelosuppression.
1. Introduction
Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancer cases, poses a significant threat to human health owing to its high prevalence and mortality rates [1,2]. Platinum-based chemotherapy, particularly cisplatin and carboplatin, remains the cornerstone treatment for NSCLC. These agents can inhibit DNA replication by binding to DNA, forming adducts, and destroying tumor cells [3]. However, the effectiveness of platinum-based chemotherapy is limited by severe side effects, including myelosuppression, nephrotoxicity, and neurotoxicity [4,5], of which myelosuppression is a significant concern because of its high incidence and serious outcomes. The occurrence of myelosuppression not only leads to a reduced dosage or delayed treatment but also impacts the prognosis and quality of life of patients [6]. The bone marrow is the primary site for blood cell production and contains numerous rapidly dividing hematopoietic stem cells. Platinum-based chemotherapy can severely impact the proliferation of bone marrow progenitors through its ability to inhibit DNA replication, disrupting hematopoiesis. This severe adverse effect is clinically characterized by leukopenia, neutropenia, and thrombocytopenia [7] and is graded from I to IV according to the Common Terminology Criteria for Adverse Events (CTCAE).
Susceptibility to platinum-based chemotherapy-induced myelosuppression varies greatly among individuals, underscoring the need to identify predictive biomarkers. Pharmacogenomic studies hold promise in identifying genetic variants associated with drug response, including both efficacy and side effects [8]. However, current methods for predicting chemotherapy-induced myelosuppression are insufficient, warranting further relevant studies. Previous studies by our group and others have demonstrated that genetic variation plays a fundamental role in inter-individual variability in drug efficacy and side effects [9–17]. Nonetheless, the specific underlying mechanism of platinum-based chemotherapy-induced myelosuppression has yet to be elucidated.
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Hanxue Huang, Junyan Liu, Qi Xiao, Chenxue Mao, Lei She, Lulu Yu, Bing Yu, Mengrong Lei, Ying Gao, Baimei He, Pinhua Pan, Xi Li, Jiye Yin, Zhaoqian Liu (2026). GWAS study of myelosuppression among NSCLC patients receiving platinum-based combination chemotherapy. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025013
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Frequently Asked Questions
What was the main objective of this GWAS study?
The main objective was to identify genetic variants associated with myelosuppression in NSCLC patients receiving platinum-based chemotherapy, using a genome-wide association study on 491 Chinese Han patients.
Which genetic variant was found to be significantly associated with myelosuppression?
The study found that rs6856089 and its linked SNPs were significantly associated with platinum-based chemotherapy-induced myelosuppression. Patients with the A allele of rs6856089 had a significantly lower risk of myelosuppression (OR = 0.1300, P = 7.59 × 10–8).
What is the potential role of EMCN in myelosuppression?
Gene-based analysis revealed that EMCN, which encodes endomucin, a marker for hematopoietic stem cells, might mediate myelosuppression. This suggests that EMCN could be a key gene in the susceptibility to chemotherapy-induced myelosuppression.
How many patients and SNPs were analyzed in this study?
The study analyzed 491 NSCLC patients and examined 4,690,998 single-nucleotide polymorphisms (SNPs) in the genome-wide association analysis.
What is the clinical significance of this study?
The findings provide a scientific basis for individual differences in platinum-based chemotherapy-induced myelosuppression, potentially enabling personalized therapeutic approaches to reduce this severe side effect in NSCLC patients.
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