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Novel association between CD74 polymorphisms and hematologic toxicity in patients with NSCLC after platinum-based
Xiaoming Tan1, Qihan Wu2, Yanyan Cai2
1Department of Respiratory Disease, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Background:
Platinum-based chemotherapy regimens can cause DNA damage. Macrophage migration inhibitory factor (MIF) plays an important role in the regulation of the cell cycle by either controlling the activity of the SKP1-Cullin/Cdc53-F-box protein ubiquitin ligase (SCF) complex or activating its receptor, CD74.
Patients And Methods:
We used a pathway-based approach to investigate the association between genetic polymorphisms in MIF-pathway genes and the outcomes of platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). We used iSelect 24×1 HD BeadChip (Illumina, Inc, San Diego, CA) to genotype 32 tag and potentially functional single nucleotide polymorphisms (SNPs) of 8 selected genes and evaluated their associations with different outcomes for 1004 patients with advanced NSCLC treated with platinum-based chemotherapy. In particular, gastrointestinal toxicity and hematologic toxicity were analyzed for associations with specific genotypes, alleles, and haplotypes.
Results:
Two polymorphisms of CD74, rs2748249 (C/A) and rs1560661 (A/G), were significantly associated with hematologic toxicity. Carrying an A allele in rs2748249 was associated with higher hematologic toxicity (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.24-2.39; P = .001) and carrying a G allele in rs1560661 was associated with lower hematologic toxicity (OR, 0.42; 95% CI, 0.25-0.70; P = .00099) compared with the wild type. Haplotype analysis revealed that the patients with the CG haplotype (consisting of rs2748249 and rs1560661) had reduced hematologic toxicity compared with patients with other haplotypes (OR, 0.70; 95% CI, 0.56-0.87; P = .0013). The binding domain shared by 3 transcription factors (activator protein-2α [AP-2α], progesterone response A/B, and TFII-I) comprised the 2 SNPs that may be involved in the regulation of CD74-related B-cell survival.
Conclusion:
Our study is the first to suggest, to our knowledge, that polymorphisms in CD74 might be a marker of lower hematologic toxicity for patients with advanced NSCLC receiving platinum-based chemotherapy.
Insights
Genetic variations in CD74 may predict lower hematologic toxicity in patients with advanced non-small-cell lung cancer (NSCLC) undergoing platinum-based chemotherapy, offering a potential biomarker for treatment management.
Area of Science:
- Pharmacogenomics
- Oncology
- Molecular Biology
Background:
- Platinum-based chemotherapy is a standard treatment for advanced non-small-cell lung cancer (NSCLC), but it can cause significant toxicities.
- Macrophage migration inhibitory factor (MIF) is implicated in cell cycle regulation and its receptor, CD74, is involved in cellular processes.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in MIF-pathway genes and chemotherapy outcomes in advanced NSCLC patients.
- To identify potential genetic markers for predicting platinum-based chemotherapy toxicity.
Main Methods:
- A pathway-based approach was used, genotyping 32 single nucleotide polymorphisms (SNPs) in 8 genes for 1004 advanced NSCLC patients.
- Patients received platinum-based chemotherapy, and associations between genotypes, alleles, haplotypes, and gastrointestinal/hematologic toxicities were analyzed.
Main Results:
- Two CD74 polymorphisms, rs2748249 and rs1560661, were significantly associated with hematologic toxicity.
- Specific alleles and the CG haplotype of these SNPs correlated with reduced or increased hematologic toxicity.
- These SNPs are located in a binding domain for transcription factors potentially regulating CD74.
Conclusions:
- Polymorphisms in CD74 may serve as a predictive marker for lower hematologic toxicity in NSCLC patients treated with platinum-based chemotherapy.
- This finding could inform personalized treatment strategies to mitigate chemotherapy-induced side effects.
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