Novel association between CD74 polymorphisms and hematologic toxicity in patients with NSCLC after platinum-based chemotherapy

Abstract

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.

Keywords: CD74; Hematologic toxicity; NSCLC; Platinum-based chemotherapy; Polymorphism.