Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients.
Experimental design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non-small cell lung cancer patients treated with platinum-based chemotherapy.
Results: The variant homozygotes of XPD p.Arg(156)Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg(156)Arg-p.Asp(312)Asn) on the risk of grade 3 or 4 hematologic toxicity.
Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg(156)Arg polymorphism on severe toxicity variability among platinum-treated non-small cell lung cancer patients.