Association of XPD Polymorphisms with Severe Toxicity in Non–Small Cell Lung Cancer Patients in a Chinese Population

Abstract

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-offlight 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 platinumtreated non-small cell lung cancer patients.

Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer

“…The study protocol was approved by the Ethical Review Committee of Fudan University and the participating hospitals, and written informed consent was obtained from each individual. The recruitment criteria and clinical data collection were described in our previous report elsewhere [10]. Patient blood samples were collected in ethylenediaminetetraacetic acid tubes and stored at Ϫ80°C for later DNA extraction.…”

“…Nonetheless, the cytotoxic effects of platinum drugs may produce severe adverse effects, by damaging normal cells, which may hinder further treatment and impact outcomes. Differences in toxicities experienced and responses in patients who have received the same chemotherapy agent or regimen are commonly observed [10,11], and these are likely to be a result of polymorphic genetic variation in genes involved in drug metabolism and DNA repair and apoptosis [5,12]. Recently, numerous clinical studies have elucidated that genes involved in drug transportation, drug metabolism, DNA repair, and apoptosis may modulate platinum-based chemotherapeutic efficacy and drug-related toxicity outcomes [13,14].…”

Susceptibility of XPD and hOGG1 genetic variants to prostate cancer

“…Therefore, an accompanying higher expression of another gene may confer increased cancer risk. Previous studies demonstrated that XPD codon 156 polymorphisms were associated with lung (20), bladder (21) and breast cancer (22) in Chinese populations. To the best of our knowledge, the present study was the first to demonstrate that the silent polymorphisms of XPD156 affect the risk of PCa.…”

Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC

“…[31][32][33] However, such studies using cell lines could not replicate the findings from population-based studies, which had reported significant associations between SNPs in multiple genes (eg, drug metabolism genes, DNA repair genes, and apoptosis genes) and the toxicity response. [34][35][36][37] This difference might have resulted from different mechanisms underlying the toxicity responses of the 2 levels (cell line and individual). The p53 pathway plays important roles in chemotherapy response and cancer progression.…”