A Xeroderma Pigmentosum Group D Gene Polymorphism Predicts Clinical Outcome To Oxalipatin-based Chemotherapy In Patients With Advanced Gastrointestinal Cancer

PurposeThe Xeroderma pigmentosum group D (XPD) protein is an essential participant in nucleotide excision repair and basal transcription. There is evidence that two common polymorphisms of the XPD gene (Asp312Asn, and Lys751Gln) may be associated with differential DNA repair activity. Because increased DNA repair plays an important role in chemoresistance to platinum-based compounds, we assessed the aforementioned polymorphisms in 55 patients with metastatic colorectal cancer and gastric cancer and determined their outcome to 5-fluorouracil/oxaliplatin. MethodsPatients with advanced colorectal cancer and gastric cancer were enrolled in the oxaliplatin based chemotherapy(FOLFOX 4 regimen and OXXEL regimen for colorectal cancer, EOF regimen for gastric cancer). Blood sample was collected from each individual, and genomic DNA was extracted from peripheral blood lymphocytes. XPD genotypes were performed using a PCR technique and sequencing.ResultsA total of 55 patients were enrolled in this study. Amplification of the PCR fragment for polymorphisms was not possible for some samples, sixty-five percent (36 of 55) occurred for the codon 312 fragment and seven percent( 4 of 55) occurred for the codon 751 fragment. Fifty-five patients were evaluated for the Lys751Gln polymorphism. Seventy-four percent (38 of 51) of the patients were homozygous for the Lys/Lys genotype. Twenty-five percent(13 of 51) were heterozygous Lys/Gln genotype, and none was homozygous for the glutamine variant. Fifty-five patients were evaluated for the Asp312Asn polymorphism. 89.5%(17/18) of patients were homozygous for the Asp/Asp genotype. 5.3%(1/18) of patients were both heterozygous Asp/Asn and homozygous Asn/Asn genotype. Among those tested for the Lys751Gln polymorphism, 42.1% (16 of 38) patients with the Lys/Lys genotype responded, versus 23.1% (3 of 13) patients with the Lys/Gln genotypes (p=0.22). The median time to progression for those with the Lys/Lys genotype was 8.1 months(95% CI: 5.9-10.3) versus 5.0 months (95% CI: 4.0-6.0) for patients with the Lys/Gln (p=0.0635).The median survival for those with the Lys/Lys genotype was 14.5 months(95% CI:11.4-17.6) versus 10.4 months (95% CI: 8.1-12.7) for patients with the Lys/Gln (p=0.0455). The polymorphisms Asp312 Asn of the XPD gene were not associated with response to 5-fluorouracil/oxaliplatin nor with time to progression and survival. Out of 37 patients with advanced colorectal cancer, the median time to progression for those with the Lys/Lys genotype was 9.8 months(95% CI: 7.5-12.1) versus 5.0 months (95% CI: 3.5-6.5) for patients with the Lys/Gln (p=0.0608).The median survival for those with the Lys/Lys genotype was 16.8 months(95% CI: 11.8-21.8) versus 11.8 months (95% CI: 9.3-14.3) for patients with the Lys/Gln (p=0.0360).ConclusionWe conclude that XPD Lys751 Gln polymorphism may be an important marker in the prediction of clinical outcome to oxaliplatin-based chemotherapy in advanced colorectal cancer and gastric cancer. Amplification of the PCR fragment for polymorphisms was not possible for Asp312Asn genotype in two thirds of patients. It can not show a relationship between an XPD Asp312Asn polymorphism and clinical outcome to chemotherapy.