Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.
OBJECTIVE
XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients.


METHODS
We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy.


RESULTS
The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found.


CONCLUSIONS
This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.
Giachino
Daniela F
DF
Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
Ghio
Paolo
P
Regazzoni
Silvia
S
Mandrile
Giorgia
G
Novello
Silvia
S
Selvaggi
Giovanni
G
Gregori
Dario
D
DeMarchi
Mario
M
Scagliotti
Giorgio V
GV
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005973:Glutamine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017671:Platinum Compounds / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D013534:Survival; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D004268:DNA-Binding Proteins; D017671:Platinum Compounds; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D005973:Glutamine; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D008239:Lysine