XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy.
OBJECTIVE
Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents for non-small-cell lung cancer (NSCLC).


METHODS
We used polymerase chain reaction-restriction fragment length polymorphism to evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with platinum-based chemotherapy.


RESULTS
Median age was 58 years (range, 32 to 77 years), 49% were females, and there were 86 deaths. Median follow-up period was 61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6 months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival (P =.003 and P =.07, respectively, by log-rank test). Similarly, when we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing overall survival (P =.009, log-rank test). These polymorphisms independently predicted overall survival even after taking into account stage, performance status, and chemotherapy regimen.


CONCLUSIONS
Genetic polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum-treated patients with advanced NSCLC.
Gurubhagavatula
Sarada
S
Department of Medicine, Massachusetts General Hospital, Boston, MA USA.
Liu
Geoffrey
G
Park
Sohee
S
Zhou
Wei
W
Su
Li
L
Wain
John C
JC
Lynch
Thomas J
TJ
Neuberg
Donna S
DS
Christiani
David C
DC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*; D016019:Survival Analysis; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin