DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer.
BACKGROUND
Genetic polymorphisms of genes involved in DNA repair and glutathione metabolic pathways may affect patients' response to platinum-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNP) of DNA-repair genes ERCC1, XPD, XRCC1 and glutathione S-transferase genes GSTP1, GSTT1 and GSTM1 predict overall survival (OS), response and toxicity in 119 non-small-cell lung cancer (NSCLC) patients treated with platinum-based regimens as first- or second-line chemotherapy.


METHODS
Patients' genotypes were determined by PCR-RFLP and sequencing approaches.


RESULTS
ERCC1 (Asn118Asn) genotype was significantly associated with response to treatment. Patients with either one or two C alleles (C/C, C/T) at Asn118Asn were more likely to respond to platinum-based chemotherapy compared with those without the C allele (Odds ratio, 0.10; 95% CI, 0.013-0.828; P = .033, by binary logistic regression). There was a significant association between the ERCC1 C8092A polymorphism and OS (P = .009, by log-rank test), with median survival times of 9.8 (C/C) and 14.1 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with an improved outcome. Cox's multivariate analysis suggested that the joint effect of ERCC1 polymorphic variants (C8092A and N118N) (0 vs. 2, hazard ratio 2.5; 95% CI, 1.26-4.96; P = .009) as well as the XRCC1 N399Q polymorphism (AA vs. GA/GG, hazard ratio 3.1; 95% CI, 1.4-6.8; P = .005) were independent prognostic factors for OS in advanced NSCLC patients treated with platinum-based chemotherapy.


CONCLUSIONS
These findings support the notion that assessment of genetic variations of ERCC1 and XRCC1 could facilitate therapeutic decisions for individualized therapy in advanced NSCLC.
Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
Aristea
A
Kalikaki
Maria
M
Kanaki
Helen
H
Vassalou
John
J
Souglakos
Alexandra
A
Voutsina
Vassilis
V
Georgoulias
Dimitris
D
Mavroudis
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D004268:DNA-Binding Proteins; D004720:Endonucleases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D009944:Organoplatinum Compounds; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein; C000619371:XRCC1 protein, human; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human; C071447:ERCC1 protein, human; C497292:ERCC2 protein, human