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.
Kalikaki
Aristea
A
Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
Kanaki
Maria
M
Vassalou
Helen
H
Souglakos
John
J
Voutsina
Alexandra
A
Georgoulias
Vassilis
V
Mavroudis
Dimitris
D
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