Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome.
BACKGROUND
Glutathione S-transferase P1 (GSTP1) and excision-repair cross-complementing repair deficiency group 2 protein (ERCC2 or XPD) may modulate the activity of platinum derivatives. The SNPs, Ile105Val for GSTP1 and Lys751Gln for ERCC2, may affect the efficiency of oxaliplatin in patients treated with an oxaliplatin-based regimen for metastatic colorectal carcinoma.


METHODS
A total of 107 patients treated with first-line chemotherapy, 59 with an oxaliplatin-based regimen and 48 with an irinotecan-based regimen, were included retrospectively. GSTP1 and ERCC2 genotypes were identified on DNA samples extracted from paraffin blocks containing either normal tissue (nodes) or tumor tissue. We analyzed treatment response, event-free and overall survival.


RESULTS
GSTP1 genotype distribution was Ile/Ile 58%, Ile/Val 35% and Val/Val 7%. ERCC2 genotype distribution was Lys/Lys 49%, Lys/Gln 44%, Gln/Gln 7%. Event-free and overall survivals were not significantly different as a function of the GSTP1 genotype, whatever the treatment received. Event-free survival was significantly different as a function of the ERCC2 genotype only in patients receiving oxaliplatin: patients having at least one variant allele had a shorter median event-free survival (6 months) than those having no variant allele (11.6 months, p = 0.008). This difference was maintained for median overall survival (15.6 vs 25.3 months, p = 0.016). Using univariate analysis, ERCC2 genotype, hemoglobinemia and carbohydrate antigen 19.9 plasma levels were significantly related to overall and event-free survival in patients receiving oxaliplatin.


CONCLUSIONS
The ERCC2 genotype appears as an important predictive factor of the survival of patients treated with oxaliplatin in first-line therapy for metastatic colorectal cancer.
Le Morvan
Valérie
V
Université Victor Segalen, Institut Bergonié, Laboratoire de Pharmacologie des Agents Anticancéreux, 229 cours de l'Argonne, 33076 Bordeaux-cedex, France.
Smith
Denis
D
Laurand
Armelle
A
Brouste
Véronique
V
Bellott
Ricardo
R
Soubeyran
Isabelle
I
Mathoulin-Pelissier
Simone
S
Robert
Jacques
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human