title: Pharmacogenetic predictors of outcome in patients with stage II and III colon cancer treated with oxaliplatin and fluoropyrimidine-based adjuvant chemotherapy.
abstract: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with colon cancer who are more likely to benefit from adjuvant chemotherapy. We investigated the effect of single-nucleotide polymorphisms (SNP) within genes involved in oxaliplatin and fluoropyrimidines metabolism, DNA repair mechanisms, drug transport, or angiogenesis pathways on outcome for patients with stage II and III colon cancer treated with adjuvant chemotherapy. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples of 202 patients with stage II and III colon cancer receiving oxaliplatin-based adjuvant chemotherapy from January 2004 to December 2009. Genotyping was performed for 67 SNPs in 32 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 patients treated with the same chemotherapy regimens. The combination of the selectin E (SELE) rs3917412 G>A G/G and the methylentetrahydrofolate reductase (MTHFR) rs1801133 T/T genotypes was associated with a significantly increased risk for recurrence in both the training [RR = 4.103; 95% confidence interval (CI), 1.803-9.334; P = 0.001] and the validation cohorts (RR = 3.567; 95% CI, 1.253-10.151; P = 0.017) in the multiple regression analysis considering the stage, lymphovascular invasion, and bowel perforation as covariates. The combined analysis of these polymorphisms was also significantly associated with overall survival in both cohorts (RR = 3.388; 95% CI, 0.988-11.623; P = 0.052, and RR = 3.929; 95% CI, 1.144-13.485; P = 0.020, respectively). Our findings suggest that the SELE rs3917412 and MTHFR rs1801133 SNPs could serve as pharmacogenetic predictors of tumor recurrence in patients with early-stage colon cancer treated with oxaliplatin-based adjuvant chemotherapy, thus allowing personalized selection of treatment to optimize clinical outcomes.
authors: Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain. anabcustodio@gmail.com.
authors: Ana
authors: A
authors: Custodio
authors: Translational Oncology Unit, Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Juan
authors: J
authors: Moreno-Rubio
authors: Medical Oncology Department, La Fe University Hospital, Valencia, Spain.
authors: Jorge
authors: J
authors: Aparicio
authors: Medical Oncology Department, General University Hospital, Elche (Alicante), Spain.
authors: Javier
authors: J
authors: Gallego-Plazas
authors: Medical Oncology Department, Valencian Oncology Institute, Valencia, Spain.
authors: Ricardo
authors: R
authors: Yaya
authors: Medical Oncology Department, Clinic University Hospital, Barcelona, Spain.
authors: Joan
authors: J
authors: Maurel
authors: Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Nuria
authors: N
authors: Rodríguez-Salas
authors: Pathology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Emilio
authors: E
authors: Burgos
authors: Pathology Department, La Fe University Hospital, Valencia, Spain.
authors: David
authors: D
authors: Ramos
authors: Pathology Department, Valencian Oncology Institute, Valencia, Spain.
authors: Ana
authors: A
authors: Calatrava
authors: Pathology Department, General University Hospital, Elche (Alicante), Spain.
authors: Encarna
authors: E
authors: Andrada
authors: Translational Oncology Unit, Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Esther
authors: E
authors: Díaz-López
authors: Medical Oncology Department, Puerta de Hierro University Hospital, Madrid, Spain.
authors: Antonio
authors: A
authors: Sánchez
authors: Biostatistics Unit, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain.
authors: Rosario
authors: R
authors: Madero
authors: Translational Oncology Unit, Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Paloma
authors: P
authors: Cejas
authors: Medical Oncology Department, La Paz University Hospital, IdiPaz, Madrid, Spain.
authors: Jaime
authors: J
authors: Feliu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair; D019040:E-Selectin / Q000235:genetics; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry*; D012008:Recurrence; D012044:Regression Analysis; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D019040:E-Selectin; D009944:Organoplatinum Compounds; D011743:Pyrimidines; D000077150:Oxaliplatin; C029269:5-fluoropyrimidine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)