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 ¼ 4.103; 95% confidence interval (CI), 1.803-9.334; P ¼ 0.001] and the validation cohorts (RR ¼ 3.567; 95% CI, 1.253-10.151; P ¼ 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 ¼ 3.388; 95% CI, 0.988-11.623; P ¼ 0.052, and RR ¼ 3.929; 95% CI, 1.144-13.485; P ¼ 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. Mol Cancer Ther; 13(9); 2226-37. Ó2014 AACR.

Methylenetetrahydrofolate reductase polymorphisms and colorectal cancer prognosis: A meta‐analysis

“…The full texts of the remaining 73 articles were retrieved. Finally, twenty‐four articles were included in the meta‐analysis …”

SELE gene as a characteristic prognostic biomarker of colorectal cancer

“…SELE expression was analyzed in 202 patients with different clinical stages of colon cancer with lymphatic vessel invasion and intestinal perforation treated with oxaliplatin-assisted chemotherapy, using sequence analysis. 25 Positive results occurred in patients with phase II and III colon cancer, suggesting that clinicians could use SELErs3917412 as a predictor for intestinal cancer. Although some studies found that the average level of selectin expression was significantly higher in CRC patients than in healthy subjects, E-selectin expression levels decreased in a stepwise manner in patients with liver metastasis, patients with lymph node metastasis, and patients without metastasis.…”

Associations of the <em>MTHFR</em> rs1801133 polymorphism with gastric cancer risk in the Chinese Han population

“…In other studies, several groups reported that carriers of the TT genotype had higher response rates or improved survival rates than the CC or CT genotypes in gastric cancer patients receiving 5-fluorouracil (5-FU) chemotherapy (32,33). Of note, MTHFR polymorphisms have an impact on the efficacy of fluorouracil, as patients with different SNPs have been shown to have different reactivities (34,35). The homozygous genotypes rs2274976-GG and rs1801131-AA were more common in reactive patients, whereas the rs2274976-A allele (GA and AA) and rs1801131-C allele (AC and CC) were more common in unresponsive patients (6).…”