MTHFR Glu429Ala and ERCC5 His46His Polymorphisms Are Associated with Prognosis in Colorectal Cancer Patients: Analysis of Two Independent Cohorts from Newfoundland

Abstract

IntroductionIn this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.MethodsThe discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.ResultsWhen adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04–2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15–2.76, p = 0.01), SERPINE1 −675indelG (HR: 0.52, 95%CI: 0.32–0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03–1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18–2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04–2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11–2.94, p = 0.018).ConclusionsIn this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.

Pharmacogenetic Predictors of Outcome in Patients with Stage II and III Colon Cancer Treated with Oxaliplatin and Fluoropyrimidine-Based Adjuvant Chemotherapy

“…In accordance with our data, some studies show a negative effect on survival or response for the 677T allele (13,37). However, other authors show no influence of MTHFR rs1801133 C>T genotype (12,26,38,39) and others again show a positive effect of the T allele (11,37,40). Our results are not consistent with in vitro findings that suggest that patients with the T/T genotype would have reduced MTHFR activity compared with those with C/C and C/T genotypes, potentiating the antitumoral activity of fluoropyrimidines.…”

“…Functional polymorphisms within genes involved in DNA repair pathways or in the metabolism and detoxification of oxaliplatin have also been associated with the efficacy of this agent. Most analysis have been conducted in patients with metastatic disease (12,15,16,18), whereas the pharmacogenetic of oxaliplatin-based adjuvant chemotherapy has not been widely studied (14,17,27). In a previous European report including 98 patients with stage III colon cancer, none of the tested SNPs in glutathione S-transferase pi 1 (GSTP1), excision repair crosscomplementing 1 (ERCC1), and excision repair cross-complementing 2 (ERCC2) were reliable markers of response to oxaliplatin therapy (14).…”

“…More recently, the necessary interactions between tumor and host in the oncological process have raised questions about how the individual genomic biology influences cancer progression and response to chemotherapy, consequently generating a great amount of critical data. In the last few years, several genetic polymorphisms within genes involved in the metabolism, transport, and detoxification of fluoropyrimidines and oxaliplatin have been considered in an attempt to optimize treatment in patients with colon cancer (10)(11)(12)(13)(14)(15)(16)(17)(18), but, up to now, their clinical applications remain limited. Furthermore, numerous variants have been identified in genes related to the DNA-repair complex, angiogenesis, and other relevant pathways that may alter their expression and/or activity, thereby causing interindividual differences in tumor recurrence capacity and chemoresistance (18)(19)(20)(21)(22).…”

Germline INDELs and CNVs in a cohort of colorectal cancer patients: their characteristics, associations with relapse‐free survival time, and potential time‐varying effects on the risk of relapse

“…Peripheral blood samples were collected from most of the patients at the time of recruitment and were used to extract genomic DNA. Patient follow‐up was performed as described by Negandhi and his coauthors . Among 750, 539 stage I–IV patients with available clinicopathological and outcome data as well as germline (i.e., blood‐extracted) DNA samples were genotyped (service provider: Centrillion ® Biosciences, CA) using the Illumina ® Human Omni1_Quad_v1 genome‐wide SNP genotyping platform, as reported previously .…”

“…In colorectal cancer, a small number of studies examined the germline (i.e., nontumor DNA) INDELs/CNVs and their links to disease susceptibility, including hereditary colon cancer syndromes such as Familial Colorectal Cancer Type X (FCCX) . A number of studies also looked at the associations of deletion of select genes (such as GSTM1 , GSTT1 ) with the disease outcome . However, a comprehensive identification of INDELs/CNVs in a large patient cohort and their examination in relation to survival outcomes have not been done before.…”