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PurposeThe aim of this study was to evaluate whether pretreatment analysis of selected molecular markers can be used for the prediction of disease-free survival (DFS)/overall survival (OS) of capecitabine adjuvant monotherapy in colon cancer patients.Patients and methodsA total of 126 patients enrolled in a capecitabine Phase IV clinical trial were analyzed for microsatellite instability (MSI), 18q loss of heterozygosity (LOH), thymidylate synthase (TYMS) 5′ variable number of tandem repeat (VNTR), and methylene tetrahydrofolate reductase (MTHFR) C677T variants. The significance in predicting 5-year DFS/OS was assessed by Kaplan–Meier and Cox regression analyses.ResultsThe MSI-high (MSI-H) genotype was significantly associated with DFS (HR 0.205, 95% CI 0.05–0.88, P=0.033) and OS (HR 0.208, 95% CI 0.05–0.89, P=0.035) compared to the microsatellite stable genotype. In models stratified according to clinicopathologic characteristics, the MSI-H genotype remained a positive predictive factor for DFS/OS only in patients with stage III (P=0.023) and patients with tumors localized proximally to the splenic flexure (P=0.004). Distal colon cancers with 18q LOH have a greater survival rate when treated with capecitabine than patients with stable tumors (81.3% vs 50.0%, HR for relapse 0.348, 95% CI 0.13–0.97, P=0.043). TYMS 5′VNTR and MTHFR C677T variants were not associated with DFS or OS.ConclusionMSI and 18q LOH markers have the potential to be utilized in the selection of colon cancer patients eligible for capecitabine adjuvant monotherapy.

Methylenetetrahydrofolate reductase (MTHFR) regulates the flow of folate groups between DNA synthesis and DNA methylation. A common C677T substitution (Ala222Val) in exon 4 of the MTHFR gene has been linked with the risk of colorectal cancer (CRC). To assess this risk in the Macedonian population, we conducted a case-control study of 413 randomly selected CRC patients and 185 controls without a clinical diagnosis of CRC. We found a statistically significant inverse association between the MTHFR T allele (35.35% for the patients and 41.35% for the controls) and the CRC risk [odds ratio (OR) 0.776; 95% confidence interval (95% CI) 0.603-0.997; p = 0.047). The prevalence of the MTHFR T allele is lower in patients with advanced CRC (Duke' s stage C and D) and with microsatellite instable tumors (MSI+), indicating the inverse association with the CRC aggressiveness and MSI status. This effect seems to be independent of gender, age of onset and localization. We concluded that the MTHFR 677T allele is more likely to have a protective effect on CRC development and progression in the Macedonian population.

Cyclin D1 G870A Variant is Associated with Increased Risk of Microsatellite Instability-Positive Colorectal Cancer in Young Male PatientsCyclin D1 (CCND1) is a cell cycle regulatory protein, which is often over expressed in human tumors and is associated with cell proliferation and poor prognosis. A common G870A single nucleotide polymorphism at codon 242 in exon 4 of the CCND1 gene is associated with an altered messenger RNA transcript and increased risk of colorectal cancer (CRC) and adenoma in some studies. Over expression of CCND1 modifies the effect of mutations in mismatch repair (MMR) genes, enhances microsatellite instability (MSI), and influences the age ofonset of hereditary non polyposis colorectal cancer (HNPCC). We have extended our study that indicated that the CCND1 A variant may influence the age of onset of CRC in the Macedonian population only in patients who exhibit MSI tumors by a case control study of 331 randomly selected CRC patients and 101 controls without clinical diagnosis of CRC. We did not observe a significant difference in overall allelic frequencies and genotype distribution of affected and unaffected mutation carriers, but found a statistically significant risk of CRC in carriers of the CCND1 A allele when patients were grouped according to gender, age and MSI status. A higher risk was observed in patients with MSI-positive tumors and particularly in male patients under 60 years of age. The consequences of the above observation were reversed in female patients. These results indicate that the CCND1 A variant may enhance CRC progression through a pathway influenced by estrogens in colonic epithelia.