Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms associated with overall survival in women with metastatic colon cancer
3600 Background: Methylenetetrahydrofolate Reductase (MTHFR) is a key enzyme regulating intracellular folate pool, which affects DNA synthesis and methylation. Recent studies found folate deficiency induces DNA damage because of impaired nucleotide-excision repairs in mouse model. Two MTHFR gene polymorphisms, C677T and A1298C are linked to altered enzyme activity. Numerous studies have shown these two polymorphisms associated with colon cancer risk and response to fluorouracil-based treatment in advanced colon cancer patients. One epidemiology study also demonstrated 1298CC genotype to be associated with a significantly lower risk of colon cancer in women, but not men. We tested whether these two polymorphisms were associated with clinical outcome in metastatic colon cancer patients treated with 5-FU/Oxaliplatin. Methods: Between 1992 and 2003, a total of 318 patients with metastatic colon cancer treated at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or the Los Angeles County/University of Southern California Medical Center (LAC/USCMC), were eligible for this study. Peripheral blood samples were collected from each patient and genomic DNA was extracted from white blood cells using the QiaAmp kit (Qiagen, Valencia, CA). Two MTHFR gene polymorphisms (C677T, A1298C) were tested by PCR-RFLP method. Results: MTHFR A1298C gene polymorphism showed statistically significant differences in overall survival (OS) in female patients with metastatic colon cancer (P=0.025, logrank test). Patients with the AA genotype had an 18.7 months median OS compared with the heterozygous AC genotype, which had a 14.3 months median OS and the CC genotype, which had a 15.9 months median OS. Conclusions: There is no significant difference in clinical outcome in male patients. However, female metastatic colon cancer patients with a MTHFR A1298C polymorphism AA genotype have significantly better overall survival than those with heterozygous AC genotype or CC genotype. This data supports the role of MTHFR polymorphisms as an independent prognostic marker in female patients with metastatic colon cancer. Further prospective study is needed to confirm these preliminary findings. [Table: see text]