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Association of Methylenetetrahydrofolate Reductase Gene Polymorphisms and Sex-Specific Survival in Patients With Metastatic Colon Cancer

Wu Zhang, Oliver A. Press, Christopher A. Haiman, Dong Yun Yang, Michael A. Gordon, William Fazzone, Anthony El-khoueiry, Syma Iqbal, Andy E. Sherrod, Georg Lurje, Heinz-Josef Lenz

From the Division of Medical Oncology and Departments of Preventive Medicine and Pathology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA

Address reprint requests to Heinz-Josef Lenz, MD, FACP, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon A. Carpenter Laboratory, 1441 Eastlake Ave, Ste 3456, Los Angeles, CA 90033; e-mail: lenz{at}usc.edu

Purpose Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate levels, which affects DNA synthesis and methylation. Two MTHFR gene polymorphisms, C677T and A1298C, are linked to altered enzyme activity. Several studies have shown these two polymorphisms to be associated with response to fluorouracil (FU) -based treatment in advanced colon cancer patients, but data are inconsistent and contradictory. Meanwhile, epidemiologic studies demonstrated that these MTHFR polymorphisms were associated with cancer risk in a sex-specific manner. We tested the hypothesis of whether these two polymorphisms are associated with sex-specific clinical outcome in metastatic colon cancer patients treated with FU-based chemotherapy.

Patients and Methods This study included 318 patients (177 men and 141 women) with metastatic colon cancer treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Peripheral blood samples were collected from each patient, and genomic DNA was extracted from WBCs. Two MTHFR gene polymorphisms (C677T and A1298C) were tested by fluorogenic 5'-nuclease assay.

Results The A1298C polymorphism showed statistically significant differences in overall survival (OS) in female, but not male, patients with metastatic colon cancer (log-rank test, P = .038). Among females, OS was greater for patients with the A/A genotype (n = 67; median OS, 18.4 months) compared with patients with the A/C genotype (n = 50; median OS, 13.9 months) or C/C genotype (n = 10; median OS, 15.6 months).

Conclusion Although preliminary, these data support the role of the A1298C polymorphism in MTHFR as prognostic marker in female patients with metastatic colon cancer. Further studies are needed to confirm these findings.

Supported by Grant No. 5 P30CA14089-27l from the National Institutes of Health, the San Pedro Guild Research Fund, and the Dhont Foundation.

W.Z. and O.A.P. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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