Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Zhang
Wu
W
Division of Medical Oncology, Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Press
Oliver A
OA
Haiman
Christopher A
CA
Yang
Dong Yun
DY
Gordon
Michael A
MA
Fazzone
William
W
El-Khoueiry
Anthony
A
Iqbal
Syma
S
Sherrod
Andy E
AE
Lurje
Georg
G
Lenz
Heinz-Josef
HJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012737:Sex Factors; D015996:Survival Rate
D000970:Antineoplastic Agents; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil