BACKGROUND AND AIM: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC. METHODS: This was a retrospective case-control study. 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFR C677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH). RESULTS: MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3-2.7, p < 0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR 'T' allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p < 0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant 'T' allele, in all cases. CONCLUSION: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.
BACKGROUND AND AIM: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC. METHODS: This was a retrospective case-control study. 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFRC677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH). RESULTS:MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3-2.7, p < 0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR 'T' allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p < 0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant 'T' allele, in all cases. CONCLUSION: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.
Authors: C M Ulrich; E Kampman; J Bigler; S M Schwartz; C Chen; R Bostick; L Fosdick; S A Beresford; Y Yasui; J D Potter Journal: Cancer Epidemiol Biomarkers Prev Date: 1999-08 Impact factor: 4.254
Authors: N M van der Put; F Gabreëls; E M Stevens; J A Smeitink; F J Trijbels; T K Eskes; L P van den Heuvel; H J Blom Journal: Am J Hum Genet Date: 1998-05 Impact factor: 11.025
Authors: B C Blount; M M Mack; C M Wehr; J T MacGregor; R A Hiatt; G Wang; S N Wickramasinghe; R B Everson; B N Ames Journal: Proc Natl Acad Sci U S A Date: 1997-04-01 Impact factor: 11.205
Authors: J Chen; E Giovannucci; S E Hankinson; J Ma; W C Willett; D Spiegelman; K T Kelsey; D J Hunter Journal: Carcinogenesis Date: 1998-12 Impact factor: 4.944
Authors: E Taioli; M A Garza; Y O Ahn; D T Bishop; J Bost; B Budai; K Chen; F Gemignani; T Keku; C S P Lima; L Le Marchand; K Matsuo; V Moreno; J Plaschke; M Pufulete; S B Thomas; G Toffoli; C R Wolf; C G Moore; J Little Journal: Am J Epidemiol Date: 2009-10-21 Impact factor: 4.897