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Background  Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 ( SHMT1 ) C1420T or methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated.    Methods  The  SHMT1  and  MTHFR  genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated.    Results  There was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for  SHMT1  TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for  MTHFR  CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene-dosage effect was observed for  SHMT1  with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the  SHMT1  T allele/ MTHFR  CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by  SHMT1  polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of  SHMT1  1420CC genotypes.    Conclusions  A protective effect of  SHMT1  1420T allele or  SHMT1  1420 T allele/ MTHFR  677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of  SHMT1  1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in  SHMT1  1420 wild-type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why  SHMT1  and  MTHFR  polymorphisms are associated only with rectal and not colon cancer risk.

SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer