Colorectal cancer and adenoma risk are inversely associated with higher total folate intake. Significant modifiers of cancer risk also include other methyl-related nutrients and alcohol. Adequate folate intake is particularly important for women at higher risk for breast cancer because of moderate alcohol consumption. The methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is associated with a reduced risk of some forms of cancer. The protective effect of this folate-related polymorphism is dependent on adequate folate status. Cancer risk may be increased in individuals with the homozygous genotype for the MTHFR 677C-->T polymorphism who have low status of methyl-related nutrients including folate. Intake recommendations to potentially reduce cancer risk include substitution of low folate foods with folate-dense fruits and vegetables and in countries where there is no mandatory folic acid fortification, increased consumption of folic acid from available fortified foods or supplements. Adequate dietary intake of vitamin B-6 and methionine can be achieved by consumption of low fat, concentrated food sources of these nutrients. The recommended intake for vitamin B-12 for individuals >/== BORDER=0>51 y should be provided predominately in crystalline form (e.g., fortified ready-to-eat cereal, supplements). If alcohol is consumed, consumption should be restricted to <15 g/d or <1 drink/d. The negative effects of low intakes of the methyl-related nutrients with high intakes of alcohol are additive, therefore changes in overall dietary patterns to ensure the consumption of a protective high methyl diet are recommended.

The consensus of epidemiologic evidence indicates that an abundant intake of foodstuffs rich in folate conveys protection against the development of colorectal cancer, and perhaps some other common cancers as well. Pre-clinical models substantiate that the relationship is a genuinely causal one. Pre-clinical models have also lent mechanistic insights into the biochemical and molecular pathways by which adequate folate exposure conveys these protective effects, and human studies are beginning to confirm the relevance of this mechanistic understanding to human cancer biology. Enhancement of genetic stability appears to be a major mechanism by which folate sufficiency protects against carcinogenesis. To date, the Wnt signaling cascade has been the pathway most examined in this regard. The relationship between folate exposure and colorectal cancer risk is a complex one, in part because a number of extrinsic and intrinsic factors act as effect modifiers. This review discusses how the intake of the other three B-vitamins integral to the 1-carbon pathway acts as one such effect modifier. In addition, two concepts that remain matters of considerable debate are whether parental intake of folate impacts on subsequent cancer risk in the offspring, and whether excessive intakes of folate may have a paradoxical cancer-promoting effect: observations underlying these two concepts are presented as well.

Esophageal cancer is the sixth most common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) is a fatal malignancy associated with low 5-year survival rate. The aim of this study was to assess the association between methylenetetrahydrofolate reductase (MTHFR) tagging single nucleotide polymorphisms (SNPs) rs1801133 C>T, rs3753584 A>G, rs4845882 G>A, rs4846048 A>G and rs9651118 T>C genotypes and ESCC susceptibility in a hospital-based case-control study. We conducted genotyping analyses for these five SNPs with 629 ESCC cases and 686 controls in a Chinese Han population. Ligation detection reaction method was used to identify genotypes of these MTHFR SNPs. Our results demonstrated that MTHFR rs1801133 C>T was associated with the risk of ESCC; however, MTHFR rs4845882 G>A and rs4846048 A>G SNPs were associated with the decreased risk of ESCC, and MTHFR rs3753584 A>G and rs9651118 T>C SNPs were not associated with ESCC risk. Our findings suggests that MTHFR rs1801133 C>T, rs4845882 G>A and rs4846048 A>G SNPs may be genetic modifiers for developing ESCC in Chinese Han population.

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency polymorphisms has steadily increased over the last years. Evidence based on meta-analyses of individual case-control studies is accumulating, defining specific individual variations in disease susceptibility. For example, genetic variations of the estradiol metabolism have been described as significant contributors to disease susceptibility with variations depending on ethnic background. In the field of obstetrics and gynecology, the genetic contribution of polymorphic markers to a series of disorders has been characterized. These disorders include recurrent pregnancy loss, pre-eclampsia, endometriosis, breast cancer, and hormone replacement therapy (HRT)-related complications such as thrombosis. Among other genetic markers, thrombophilic genetic variants, such as the Factor V Leiden and prothrombin G20210A polymorphisms, as well as genetic variants of cytochrome P450 (CYP) enzymes, for example, CYP19 and CYP1B1, have been established as genetic risk markers and disease modifiers of recurrent and sporadic pregnancy loss and HRT-independent and -dependent breast cancer, respectively. In addition, meta-analyses of data in the literature established the TGFBR1*6A, GSTP I105V, and TP53 R72P polymorphisms, as well as the GSTM1 gene deletion as low-penetrance genetic risk factors of sporadic breast cancer. With respect to genetic modulation of therapeutic effects, beneficial effects of estrogen replacement therapy and HRT are modulated by the carriage of single nucleotide polymorphisms, for example, osteoprotection and blood lipid changes by the estrogen receptor-alpha (ER-a) PvuII polymorphism. Polymorphisms of the catechol-O-methyltransferase (COMT), ER-alpha, IL-1 receptor antagonist, and Factor V genes have been demonstrated to modulate the timing of natural menopause. Lastly, a strong genetic contribution of polymorphisms to the development and the clinical course of endometriosis has been established with data pointing to polymorphisms of the COMT, GST, NAT-2, and ER-alpha genes as susceptibility markers. In summary, the available evidence points to a number of polymorphisms of a wide variety of genes as strong hereditary determinants of the susceptibility to benign and malignant gynecologic and obstetric conditions.

Avascular necrosis (AVN) of the humeral and femoral heads is a frequent and debilitating complication of sickle cell disease. Some of the risk factors for AVN are alpha-thalassemia and age. Recently, newly discovered thrombophilia mutations have been associated with AVN in patients without sickle cell disease. We studied the frequency of the thermolabile methylene tetrahydrofolate reductase (MTHFR) variant (C677T) in adult sickle cell patients with and without AVN. The frequency of the MTHFR mutation was 35.6% in patients with AVN and 12.9% in those without AVN (p = 0.006). These data suggest that the thermolabile MTHFR variant may be a contributing risk factor for AVN in some populations with sickle cell disease.

Vaso-occlusion is a determinant for most signs and symptoms of sickle-cell anemia (SCA). The mechanisms involved in the pathogenesis of vascular complications in SCA remain unclear. It is known that genetic polymorphisms associated with thrombophilia may be potential modifiers of clinical features of SCA. The genetic polymorphisms C677T and A1298C relating to the enzyme methylenetetrahydrofolate reductase (MTHFR), a clotting Factor V Leiden mutation (1691G→A substitution of Factor V Leiden), and the mutant prothrombin 20210A allele were analyzed in this study. The aim was to find possible correlations with vascular complications and thrombophilia markers in a group of SCA patients in Pernambuco, Brazil. The study included 277 SCA patients, divided into two groups: one consisting of 177 nonconsanguineous SCA patients who presented vascular manifestations of stroke, avascular necrosis, leg ulcers, priapism, and acute chest syndrome (group 1); and the other consisting of 100 SCA patients without any reported vascular complication (group 2). Molecular tests were done using either polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR techniques. Comparisons between the groups were made using the χ(2) test. The 677 CT and TT genotypes showed a significant risk of vascular complications (p=0.015). No significant associations between the groups were found when samples were analyzed for the MTHFR A1298C allele (p=0.913), Factor V G1691 (p=0.555), or prothrombin G20210A mutation (p=1.000). The polymorphism MTHFR C677T seemed to be possibly predictive for the development of some vascular complications in SCA patients among this population.

Polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) modify the risk and severity of sporadic breast cancer (BC). In this context, the MTHFR C677T and A1298C polymorphisms have been associated with risk and severity of sporadic BC.