Hypothesis for a role of main functional genetic variants in one-carbon metabolism and cancer risk through DNA methylation.

<p>Polymorphic genetic variants in one-carbon enzymes can affect the balance between biological methylation and nucleic acids synthesis pathways inducing an aberrant DNA methylation and eventually leading to cancer development. BHMT, betaine-homocysteine S-methyltransferase; DHFR, dihydrofolate reductase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase; RFC1, reduced folate carrier 1; SHMT1, serine hydroxymethyltransferase 1; TCII, transcobalamin II; THF, tetrahydrofolate, and TS, thymidylate synthase.</p

<i>MTHFD1</i> 1958G>A genotypes and cancer risk.

<p>The <i>MTHFD1</i> 1958A allele is associated to a lower cancer risk as expressed by means of Odds Ratio (OR) adjusted for sex and age.</p

Comparison of polymorphic variants frequencies between cancer patients and cancer-free subjects.

<p>Comparison of polymorphic variants frequencies between cancer patients and cancer-free subjects.</p

Global DNA methylation levels in PBMCs according to the <i>MTHFD1</i> 1958G>A genotypes.

<p>Global DNA methylation levels according to the <i>MTHFD1</i> 1958G>A genotypes in cancer patients and cancer-free subjects. GG: n = 72, GA+AA: n = 332. The error bar represents standard deviation (SD).</p

<i>MTHFD1</i> 1958G>A genotypes and colon cancer risk.

<p>The <i>MTHFD1</i>1958AA genotype is associated to a significantly reduced colon cancer risk by means of Odds Ratio (OR) adjusted for sex and age.</p

Pattern of reactions and functions of Methylene tetrahydrofolate dehydrogenase 1 (MTHFD1).

<p>The MTHFD1 enzyme catalyzes three sequential and reversible reactions in the pathway of conversion of tetrahydrofolate (THF), the active form of folate, into substrates essential for the <i>de novo</i> purine and thymidylate synthesis.</p

Clinical and biochemical characteristics of cancer patients and cancer-free subjects.

<p>Clinical and biochemical characteristics of cancer patients and cancer-free subjects.</p

Survival curves plotted by Kaplan-Meier analysis according to <i>RFC1 80G>A</i> genotypes.

<p>(A) The survival rate was worse in <i>RFC1 80AA</i> (22.2%) patients as compared to the <i>RFC1 80GA</i> (76%) and <i>RFC1 80GG</i> (61.5%) genotypes (p = 0.005). (B) The survival rate was lower among the <i>RFC1 80 AA</i> patients as compared with the G allele carriers (<i>RFC1 80GG</i>+<i>GA</i>) (p = 0.002). The percentage of survivors was 22.2% and 71.1%, respectively.</p

RFC1 80G>A genotypes frequencies in primary liver cancer patients (n = 47).

<p>RFC1 80G>A genotypes frequencies in primary liver cancer patients (n = 47).</p

Mortality risk by Hazard Ratio for <i>RFC1 80AA</i> genotype with either high or low mCyt levels.

<p>The <i>RFC1 80AA</i> genotype with low mCyt levels (≤5.34%), had a higher Hazard Ratio (HR) as compared to <i>RFC1 80G</i> carriership (<i>RFC1 80GA</i> plus <i>RFC1 80GG</i>) (HR = 6.62, 95% CI 2.17–20.25, p = 0.001). The HR for <i>RFC1 80AA</i> genotype with high mCyt levels (>5.34%) did not differ from the <i>RFC1 80G</i> carriership group (HR = 2.05, 95% CI 0.45–9.32, p = 0.351).</p