{Too much information for those not interested in MTHFR - best to skip.}
In the recent thread on folate, Captain_Dave & Homer13 mentioned the MTHFR, 677CT and 1298AC polymorphisms (which they have). & some here might have them without knowing it (including me). It's an interesting area, & affects the SAM (SAMe) cycle {aka the methyl cycle} that I have written about.
Briefly the cycle is:
... Methionine--->SAM--->minus Methyl=Homocysteine--->plus Folate=Methionine ...
SAM is the methyl donor in the body. It gets its methyl from methionine. When SAM drops off its methyl to cells, we are left with homocysteine. There is not enough methionine in the average diet to meet methyl demands, so it is important that homocysteine be recycled back to methionine. The major dietary methyl donor to achieve this is folate (or synthetic folic acid).
MTHFR is an enzyme that is needed for the last phase of the cycle.
(Incidentally, MTHFR is Methylene tetrahydrofolate reductase. & I thought MTHFR was a mouthful.)
From Wiki [1]: "Natural variation in this gene is common in healthy people." "Some mutations in this gene are associated with {MTHFR} deficiency."
From Wiki [2]: "(MTHFR) deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle."
Essentially, MTHFR variations can result in suboptimal SAM levels. This means that there will not be enough methyl to satisfy cellular needs, & this can lead to DNA instability & a small increase in the risk of certain diseases. A SAMe supplement will provide bioavailable methyl, although it will do nothing for elevated homocysteine.
The obvious question here is whether any of the MTHFR variants (polymorphisms) affect PCa risk & survival. See below.
Unfortunately, when PCa is present, SAMe supplementation might increase the risk of aggressive disease. That is because PCa cells have a very high uptake of methyl (when it is freely available). The cells are almost always hypermethylated in serious disease. The DNA promoter regions for tumor suppressor genes are invariably silenced via methylation. So a MTHFR variant that keeps methyl availability somewhat depressed should have survival benefit. Does the literature support that?
...
In the following studies, C677T was associated with more PCa, but less aggressive PCa. This is consistant with (a) increased instability leading to PCa, but (b) methyl restriction being protective after diagnosis. [3] Less aggressive disease = better survival.
On the other hand, A1298C was associated with aggressive disease. (No explanation. Did this depend on folate or methionine status?)
Two studies (from Croatia [5] & Sweden [6]) found no increased risk for PCa with C677T, while a Spanish study [7] did.
A U.S. veterans study found an increased risk from A1298C when there was high methionine in the diet (probably from high levels of protein) [8].
...
[3] (2004) - Cleveland Clinic:
"Two common polymorphisms in the MTHFR gene, C677T and A1298C, have been described."
"Two studies have looked at the C677T variant and prostate cancer: one reported a positive association overall (3.8), whereas another found a weak positive association with higher tumor grade (3.9). Here, we give results from a sibling-based case-control study evaluating the relationship between both C677T and A1298C variants and prostate cancer risk and aggressiveness."
"... among men with low aggressive disease at diagnosis, the C677T variant was positively associated with prostate cancer (OR 1.86 ...), whereas, in men with high aggressive disease, the variant was inversely associated with disease (OR 0.51 ...)."
"In contrast, the A1298C variant was positively associated with disease among men with more advanced prostate cancer (OR 1.79 ...)."
"Including both polymorphisms in a single model slightly weakened these individual associations but did not materially alter the OR estimates ..."
[4] (2006) - Sweden:
This study related "the MTHFR 677C-->T and 1298A-->C polymorphisms to the risk of prostate cancer, taking into consideration prospective plasma levels of folate, vitamin B12 and homocysteine."
"After adjustment for MTHFR 1298A-->C, plasma folate, vitamin B12, homocysteine, body mass index and smoking, the odds ratios were, for the 677 CT genotype, 1.52 .., and for TT, 0.91 ..."
"We found that the MTHFR 677C-->T polymorphism is not likely to have a major role in the development of prostate cancer, although it may possibly increase the risk in combination with high plasma folate levels."
[5] (2007) - Croatia:
"Our data indicate that the C677T MTHFR polymorphism does not significantly contribute to the inherited genetic susceptibility to breast and prostate cancer, while we show some evidence for possible genetic contribution of this polymorphism to the development of head and neck carcinoma."
[6] (2007) - Sweden:
"... our results do not provide strong support for the hypothesis that the MTHFR 677C-->T polymorphism is related to prostate cancer risk."
[7] (2008) - Spain:
"We conclude that the polymorphism MTHFR C677T is clearly related to prostatic carcinogenesis .."
[8] (2012) - U.S. Veterans study, NC:
Just to complicate things ...
"Higher dietary methionine intake was associated with PC risk (OR = 2.1 ...) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75 ...). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6.7 ...), compared to MTHFR A1298A noncarrier men (OR = 0.9 ...)."
"Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk"
"Our key findings were that high intake of methionine, which after its conversion to S-adenosylmethionine {SAM} becomes the principal methyl donor for DNA methylation, was associated with higher overall risk of PC and that association was only evident in men with carriers of the MTHFR A1298C genotype."
"Our findings that high methionine intakes were associated with increased PC risk, may imply that methionine availability at higher than optimal levels may lead to higher bioavailability of S-adenosylmethionine {SAM} to donate methyl groups to DNA, resulting in DNA hypermethylation of regulatory regions of key genes, including tumor suppressors."
"Alternatively, higher bioavailable methionine levels could also disrupt the physiologic equilibrium concentrations of S-adenosylmethionine and homocysteine, reducing MTHFR activity ..."
"In summary, our results suggest that higher intakes of methionine, presumably through higher protein consumption, is associated with increased PC risk, regardless of grade of lesion, but only in men carrying the polymorphism MTHFR A1298C."
-Patrick
[1] en.wikipedia.org/wiki/Methy...
[2] en.wikipedia.org/wiki/Methy...
[3] cebp.aacrjournals.org/conte...
[3.8] cancerres.aacrjournals.org/...
[3.9] ncbi.nlm.nih.gov/pubmed/110...
[4] ncbi.nlm.nih.gov/pubmed/163...
[5] ncbi.nlm.nih.gov/pubmed/175...
[6] ncbi.nlm.nih.gov/pubmed/178...
Homocysteine, hypermethylation/PCa aggressiveness and MTFHR mutation
