Familial Breast Cancer Is Mainly Driven By Methylation, Not Genes

[haidut]

I think this is a very important study because it shakes the foundations of one of the most solid cases cited by mainstream oncology in favor of cancer begin driven by genes. Familial breast cancer, purportedly linked to the infamous (and patented) genes BRCA1 and BRCA2, is thought to be one of the clearest examples of genetically predetermined cancer risk. Many women (Angelina Jolie anyone) who have tested positive for mutations in BRCA1/BRCA2 have undergone "preventative" mastectomy with the hope of avoiding the "guaranteed" cancer. Sadly, not only is this whole explanation a mountain of nonsense but the "preventative" mastectomy has been shown to increase the risk of a number of other cancers including cervical, ovarian and endometrial. The medical industry has started to wisen up to the fact that this gruesome procedure really does not provide much benefit but I think it is still quite widespread. I know @Blossom works in a hospital so maybe she can shed some light on how common is that practice these days.
So, as the study shows, while breast cancer risk is heritable it is not the genes that matter but the methylation patterns. Excessive methylation is known to be highly associated with cancer risk, and Peat has written about the effects of CO2, niacinamide, progesterone, aspirin and a few other chemicals to reverse excessive methylation in humans. Thus, once again we see that cancer risk is something not written in stone but dynamic and influenced by our environment and the choices we make every day.

https://www.nature.com/articles/s41467-018-03058-6
https://eurekalert.org/pub_releases/2018-02/uom-fbc022518.php
"...Mutations in known breast cancer genes such as BRCA1 and BRCA2 are identified in only approximately 20 per cent of women who are offered genetic testing for familial breast cancer. Researchers at the University of Melbourne, led by Professor Melissa Southey, looked at 210 people from 25 multiple-case breast cancer families. They identified 24 previously unknown epigenetic changes that alter a woman's risk of breast cancer and can be passed down through generations without involving changes in the DNA sequence of genes. "For the majority of women who undergo genetic testing, there is no explanation for their breast cancer predisposition," said Professor Southey, from the Department of Clinical Pathology at the University of Melbourne and Chair of Precision Medicine at Monash University. "This ground-breaking work is not only helpful for women from families with many cases of breast cancer, it will improve breast cancer risk prediction for all women, and pave the way for the development of epigenetic therapeutics for breast cancer." The study, published in Nature Communications, looks at epigenetic changes called DNA methylation, where methyl group chemicals modify DNA without changing its sequence. DNA methylation can mimic genetic variation, predisposing a family to breast cancer. The study is one of the first to systematically scan the genome for places where DNA methylation is heritable, and is the first to apply this to familial breast cancer."

 

[steel_reserve]

I was born with blond hair now i have dark brown hair.

Does that mean i was methylated?

 

[haidut]

I was born with blond hair now i have dark brown hair.

Does that mean i was methylated?

Don't know for sure. Could be due to hormonal changes, even though they seem to affect skin more than hair.
https://raypeatforum.com/community/...ns-skin-color-progesterone-lightens-it.10776/

 

[ecstatichamster]

this is fascinating and shows that most doctors and almost every person believes in a genetic theory that is 150 years out of date.

 

[Koveras]

I was born with blond hair now i have dark brown hair.

Does that mean i was methylated?

Don't know for sure. Could be due to hormonal changes, even though they seem to affect skin more than hair.
https://raypeatforum.com/community/...ns-skin-color-progesterone-lightens-it.10776/

Factors that affect proopimelanocortin (POMC), melanocortins, micropthalmia-associated transciption factor (MITF) will affect the production of melanin pigment in the hair as well as skin.

Leptin is upstream of POMC and is probably one of the mechanisms good energy status (sufficient body fat and liver glycogen) influences libido (melanocortins increase dopamine signalling).

 

[Zpol]

Apparently there is some sort of sweet spot we need to achieve. I've seen other research indicating some DNA methylation is protective...

http://raypeat.com/articles/articles/co2.shtml
"With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes and protects cells when growth and regeneration aren't possible (and that it's likely to increase when CO2 isn't available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively."

http://news.mit.edu/1998/jaenisch-0930
"Our present study shows that reduced methylation may be responsible for the decrease in genomic stability, and therefore, the increase in mutations and chromosome loss seen in the early cancer cell."

In the first article RP also states...
"Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria."

(@aguilaroja and @BingDing pointed out this discrepancy a while back, I still don't what to make of it all)

It seems people who have gene variances which result in undermethylation (symptomatically this manifests as high Homocysteine and low vitamin B 's and C, and glutathione status) are very sick, conversely people who overmethylate are also sick (or will be as they age).
People who are undermethylators often take Creatine, Betaine Hcl (trimethylglycine), and even methylated forms of folate and B-12 and they feel better, plus blood labs come back within 'healthy' range. All these supplements are methyl donors, but they feel better and are verifyably better, but; is it just a temporary thing... and all this healthiness they experience is actually going to end up causing them cancer or some other terrible disease later?

@haidut or anyone, if someone could help me understand this, I'd be so thankful. I don't have a background in biochem so maybe I'm missing some fundamental piece of info that would help bring this all together. I am one of those undermethylators and very symptomatic. I'm so tempted to take all those supplements but this DNA methylation issue, and my lack of understanding of it all, is preventing me from taking them. And if I don't take them; I'm not really sure what to do.

 

[Nathan777]

It seems people who have gene variances which result in undermethylation (symptomatically this manifests as high Homocysteine and low vitamin B 's and C, and glutathione status) are very sick, conversely people who overmethylate are also sick (or will be as they age).
People who are undermethylators often take Creatine, Betaine Hcl (trimethylglycine), and even methylated forms of folate and B-12 and they feel better, plus blood labs come back within 'healthy' range. All these supplements are methyl donors, but they feel better and are verifyably better, but; is it just a temporary thing... and all this healthiness they experience is actually going to end up causing them cancer or some other terrible disease later?

Creatine isn't a methy donor is it, it just lessens the methylation demand since as Masterjohn says half of the methylation activity by the body is for creatine synthesis so if you supplement exogenously you could theoretically cut your methylation demand in half. I think it's more complicated than just looking at the SNPs and supplementing. I'm homozygous C677T yet my RBC Folate and B12 are off the chart high, which for B12 makes sense as I've always supplemented a little here and there (and probably will never supplement again as it just doesn't seem to be necessary for me given labs always showing it >2000 which is actually little scary) and it lasts a long time in the body, but I've never gotten much folate (never ate a lot of greens or legumes, folic acid fortified foods very rarely, some liver and OJ recently), and my symptoms tend to exhibit more overmethylation than under lately, so maybe my SNP isn't expressing at all as I don't seem to react well to methylfolate. My homocysteine was 13.9 a month ago, and 11 last week after dabbling with creatine, TMG, and some B's, so I'm thinking a deficiency in betaine or B6 ("Peaters" aren't getting much of either of these from food) is more likely the cause for my elevated homocysteine rather than the usual culprits of B12 and Folate. Ultimately I think health and wellbeing are most important. If someone megadoses B12 and 5-MTHF and feels better and finally vibrant then to me that would outweigh the potential negatives of cancer well into the future... People will also say that it's folic acid and cyanocobalamin that tend to show an association with cancer and that methylated forms are different but I'm not well-educated enough on that to have an opinion.

It's funny, when I first started my health journey 8 or so years ago, low stomach acid and supplementing with betaine Hcl was the big thing, and still you hear about it some. So I started supplementing and it was like a miracle drug. It truly saved my life for a few years and was almost instantaneous how much better it made me feel. I was never without a bottle. Now looking back I wonder if it was just the betaine that made me feel so good, and not necessarily some low stomach acid issue it was correcting. Eventually I couldn't take it because it started irritating my stomach and throat, but maybe rather than cutting out betaine completely I should have just gone with pure TMG, which I've recently started in fairly low dose.

 

[Mito]

yet my RBC Folate and B12 are off the chart high,

Did you also test serum folate? RBC folate reflects total folate status. Serum folate is almost exclusively methylfolate. How did you measure B12? To assess methylation by measuring folate and B12, serum folate and methylmalonic acid (B12) need to be measured.

 

[Nathan777]

Did you also test serum folate? RBC folate reflects total folate status. Serum folate is almost exclusively methylfolate. How did you measure B12? To assess methylation by measuring folate and B12, serum folate and methylmalonic acid (B12) need to be measured.

Isn't it the opposite? Serum folate includes unmetabolized folic acid as well as frequent fluctuations with short-term dietary intake and RBC folate is a better measure of actual folate status within the cells? At least that seems to be Ben Lynch and a few others' thoughts but I'm not sure. MMA was also measured and came out at .16 umol/l, reference <=.40.

Edit: This study seems to suggest serum folate correlates more with tHcy than RBC folate though so maybe there's more to it. I'll test serum folate soon. Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China - ScienceDirect

 

[Mito]

Isn't it the opposite? Serum folate includes unmetabolized folic acid as well as frequent fluctuations with short-term dietary intake and RBC folate is a better measure of actual folate status within the cells?

“In any case remember the three most important things are Number 1: homocysteine should be in the optimal range, Number 2: plasma or serum folate should be high enough, not red blood cell necessarily, and Number 3: your glycine should be in the middle of the range, sarcosine as low as possible.”
https://chrismasterjohnphd.com/2017/12/11/bloodwork-get-mthfr/

 

[Nathan777]

“In any case remember the three most important things are Number 1: homocysteine should be in the optimal range, Number 2: plasma or serum folate should be high enough, not red blood cell necessarily, and Number 3: your glycine should be in the middle of the range, sarcosine as low as possible.”
https://chrismasterjohnphd.com/2017/12/11/bloodwork-get-mthfr/

Awesome. Somehow hadn't come across that presentation of his. Thanks! Will definitely look into serum/plasma folate.

 

[Zpol]

Creatine isn't a methy donor is it, it just lessens the methylation demand since as Masterjohn says half of the methylation activity by the body is for creatine synthesis so if you supplement exogenously you could theoretically cut your methylation demand in half.

True, I've read this by Masterjohn. It's confusing to me because methonine is one of the amino acids in it and it is a methyl donor, hence RP speaks of it in a bad light, saying that the "age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity." I have a hunch though that the glycine element in creatine somehow negates this, not sure the mechanism yet, maybe I should see if Masterjohn addresses this somewhere.

Now looking back I wonder if it was just the betaine that made me feel so good, and not necessarily some low stomach acid issue it was correcting. Eventually I couldn't take it because it started irritating my stomach and throat, but maybe rather than cutting out betaine completely I should have just gone with pure TMG, which I've recently started in fairly low dose.

Yes, I hear this so often...people miraculously 'cured' by Betaine HCL. I found out about it when I started researching gut health many years ago, it was the go-to supplement. Now, I'm researching methylation and it's popping up all over the place again! I never took it due to possibility of the it burning my esophagus, I have severe GERD and LPR so I didn't want to chance it. But you bring up a very good point, maybe it's best to take the straight-up TMG form for those of us who could use could use the extra methyl donors. @haidut has pointed out many studies indicating Taurine and Glycine are helpful for stomach acid issues, I've been using them in addition to collegen hydrolosate and bone broth but can't say I notice a difference. My gut issues are atypical, they do not respond to any of the usual conventional and alternative treatments. My guess is that they are caused by something much further down stream, methylation issue is a possibility.

Ultimately I think health and wellbeing are most important. If someone megadoses B12 and 5-MTHF and feels better and finally vibrant then to me that would outweigh the potential negatives of cancer well into the future... People will also say that it's folic acid and cyanocobalamin that tend to show an association with cancer and that methylated forms are different but I'm not well-educated enough on that to have an opinion.

Same here, I don't know about all the different results between the regular and methylated forms of Folic acid and B12 supplementation. I wonder if any of the women in the families of the second study the OP posted had taken B vitamin supplementation.

Okay, so here's a thought...
The DNA methylation happens when methyl donors tend to damages in DNA (which are caused by estrogen and other things), this is good thing. The methyl donors stay there even after the damage is fixed, and even transfer to other areas when the DNA curls, so there is over-methylation of the DNA which disregulates the 'methylation balance' and silences the tumor suppressor genes. So we need to restore balance.

@haidut Do you think Niacinamide might be able to mop up all these rogue DNA methyl donors but not disrupt the methyl donors who are doing their job?
Do you know of any studies where Niacinamide was used to reverse the silencing of the cancer suppressive genes caused by the DNA modification? Actually I could probably find studies on this myself, if they even exist yet.
Perhaps we could take Niacinamide along with TMG, to mop up the two spare methyl donors, one would also have to supplement B6 to prevent a rise in Homocysteine.

“In any case remember the three most important things are Number 1: homocysteine should be in the optimal range, Number 2: plasma or serum folate should be high enough, not red blood cell necessarily, and Number 3: your glycine should be in the middle of the range, sarcosine as low as possible.”
https://chrismasterjohnphd.com/2017/12/11/bloodwork-get-mthfr/

Awesome, thanks for this link!

 

[haidut]

@haidut Do you think Niacinamide might be able to mop up all these rogue DNA methyl donors but not disrupt the methyl donors who are doing their job?

Yes, niacinamide, glycine, sucrose, and some quinone are well known to reduce methylation. I think taurine may be able to do it as well but the data on that is very sparse. Thyroid, methylene blue and aspirin are other agents that can do the same as niacinamide in regards to methylation.

 

[Mossy]

Did you also test serum folate? RBC folate reflects total folate status. Serum folate is almost exclusively methylfolate. How did you measure B12? To assess methylation by measuring folate and B12, serum folate and methylmalonic acid (B12) need to be measured.

Hi Mito, on my blood test I have high serum folate and low B12 -- is there an optimal range or ratio to be desired there? Thanks!

 

[Herbie]

Interesting. Angelina Jolie's Mother Marcheline Bertrand died of ovarian cancer.

 

[haidut]

Interesting. Angelina Jolie's Mother Marcheline Bertrand died of ovarian cancer.

Yes, and Angelina tested positive for the BRCA mutations so the doctors convinced her to get both of her breasts amputated, even though if genetics was really at play they should have advocated ovariectomy instead. Removing the breasts has been shown to increase risk for ovarian cancer so sadly Angeline may have inadvertently made her situation much worse.

 

[Mito]

Hi Mito, on my blood test I have high serum folate and low B12 -- is there an optimal range or ratio to be desired there? Thanks!

Low (below reference range) serum B12 probably indicates a deficiency that you may want to address, but methylmalonic acid (in urine) is usually considered the best marker for B12. High serum folate indicates you have high levels of methylfolate. So your MTHFR enzyme is working well creating the active form of folate. If you are supplementing with methylfolate you may want to consider stopping. Too much methylfolate can cause overmethylation. Haidut doesn’t include folate in his Energin product because he has concerns about excess folate (High intake of vitamin B6 protects from Parkinson).

 

[Mossy]

Low (below reference range) serum B12 probably indicates a deficiency that you may want to address, but methylmalonic acid (in urine) is usually considered the best marker for B12. High serum folate indicates you have high levels of methylfolate. So your MTHFR enzyme is working well creating the active form of folate. If you are supplementing with methylfolate you may want to consider stopping. Too much methylfolate can cause overmethylation. Haidut doesn’t include folate in his Energin product because he has concerns about excess folate (High intake of vitamin B6 protects from Parkinson).

Thanks, Mito.

Ok, if I understand correctly, I may need to supplement with B12, but if the B12 that I have is methylcobalamin it may contribute to overmethylation? So, maybe B12 from food would be better?

On a side note, is it accurate to say that if I have high levels of methylfolate I should have low histamine? Strange, if this is the case, because I do get histamine effects from time to time.

 

[Nathan777]

Thanks, Mito.

Ok, if I understand correctly, I may need to supplement with B12, but if the B12 that I have is methylcobalamin it may contribute to overmethylation? So, maybe B12 from food would be better?

On a side note, is it accurate to say that if I have high levels of methylfolate I should have low histamine? Strange, if this is the case, because I do get histamine effects from time to time.

Pure Encapsulations makes a hydroxy/adeno B12 in both liquid and capsules: Adenosyl/Hydroxy B12 liquid Food might be better, but it can be tough to build up your stores even eating high B12 foods as you can only process so much at once. Masterjohn talks about this in a few vids and articles.

 

[Mossy]

Pure Encapsulations makes a hydroxy/adeno B12 in both liquid and capsules: Adenosyl/Hydroxy B12 liquid Food might be better, but it can be tough to build up your stores even eating high B12 foods as you can only process so much at once. Masterjohn talks about this in a few vids and articles.

Interesting, thank you. Would you say this hydroxy/adeno B12 would be a better way to supplement B12, in order to avoid overmethylation? I ask, because I have plenty of methylcobalamin already, but won't take it if it's no good.