New study below.
It's a big study, involving 6,875 cases from 6 cohorts, & researchers from England, Spain, Norway, Sweden, Greece, Italy, Malaysia & the U.S.A.
"Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels."
No mention of the back story in the Abstract. But first, I'll mention my own. This goes back ~8 years.
I had been doing something new, & perhaps risky, so started to have PSA tested monthly. I had 6 identical readings in the first 6 months, but I began seeing an integrative medicine doctor, who asked why my regular doctor had not addressed a high homocysteine test result. He had already suggested a hair analysis, which is inexpensive & gives some insight on one's status regarding an array of minerals, good & bad. This showed zero cobalt.
There are a number of reasons why homocysteine might be high, & they mostly relate to the SAM cycle. B12 deficiency is one possibility, since B12 is a cofactor in folate processing, which is key to the SAM cycle. I was taking a B-complex supplement daily, but he told me that it was not uncommon for older men to produce less intrinsic factor [IF] in the stomach. IF is required for the uptake of B12 in the intestines. Since B12 is a cobalt-containg vitamin, the absence of cobalt in my hair was suggestive of a B12 deficiency, & this would likely explain my elevated homocysteine.
For $24 I received a 6 month supply of B12, syringes, & instructions on how to inject into belly fat.
There were PSA increases over the next 3 months - a 20% increase in the third. I was puzzled but did not suspect the B12. But after the third reading I figured it was prudent to look for a PCa connection. I found a handful of papers on PubMed from Scandinavia & threw out the B12.
The SAM cycle, which is part of "one carbon metabolism" can be simplied here to:
Methionine ---> SAM ---> Homocysteine ---> Methionine
1] Methionine is the natural source of methyl in the body, but dietary sources are low.
2] Methionine converts to SAM, which is the universal methyl donor in the body.
3] When SAM has dropped off its methy to a cell, homocysteine remains in circulation.
4] Methionine levels are restored by recycling homocysteine back to methionine. This requires a dietary methyl donor, & folate (from leafy greens, i.e from foliage) is the normal source for many people.
If a cell does not have enough methyl, its DNA can become unstable. This is why hypomethylation is associated with cancer.
However, once PCa occurs, the cells become greedy for methyl. They become hypermethylated. In particular, DNA CpG islands that are the promoter regions for tumor suppressor genes, become methylated. This never happens in normal cells. Methylation effectively silences those genes.
Note that this is not a gene mutation effect. The silencing occurs above the gene level (i.e. is an epigenetic change) & is therefore reversible. Several demethylation agents have been developed as potentially useful in cancer.
The Scandinavian studies, in effect, indicated that folate insufficiency was protective. What I think was going on was that, in a population not heavily invested in PCa screening, folate insufficiency was slowing down progression (because tumor suppression genes were still functional) & lowering the detection rate. But more importantly, preventing progression to an aggressive form.
In the U.S. where grain products are 'enriched' with synthetic folic acid as a source of folate, & where PSA screening reveals cancer at an earlier stage, the effect on statistics should be far less pronounced.
And folate is not the only souce of methyl. e.g. betaine, from beets, is a good source.
In other words, one should not expect population studies to be consistent. Pointless to look at folate status as a surrogate for methyl status, if the population is generally not deficient, or not dependent on folate for methyl.
Earlier researchers who looked at folate status also considered homocysteine. As expected, elevated homocysteine was 'protective'.
Not really. Those & other studies - includin B12 studies - were attempting to link a dysfunctional SAM system to PCa incidence / severity. What those studies couldn't do was report on the methylation status of actual PCa cells. Implicit, though, is that aggressive PCa has turned off tumor suppressor genes via hypermethylation.
For an American these days, the fortification of grains with folic acid has almost ruled out folate-insufficiency as a PCa-protective strategy. I feel fortunate in being able to flirt with B12 deficiency. My risk for dementia is perhaps 1% higher, but I have more immediate concerns.
From the new study:
"The association with folate varied by tumour grade ... higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 ..), with no association for low-grade disease. "
Eur Urol. 2016 Apr 6. pii: S0302-2838(16)00379-1. doi: 10.1016/j.eururo.2016.03.029. [Epub ahead of print]
Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.
Price AJ1, Travis RC2, Appleby PN2, Albanes D3, Barricarte Gurrea A4, Bjørge T5, Bueno-de-Mesquita HB6, Chen C7, Donovan J8, Gislefoss R9, Goodman G7, Gunter M10, Hamdy FC11, Johansson M12, King IB13, Kühn T14, Männistö S15, Martin RM16, Meyer K17, Neal DE18, Neuhouser ML7, Nygård O19, Stattin P20, Tell GS21, Trichopoulou A22, Tumino R23, Ueland PM24, Ulvik A17, de Vogel S21, Vollset SE25, Weinstein SJ3, Key TJ2, Allen NE26; Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group.
1Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK; London School of Hygiene and Tropical Medicine, London, UK. Electronic address: email@example.com.
2Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
3Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda MD, USA.
4Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.
5Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Cancer Registry of Norway, Oslo, Norway.
6Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
7Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
8School of Social and Community Medicine, University of Bristol, Bristol, UK.
9Cancer Registry of Norway, Oslo, Norway; Institute of Population-based research, Montebello, Oslo, Norway.
10Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
11Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.
12International Agency for Research on Cancer, Lyon, France; Department of Biobank Research, Umeå University, Umeå, Sweden.
13Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
14Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
16School of Social and Community Medicine, University of Bristol, Bristol, UK; Medical Research Council/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK; National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK.
17Bevital AS, Bergen, Norway.
18Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
19Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
20Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
21Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
22WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, Greece; Hellenic Health Foundation, Athens, Greece.
23Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.
24Department of Clinical Science, University of Bergen, Bergen, Norway.
25Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Norwegian Institute of Public Health, Bergen, Norway.
26Clinical trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK.
Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.
To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.
DESIGN, SETTING, AND PARTICIPANTS:
A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
Incident PCa and subtype by stage and grade.
RESULTS AND LIMITATIONS:
Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.
The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.
Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.
Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Folate; High grade; Pooled data meta-analysis; Prospective cohort; Prostate cancer; Vitamin B(12)
PMID: 27061263 [PubMed - as supplied by publisher]