Thursday, October 20, 2011

Patients with high serum folate levels have increased prostate cancer cell growth

A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (Figueiredo et al., J Natl Cancer Inst 2009; 101(6): 432-435). As tumor cells in culture proliferate (grow) directly in response to available folic acid, the goal of this study was to determine if there is a similar relationship between patient folate status, and the proliferative capacity of tumors in men with prostate cancer.  We determined serum folate and/or prostate tissue folate in 87 randomly selected patients undergoing surgery for prostate cancer, and compared to tumor proliferation in a subset.

the findings indicate that:

1)  Fasting serum folate levels were positively correlated with prostate tumor tissue folate content (n = 15; r  = 0.577, P < 0.03). That means that steady-state levels of circulating folate are an indicator of how much folate is in the prostate tumor tissue of the same patient.  Interestingly, this was not the same for non cancerous prostate tissue suggesting the tumor has the ability to take up more folate than normal tissue.

2)  The average serum folate was 62.6 nM (ranging from 7.5-145.2 nM) -- wow! that is a HUGE range!  keep in mind that deficient folate levels are less 6.81nM, while adequate levels are greater than 13.62nM.  So some of the patients are in the inadequate range, and some of them have more than ten-fold the adequate level. 

3)  39.5% of patients used supplements containing folic acid (the chemical form of folate, not found in nature).

4)  The top 25% of patients had serum folates above 82 nM, six times the level considered adequate. Of these, 48% reported NO SUPPLEMENT use. So how did they get serum folates that were so high? Before folic acid fortification of the diet, mandated in the U.S. in 1998, almost all adults were considered folate deficient or to have inadequate folate levels....definitely a bad thing from many aspects...but seems to be the opposite, which would be OK if high levels of folate just meant more of the good stuff....more of that miracle vitamin..

5) Among 50 patients with Gleason 7 prostate cancer, the number of cells actively growing at the time the tumor was resected from the patient was 6.17% in the tumors from patients with the highest folate levels, and 0.86%  in the tumors from patients with the lowest serum folate, respectively (P < 0.0001).  That's a big difference.

Take home message:

Increased cancer cell proliferation in men with higher serum folate concentrations is consistent with an increase in prostate cancer incidence observed with folate supplementation. Unexpectedly, more than 25% of patients had serum folate levels greater than sixfold adequate. Nearly half of these men reported no supplement use, suggesting either altered folate metabolism and/or sustained consumption of folic acid from fortified foods.  So if you have prostate cancer, one suggestion would be to avoid taking folic acid supplements unless your doctor specifically okay's it.  As for natural folates from food, it is highly unlikely anyone could eat enough spinach, liver or yeast (or other natural sources of  folate) to get high serum folate levels. Fortified foods on the other hand, are supplemented with folic acid.  So while folate is a miracle vitamin and deficiency can actually cause at least some cancers, too much might not be a good thing for everyone...

you can read all about this study at  "Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate", by Tomaszewski et al. - and yes, this is a publication from our own lab...we are currently following up on these findings....

UPDATE SEPTEMBER 3RD 2012:  Our research for this paper was funded by the National Institutes of Health, therefore we have made it publicly available 12 months after publication in The Prostate, as per the PHS mandate - that means if you click on the above link, it will now take you to the whole paper for free.

Wednesday, October 12, 2011

Vitamin E supplementation increases prostate cancer incidence by 17%

In a follow up to their original study, Eric Klein M.D.  from the Cleveland Clinic and the rest of the SELECT clinical trial team report that supplementation with vitamin E at levels found in typical over the counter antioxidant preparations at your local grocery store can have long term effects, resulting in an increased incidence of prostate cancer years after the supplementation.  Furthermore, this effect was seemingly blocked by combining vitamin E with selenium and accordingly there was a statistically significant interaction -- however selenium alone (at least in the form it was provided) did not protect against prostate cancer in the long-term.  The take home message here is that despite all the reports that various vitamins or supplements may protect patients from disease, if there is such an effect, it may depend on the individual patient's biology, genetics and former and present environment.  Furthermore, the level of supplementation needed to see a positive effect may be within a narrow range, outside which too little or too much is actually hazardous to the patient's health -- the "goldilocks effect".  Read about it at JAMA

Saturday, October 8, 2011

ERG, the partner in the TMPRSS2-ERG fusion, is frequently methylated in prostate cancer

From the Alumkal lab at OHSU, comes the paper

A DNA methylation microarray-based study identifies ERG as a gene commonly methylated in prostate cancer 
Bascially, ERG is normally repressed in CaP in absence of the TMPRSS2-ERG fusion -- where it is upregulated by virtue of the TMPRSS2 promoter -- this report describes the findings from a methylation array, showing that 74% of prostate tumors are methylated at ERG.  This is interesting as the argument to date has been that TMPRSS2-driven ERG expression is a bad player in prostate cancer -- but if ERG is repressed by methylation specifically in the tumors, that would suggest inactivation of ERG is a bad player.  Do these two expression states of ERG define biologically distinct tumor types?  Can both events occur simultaneously - one allele forming the fusion and one that is methylated?  Is ERG activation or inactivation not so important because neither event actually drives tumorigenesis or progression?  read all about it if you have access to Epigenetics (link above)!

Friday, October 7, 2011

A nucleolar protein, H19 opposite tumor suppressor (HOTS), is a tumor growth inhibitor encoded by a human imprinted H19 antisense transcript.

Andy Feinberg and Paddy Onyango have just published (gasp) the long-sought after, real WT2 (Wilm's Tumor) locus....and it encodes "HOTS" the H19 opposite tumor suppressor - which is maternally expressed.  The paper, in PNAS demonstrates beautifully how easy it is to miss something that was right there all along - read about it for yourself, for FREE at Onyango and Feinberg, PNAS

what if Steve Jobs had been a scientist?

Hailed as a great, irreplaceable visionary that changed the world, the Einstein of our time, thinking of the passing of Steve Jobs and all he accomplished leads me to wonder what kind of impact Jobs could have had if he had been, say, a medical researcher - or head of the NIH?  I guess we'll never know because that's the whole point, there is no one who thinks quite like him....meanwhile, I often like to think of this quote of his when a paper or idea gets rejected because the reviewer or a colleague just "doesn't get it" --

"Your time is limited, so don't waste it living someone else's life.
Don't be trapped by dogma - which is living with the results of other people's thinking. Don't let the noise of others' opinions drown out your own inner voice. And most important, have the courage to follow your heart and intuition. They somehow already know what you truly want to become. Everything else is secondary." - Steve Jobs, R.I.P.

Wednesday, October 5, 2011

Biotechniques virtual symposium occuring now!

this is just like being at a conference, complete with poster sessions, exhibitor hall and seminars!

Mitch Guttman, who just had a first author paper in Nature last month will be speaking at 11:40, on large intergenic noncoding a bunch of other talks -- you can register for free and attend by clicking

Tuesday, October 4, 2011

house puts forward draft budget for 2012 that includes $1 billion increase for NIH

this is probably too good to believe, but if it passed the house....check out the story at The Scientist
of course it would make good sense :)

whoa! DNA methylation regulates alternative splicing!

What regulates alternative splicing of pre-mRNA has always been an enigma -- it is especially important in cancer research where it seems many genes become alternatively spliced, potentially giving them novel functions, or making them inactive.  In a Nature epub by Shukla et al., we see that DNA methylation may be involved in this process; the authors show that CTCF binding permitted inclusion of upstream exons by causing a pause in RNA pol II and thus slowing the transcription rate.  Furthermore, they demonstrated that (as we already know) CTCF binding to its target sequence can be prevented by DNA methylation. When this occurred, the upstream exon was excluded from the maturely spliced mRNA transcript.  These findings were shown in a model system, but also occurred as a global phenomenon.  It follows that loss of intergenic or intronic DNA methylation, as occurs frequently in cancer, not only causes genomic instability and potentially activates previously silenced genes, but now may result in the mRNA scramble that we see as well.  Presumably alternative variants that provide a growth advantage for the cell will be selected for -- meanwhile for those of us studying regulation of altered methylation patterns, we just got more places to all about it at Nature --CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing by Shukla et al.