Switzer now finds (some) XMRV in Prostate Cancer

[RRM]

I am not a patient and once registered to correct a mistake, so I'll refrain from further comments, but as I know you'll find this interesting in the midst of the Singh news:

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019065#abstract0

No Association of Xenotropic Murine Leukemia Virus-Related Viruses with Prostate Cancer

Abstract

Background

The association of the xenotropic murine leukemia virus-related virus (XMRV) with prostate cancer continues to receive heightened attention as studies report discrepant XMRV prevalences ranging from zero up to 23%. It is unclear if differences in the diagnostic testing, disease severity, geography, or other factors account for the discordant results. We report here the prevalence of XMRV in a population with well-defined prostate cancers and RNase L polymorphism. We used broadly reactive PCR and Western blot (WB) assays to detect infection with XMRV and related murine leukemia viruses (MLV).

Methodology/Principal Findings

We studied specimens from 162 US patients diagnosed with prostate cancer with a intermediate to advanced stage (Gleason Scores of 510; moderate (46%) poorly differentiated tumors (54%)). Prostate tissue DNA was tested by PCR assays that detect XMRV and MLV variants. To exclude contamination with mouse DNA, we also designed and used a mouse-specific DNA PCR test. Detailed phylogenetic analysis was used to infer evolutionary relationships. RNase L typing showed that 9.3% were homozygous (QQ) for the R462Q RNase L mutation, while 45.6% and 45.1% were homozygous or heterozygous, respectively. Serologic testing was performed by a WB test. Three of 162 (1.9%) prostate tissue DNA were PCR-positive for XMRV and had undetectable mouse DNA. None was homozygous for the QQ mutation. Plasma from all three persons was negative for viral RNA by RT-PCR. All 162 patients were WB negative. Phylogenetic analysis inferred a distinct XMRV.

 

[eric_s]

Yes, i find it interesting as well and i think there's no problem for you to post here, even though you don't have ME/CFS... Or is there? I don't think anyone here minds good contributions.

As i've said on the other thread, this does seem to contradict Switzer's ME/CFS studies and the "it's all contamination and should be left behind" point of view. And i love if "the other side" is contradicting themselves :tongue:

See those Switzer studies:
http://www.ncbi.nlm.nih.gov/pubmed/21342521

we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS.

http://www.ncbi.nlm.nih.gov/pubmed/20594299

DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative.

So they have tested 234 subjects and 0 were positive. Assuming a prevalence of 1.9% and that those were different subjects in the two studies, the chance for this to happen is probably quite small, i don't want to do the calculation at the moment, though, maybe somebody else can do it.

So either it's found more often in prostate cancer than in the general population and then i don't really see how they could say there's no association or XMRV doesn't occur everywhere.
Or then either the negative studies or the latest, positive, one can't be right. Correct?

 

[omerbasket]

We knew about this finding some time ago.
I wonder: Switzer seems not to believe that his samples were contaminated. And he DID find XMRV (or something very realted to it) in 3 samples. So, does Switzer believe that XMRV is not a human infection, and is just a result of mouse contamination? Because if so, than his study was contaminated (and he seems to believe it wasn't). And if he does not believe that - well, than his thought is significantly different than Coffin's thought.
So, it seems that Switzer and Coffin does not agree - even if they would agree that XMRV is not pathogenic (by the way, I believe that even if it was found in just one of those patients - if it's real, it might be pathogenic in that patient. So it would be reliable for about 1/162 cases of prostate cancer - but that also gives you, probably, hundreds of thousands of sick people, at least).

 

[eric_s]

It's the same as with the latest study by Ila Singh. She now has studies out that probably contradict each other and for Switzer it's the same.

So i guess they will have to discard one part of them. Either the positive prostate cancer ones or the negative ME/CFS ones.
They should now please go back to work and tell us which it will be...

And the good thing is that even if you're paranoid there's no reason to assume any male researcher would call the association between XMRV and prostate cancer non-existent, if he's not sure about that. Nobody wants to get cancer.

 

[currer]

Feel free to post here RRM. I dont mind if you're not a patient! I know lots of people who are not patients and even talk to some of them!

 

[omerbasket]

I think you'd be surprised, eric, if you knew how many people are willing to take a small risk for their health (and if it's "just" inm 3/162 prostate cancer patients, and prostate cancer patients are also, after all, a minority in the population - then statistically the risk is pretty much small) in order to gain other things (not only money).

 

[eric_s]

The other studies have yielded numbers that are higher than 3/162. And prostate cancer is the third most common cause of death for men in the USA. And even if you survive it the surgeries are no fun.

 

[WillowJ]

thanks for this info; it is interesting and I haven't had the time/energy to follow the studies lately so I hadn't seen that yet.

and, yes, RRM, you're welcome to post here. I'm not sure if you're a scientist or another person who follows the studies, but either way you're welcome to continue discussion if you'd like to do so. We have a couple of other researchers and physicians (who are not also patients) here on the forum, at least one who is here a lot and shares a wealth of knowledge, and we appreciate that immensely.

 

[currer]

My concentration isn't good today so I'll keep it short, but this paper found much greater diversity in the xmrv sequences it found, even though it didn't find many. They sequenced all of them.

So XMRV cannot be a contaminant from an infected cell-line but a variable mutating wild virus, replicating in humans.
In fact the paper concludes that these findings are consistent with the variation to be expected in a wild replicating virus.

So the theory about pre-XMRV 1 and 2 doesnt fit, nor does the theory of infection from the 22rv1 cell line, and neither do all the theories based on the supposed lack of variation in this virus. Also all the theories based on the assumption that it exists only as a laboratory contaminant will need to be revised because of the variability found in this study.

It also states that all the patients (even the XMRV positive ones) were antibody negative and had no detectable virus in plasma (!)

Despite its bland title this paper is a reversal of all the previous ideas on XMRV. A bit of a bombshell.
It deserves more notice. Read it.

PS can someone check my interpretation. I've had a very busy few days and cant think clearly but I think I have made sense out of this.

So where do we go from here?

 

[eric_s]

I agree with you, Currer.

Where do we go from here? Not draw quick conclusions and not be satisfied until we are sure we know the truth about XMRV. That's my position.

I would like to see the assays from the negative studies (Dr. Singh and Bill Switzer) be used on the subjects they have found positive. That would be interesting, unless i'm making some logical error here. And under blinded conditions.

 

[Bob]

It also states that all the patients (even the XMRV positive ones) were antibody negative and had no virus in plasma.!

And then they give a suggested possible reason for this, which suggests that they are happy with the conclusion that some of these patients were indeed infected with XMRV, which is interesting:

The finding of undetectable antibodies and viremia in all three patients may reflect latent infection.

And then, in the 'Discussion' section, they go on to say:

Loss of antibody during a latent infection, while atypical of most retroviral infections, has been described previously for natural infection of macaques with simian type D retroviruses (SRV)

Our results are also consistent with those seen recently in macaques experimentally infected with XMRV in which tissues at necropsy are PCR-positive but viremia and detection of provirus in PBMCs disappear quickly, followed by loss of antibody detection

And this is an interesting admission about the possibility of low copy numbers, in relation to low detection rates:

Additional testing of DNA extracted from another prostate tissue section of 6203 was repeatedly negative, likely reflecting an uneven distribution of low copy XMRV in this tissue.

Here's a bit about viral diversity:

a viral strain in three prostate cancer patients that is distinct from the XMRV seen in previous studies is significant and demonstrates a broader viral diversity

And an interestingly positive note to finish on:

...more work is needed to better understand the prevalence of XMRV and MLVs in humans and their role in human disease.

This seems like a very significant study, especially because it is from the CDC... And the attitude of the authors in the discussion is really upfront, honest and positive... It seems to reflect a genuine curiosity and a desire to find out more... It's really refreshing...

I don't understand why we haven't made more of this study... I've not even seen it before.

ETA: Ah, it's a brand new publication... It was published this week, on 4th May 2011.

 

[Bob]

Here's a link to download a free copy of the paper as a PDF, in case it's useful:
http://www.plosone.org/article/fetc....1371/journal.pone.0019065&representation=PDF

 

[alex3619]

So they have tested 234 subjects and 0 were positive. Assuming a prevalence of 1.9% and that those were different subjects in the two studies, the chance for this to happen is probably quite small, i don't want to do the calculation at the moment, though, maybe somebody else can do it.

So either it's found more often in prostate cancer than in the general population and then i don't really see how they could say there's no association or XMRV doesn't occur everywhere.
Or then either the negative studies or the latest, positive, one can't be right. Correct?

Hi eric_s, I haven't commented on these posts from you because they were self evidently a logical conclusion, and didn't need commenting. The studies that cannot find XMRV in controls at even a low background rate are highly suspect.

Let me recap:
1. XMRV is a real replicating retrovirus.
2. XMRV can infect humans.
3. XMRV has a very high probability of existing in a moderate background rate in the general population. Switzer's prostate patient prevalence rate is close to the early Japanese general population prevalence rate.
4. Therefore any large group of controls will have some XMRV to a high order of probability. This is not just one zero-zero study, there are quite a few now.
5. Failure to detect XMRV in any large control group, or even any large ME/CFS group, it therefore a statistical anomaly.

I have said it before, and it is worth repeating, there is something very strange about XMRV. I think we are in for a few surprises before this is over. It would not surprise me if high levels of lmw RNaseL can affect testing if handled certain ways or not others - or some other explanation. A whole family of viruses with different geographical distribution is also a possibility. Yes, that does leave the door open for contamination theories, but the requirements for contamination to be correct, explaining all the findings, are growing enormously - contamination is at least as unlikely as association at this point. This is the kind of puzzle that will lead to a few books in the future, regardless of how it turns out.

Bye
Alex

 

[Bob]

This study gets more interesting the more I read it and think about it.
The most interesting thing is Switzer's (i.e. the CDC's) attitude towards XMRV.

Switzer is now saying that, despite all of the negative research to date, the XMRV that he has detected looks like a real human virus, and is not mouse contamination, is not lab contamination, and is not contamination from a cell line. The virus is from the patients themselves.

He also admits that he is at the limits of detection which is why he can't always detect the virus. He says that absence of virus in the blood and absence of antibodies is due to biological reasons, not because there isn't any virus.

And he has detected entirely new strains of XMRV, which are not the same as the ones found growing in the cell line, and that "This would be an expected result consistent with virus evolution during spread and persistence." In other words, this is a real wild human virus.

And he says that more research is needed, and desirable.
This seems like a really significant study, partly because it's coming from the CDC.

 

[eric_s]

Yes, i totally agree, but we should hear the alarm bell. We should not be separated from prostate cancer patients and left behind, in case we have the same virus.
When that fear was first voiced, maybe half a year back or a bit more, i was not really sharing it. Now there appears to be that danger.

 

[currer]

Yes, I agree with you Bob.
Like you I thought the tone of the discussion elements in the paper very fair and scientific. I thought it a good quality paper. As far as I can see it demolishes all the previous contamination theories at a stroke. Surely that is highly significant.

But there seems only to be the three of us here! Everyone else is on other threads!

I think people cant take getting interested in XMRV again - it is too much of a rollercoaster.

 

[Bob]

Yes, i totally agree, but we should hear the alarm bell. We should not be separated from prostate cancer patients and left behind, in case we have the same virus.
When that fear was first voiced, maybe half a year back or a bit more, i was not really sharing it. Now there appears to be that danger.

I think that if Switzer is honestly investigating XMRV, in any patients, and actually learning about the virus and how to detect it, then this goes in our favour. I share your fears, but I believe that this is all positive news for us.

 

[eric_s]

But Switzer earlier on has published studies concluding there is no association between XMRV and ME/CFS.
For Ila Singh it's the same, prostate cancer (+), ME/CFS (-).

Ila Singh now says, as you can read in the article on CFS Central, that she believes there is XMRV in prostate cancer, but not in ME/CFS.
Who tells you Switzer will not do the same. It seems a real risk to me. And he's from the CDC. What they say matters.

I agree about it being positive news, but not necessarily because of what Switzer is going to make of it, but because it hints the 0/0 studies might not allow to draw any conclusion.

 

[Bob]

Yes, I agree with you Bob.
Like you I thought the tone of the discussion elements in the paper very fair and scientific. I thought it a good quality paper. As far as I can see it demolishes all the previous contamination theories at a stroke. Surely that is highly significant.

Yes, I totally agree with you currer.

But there seems only to be the three of us here! Everyone else is on other threads!

Yes, everyone is distracted by Singh's negative study. I've posted a link to this thread in the Singh threads, so hopefully people will come and look.

I think people cant take getting interested in XMRV again - it is too much of a rollercoaster.

Yes, people are understandably getting frustrated by the ups and downs (well, mainly the downs), but the XMRV research was always going to be slow and difficult.

 

[currer]

Eric, I think we have to start by investigating XMRV itself. This was a good paper and increases our knowledge of the XMRV strains out there. This will have implications for both prostate and ME research but it will take time to inveatigate. I'm glad he said they should do further research.
It offers a reason (variability) as to why the 0-0 studies reach the conclusion they do and that applies to ME/CFS as much as any other disease they investigate.