MS and Cancer

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MS and Cancer

Postby jana » Tue Jun 19, 2007 1:06 pm

I heard, that occurrence of cancer is much lower at people with ms. But I personally think, it´s nonsense, isn´t it? Can it have some scientific explanation? Is there any paper on this topic? Do not you know?

It would be sufficient satisfaction (for me at least). Over 27% of all death in Czech Republic is of cancer!
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Postby dignan » Tue Jun 19, 2007 2:07 pm

This thread from last summer addresses MS and cancer. Hope you find it interesting.

http://www.thisisms.com/ftopict-2685.html
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Postby Lyon » Tue Jun 19, 2007 2:42 pm

Hi jana,
BioDocFL would probably be the perfect person to give an opinion on that one because he works with cancer, but I haven't seen Wesley around here in a while.

A LONG time ago I read a magazine article based on research of the time and it said that rates of throat cancer were much higher in people who drank scalding hot tea and coffee, which was a particular concern for me because my Mom is a coffee drinker.

The article went on to say that cancer cells are an abnormal mutation of human cells and the reasoning for the higher cancer rates among scalding coffee drinkers was because they were injuring their throats in an ongoing daily basis. Obviously with an ongoing injury the body is constantly having to repair itself which requires constantly producing new cells for the repairs. The higher the number of cells your body has to make, the higher the odds that a mutant cell is going to be created and replicate.

With the above in mind, I've always thought that people with autoimmune diseases would be more likely to experience cancer at the site of self reactivity. I don't know of any specific research regarding MS and brain cancer but I do know that it's come out in recent years that people with inflammatory bowel disease (Crohn's and Ulcerative Colitis--both autoimmune) are much more likely to experience cancer of the digestive tract as are people with ignored heartburn/stomach ulcers.

Your guess is as good as anyone else's on this one but if there is any reason to think that people with MS have a lower cancer rate I would love to hear the reasoning!

Bob
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Postby Loriyas » Tue Jun 19, 2007 3:07 pm

Jana
I'm the one who questioned MS and cancer last summer because I was diagnosed with breast cancer then. I caught it early, had surgery, radiation and am considered "cured" if that is the right word to call it. No evidence of it at the site, at least not now. I researched as much as I could at the time trying to find some kind of connection and was unable to find any. It seemed to me, from what I found, that one had nothing (or very little) to do with the other. That is just what I found at the time, and to be honest, I stopped researching after I had dealt with all of that. I had just had enough of everything and wanted to get back to "normal". Maybe others have found some additional information in the meantime. If I come up with anything that I learned last year, I will let you know.

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Postby Lyon » Tue Jun 19, 2007 3:18 pm

Jana,
You are correct in that there is a study investigating the situation http://tinyurl.com/38k8bo

This is from 2006 Multiple Sclerosis Magazine "Oral Presentations-young researchers-session I"???

P475
Cancer incidence in multiple sclerosis: annual report of the
CARIMS cohort
C. Lebrun, M. Debouverie, P. Vermersch, P. Clavelou, L. Rumbach, J.
Deseze, G. Defer, D. Aufauvre, R. Deschamps, F. Berthier, A. Danzon on
behalf of the Club Francophone de la SEP
Background: Controversial results have been published between
cancer risk was not increased but female MS patients has an
increased risk of breast cancer. All except one published studies do
not consider potential risk factors such as medication, smoking and
diet. Objective: To evaluate Cancer Risk In Multiple Sclerosis
Cohort (CARIMS). To collect and study in 8 French MS centers the
patients’ profil with an history of cancer and multiple sclerosis.
Methods: Prospective study on MS patients with a documented
oncological event. Standardized incidence ratios were assessed to
compare observed number of cancer with expected in the general
population, as measure of relative risk. Data from the FRANCIM
network of French population-based Cancer Registries (available
from period 1975  2000) were used as reference. Results: 7322
MS patients were gathered: 117 patients (1,6%) with definite MS and
cancer; 100 women, 17 men with mean age at MS diagnosis: 37 yrs,
compared to 32.4 yr for the non cancer patients (pB/0.0001). MS
forms were RR 64%, SP 34%, PP 19%. Mean age at cancer diagnosis
was 46.2 yr. 17 patients had an history of cancer before MS
diagnosis and 100 after MS diagnosis. 22 patients (19%) had familial
relevant history of cancer and 5 of MS. Cancer was diagnosed in 53
patients (47%) without history of modifying disease treatments.
Histologies were breast cancer (37%), gynecologic: ovarian, cervix,
uterin (24%), skin (9%), acute leukemia (5%), colonic (6%), kidney
and bladder (5%), lung (2.6%), digestive (2.6%). Cancer’s location and frequencies had no specificity compared with non MS patients,
excepted for the age incidence. Free interval from MS diagnosis to
cancer was 7.3 yrs (/23//34). Female patients had more cancers
than males (RR: 2.35 vs; p/0.0022). PP and SP patients had a higher
cancer risk than RR patients (RR: 2.03; p/0.0004). Standardized
incidence rates calculated for all MS associated with cancer were
0.11 for men and 0.67 for women. Conclusions: According to the
recent literature, overall incidence of cancer in our MS population is
lower than expected in the general population. Matched to age,
gender, MS form and histologies of French Cancer Registry, cancer
in MS is associated with young age, female gender, SPMS form and
familial history of cancer.

Pubmed also spit these two out http://tinyurl.com/2qz2qx
http://tinyurl.com/2sho8r
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Postby Wonderfulworld » Wed Jun 20, 2007 5:06 am

Bob
I think your theory about ongoing injury to a portion of your body and the connection to cancer may be correct - at least in the case of coeliac disease anyway. I also have coeliac disease and bowel cancer risk is much higher in coeliacs - and it is your bowel that is damaged, the villi get flattened and destroyed if you eat glutn - so there seems to be a lot of sense in what you're saying,
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Postby CureOrBust » Wed Jun 20, 2007 5:29 am

Background: Controversial results have been published between
cancer risk was not increased but female MS patients has an
increased risk of breast cancer
Didn't I recently read a post that Vitamin D reduces the risk of brest cancer? and arent MS patients normally D defficient? so it would seem to me the two may be connected.
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Postby TwistedHelix » Wed Jun 20, 2007 6:35 am

Hello Jana,
There doesn't seem to be a huge amount of research in this area, perhaps because the statistics don't point in any obvious direction – people with MS don't appear to have much difference in their cancer risk from the general population. In the UK around 30 per cent is the national average lifetime risk of cancer. With MS, there is a slightly lower general risk and a slightly higher breast cancer risk. This quote from the centres for disease control in America is typically vague
"Dr. Matthew M. Zack of the Division of Chronic Disease and Health Promotion for the Centers for Disease Control and Prevention has provided extensive references from MEDLINE that show studies of the risk of cancer associated with multiple sclerosis since 1966.
One study from Norway has found an increased risk for breast cancer in multiple sclerosis patients. Another study found an increased risk for cancers in multiple sclerosis patients due to one type of treatment for multiple sclerosis. Other studies found no association or a decreased risk for all cancers in multiple sclerosis patients. Still other studies are more speculative hypotheses that need further testing to be conclusive."

Some people think that immunosuppressive drugs remove part of the body's natural defences against cancer cells.

I think that if there was an obvious link between MS and cancer it would have been much more widely discussed by now.
Lori, I wasn't a regular visitor last year so I didn't know about your illness. I am so pleased you caught it early and you're doing so well -long may it continue!
Dom
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Postby jana » Wed Jun 20, 2007 9:06 am

Thanks for interesting answers. I´m much cleverer now. Loriyas thanks, with others I hope the cancer is away forever!
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Postby BioDocFL » Wed Jun 20, 2007 10:14 am

I don't think I can add much to the MS/cancer question. However, my mother had rheumatoid arthritis & Sjogren's syndrome for over 20 years, was on prednisone and hormone replacement therapy, and who knows what all. She eventually died after a 5 year battle with breast cancer. I don't know how all that relates between the autoimmune diseases, breast cancer, and the therapies for both. As she was battling the cancer she said her arthritis problems slacked off. Probably just an overall numbing effect of the cancer treatment on her immune system.
I tend to think similar mechanisms are possible in MS and some cancers at the cellular level. It is just that when the mechanism occurs in mature cells like oligodendrocytes that are more posed for cell death than proliferation, then you get an autoimmune response to the debris from the cell death. In less mature cells where the cell is posed for further proliferation, then the mechanism can lead to uncontrolled cell replication as in cancer.
The mechanism I am interested in would be disruption of the epigenetic control of the X chromosome, especially the X that is supposed to be inactivated. With 2 X chromosomes in a female cell and only one is needed (for the most part), the other one is inactivated (for the most part) to give gene expression equivalent to male cells which only have one X. If something happens to the X inactivation process, there could be overexpression of X-linked genes. I have suggested polyamine-related genes on the X. Polyamines are elevated in most cancers and appear to have a role in autoimmune diseases. I have been talking previously about polyamine genes on the short arm (P) of the X chromosome. how they could become overexpressed. There is also a so-called pseudo-gene of S-adenosylmethionine decarboxylase (SAMDC) on the long arm, (at Q28) that is becoming very interesting. Apparently it codes for a functional, intronless copy of SAMDC that is potentially even more active than the normally expressed SAMDC (which I think is on chromosome 6 or 8, can't remember) when expressed. I would imagine this pseudo-gene (but apparently a real gene) is like an alarm and is not normally expressed from either X. But if it suddenly gets expressed from disruption of the X, it would not need to be spliced (removal of introns) and could go right to work converting SAM to decarboxylated SAM (dcSAM). dcSAM is used for polyamine synthesis whereas the SAM is needed for histone and DNA methylation, gene silencing. I think this could be quite a turning point in the cell, leading either to uncontrolled replication or cell death. There are a lot of other events that could be occurring simultaneously with this disruption. With this reduction in the available SAM for gene silencing, you could have activation of other genes that aren't normally expressed, such as endogenous reverse transcriptases. One of the primary RNA transcripts that the reverse transcriptases would pick up are Alu sequences. There is an increase in Alu DNA in the serum of lupus patients and there are autoantibodies directed at Alu DNA in lupus patients.
I'm trying to get time to write up another hypothesis article on my ideas but I want to send it to a different journal this time. It is getting so complicated that I think I need to write a book on it but I am just very busy. I have not been satisfied with any of the published literature as to how the X chromosome could be involved in autoimmune diseases. Typically there is discussion of skewing of X inactivation (whether the father's or the mother's X is chosen more often for inactivation) and how that skewing might lead to autoimmune diseases but even that topic has not been conclusive. I think the whole areas of X chromosome fragmentation, aneuploidy, and epigenetic disruption need to be addressed, and not just in terms of X-linked immune system genes.
What is interesting in working in cancer research is that many of the projects are relevant to autoimmune research. Some of the projects I am involved in are on histone deacetylases and histone methyltransferases, S-adenosylmethionine decarboxylase, and vitamin D receptor. We are trying to find inhibitors and sometimes enhancers of cancer-related proteins, either for new drugs or at least for mechanistic studies to see what happens when you inhibit or enhance the protein activity in a cell culture.
Anyway, time to get back to work.

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Postby TwistedHelix » Wed Jun 20, 2007 11:17 am

Hello Wesley, you're obviously a busy and phenomenally well informed man; thank you for sparing some of your time to share your knowledge with us.
I've only read through your post once and I'm going to have to look most of the words up, but my initial reaction is this: could the involvement of the X chromosome by the beginnings of an explanation for the sex bias in autoimmune diseases?
Just the musings of an uninformed mind.
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Postby BioDocFL » Wed Jun 20, 2007 12:21 pm

That's been my thoughts on it. The female bias of MS (and lupus, RA) suggests the X chromosome or hormones. The fact that females have an extra X that is 70% inactivated means there is a vulnerability of reactivation of portions of it. As a result there could be overexpression of some X-linked genes since now you would have two copies of the gene active. For some genes, such as polyamine synthesis genes, this could cause an imbalance in some precursors like SAM that is needed for gene silencing via DNA or histone methylation.
The fact that Klinefelter's syndrome males (XXY) have a higher incidence of lupus than normal males (XY) suggests the extra X chromosome is suspect. In Klinefelter's the extra X is normally inactivated, but in Klinefelter's with lupus, my thought is that the extra X has had some reactivation, leading to overexpression of X-linked genes.
In some cases where normal males get autoimmune diseases, it could be because of fragmentation of their one X chromosome or aberrant duplication of all or part of their X, leading to daughter cells that inherit extra segments or copies of the X. The result is a cell with overexpression of X-linked genes. I've cited some previous work by an Italian group that found increased chromosomal abnormalities in MS patients versus controls, and many of the abnormalities related to the X. I have also cited previously cases of mothers with X-linked chronic granulomatous disease (mutations at Xp21.2) whose sons have lupus-like symptoms. Xp21.2 lies between the X-inactivation center (Xq13) where inactivation initiates and Xp22.1 where some polyamine genes are. The mutations sometimes have led to duplication of Xp21.2-Xpterminal, thus duplicating Xp22.1. Alternatively, fragmentation separating Xq13 from Xp22.1 could lead to overexpression of the Xp22.1 genes. The pseudo-gene of SAM decarboxylase I mentioned is at Xq28, towards the end of the long arm. So it might escape X-inactivation is some cases leading to its overexpression.
Cancers are complicated, multi-step diseases with initial initiation, progression, invasion allowing the tumor cells to push into other tissues, loss of adhesion allowing for the tumor cells to move to new sites in the body, angiogenesis allowing the tumor to grow additional blood vessels in its mass to support its needs. We can try attacking each of these steps in fighting cancer.
Autoimmune diseases are also complicated, multi-step. The immune response may be a later event. It can be targeted but there are probably earlier events that could also be targeted and have more impact. My feeling is that any polyamine gene overexpression could be a good early target. MTA (methylthioadenosine) has been shown to block neurodegeneration in a mouse model. It is also a known inhibitor of spermine synthase, one of the genes at Xp22.1 I have spoken of before. Also, there are two mouse strains, Jimpy and Quaking, that have progressive neurodegeneration. It was shown that there is an imbalance in the ratio of the polyamines: spermidine and spermine in these mice that gets progressively worse. DFMO (difluoromethyl ornithine) has been shown to suppress lupus in mouse models. DFMO inhibits ornithine decarboxylase, one of the key initial enzymes in polyamine synthesis.
I've discussed before how I think polyamines can interact with things like DNA and generate auto-antigenic complexes. Polyamines (especially spermine) can stabilize Z-DNA conformations (lefthanded coiling as opposed to the usual righthanded B-DNA conformation). Z-DNA sequences (and G-C rich sequences that can form Z-DNA) are frequent targets in lupus patients.
I could keep going but... back to work with me.

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Postby Lyon » Wed Jun 20, 2007 2:21 pm

Hi Wesley,

I wasn't sure if you even came this way anymore! Thanks for posting and good to hear from you again.

The first I've heard of Klinefelter's syndrome is your mention of it above so I'm pretty naive. Is there a chance that males with MS might have the extra X chromosone and not show active signs, or if a male has the extra X chromosone it's immediately and obviously noticeable?

Bob
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Postby BioDocFL » Wed Jun 20, 2007 2:57 pm

Most males with MS probably do not have Klinefelter's. It is somewhat obvious by feministic features. I can't give you a specific list on all of them without blushing. But a chromosomal analysis with markers for the X chromosome would confirm the syndrome. And most Klinefelter's patients do not have extensive autoimmune problems but you might see it noted as an aspect of the syndrome in overall descriptions of Klinefelter's. It is just one of those tidbits of information in our overall medical knowledge base that gives hints from one syndrome or disease as to what is going on in another disease. We should use diseases against each other, knowledge-wise. That is why I keep harping on comparing MS and lupus especially, but also cancer and autoimmune diseases. There are even cases where we have successfully used one real infection (cow pox) to fight another disease (small pox).
I think with many male MS patients (and with many female MS patients) there might be something going on with the X in a few cells that is leading to cell death, which gets magnified into a lesion when it is a few key oligodendrocytes at a key nerve bundle. The X chromosome may be fragmented or somehow unable to maintain the normal control on gene expression. Perhaps it is some latent EBV viral gene expression or some other virus or perhaps it was some heavy metal exposure that has caused DNA damage. Normally DNA is repaired efficiently but there can be interference with the process. When we grow cell cultures starting with normal cells and look at the chromosomes in them, they can vary as to the number of copies and fragments. Of course cell culture is a very stressful, abnormal environment for cells but something similar might happen in the body on rare occasions. The inactive X chromosome is especially hard for accessing by the DNA repair enzymes since the inactive X (Barr body) is usually off to the periphery of the nucleus away from the other chromsomes and the inactive X replicates later than the other chromosomes. I am thinking it might replicate too late for problems to be caught by the cell's cell cycle checkpoints.
So, to make a short story long, I don't think male MS patients have an extra X chromosome in all their cells but might have perhaps an uneven inheritance of X chromosome gene expression due to fragmentation or disruption in a few cells. It's really a difficult thing to research though since it would occur so infrequently in an individual. Even in a lesion and surrounding it, there may be little hint of what originally occurred since the abberant cells may have long died off and been disposed of.

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Postby Lyon » Wed Jun 20, 2007 3:58 pm

Hi Wesley.

Yet another wake-up call that there are no easy answers when it comes to MS!

As someone interested in the "loss of evolutionary normal conditions" as a possible precurser to autoimmune disease I've also wondered if cancer, or some cancers don't owe their increases in per capita incidence to some of the same underlying circumstances.

Interesting stuff! I hope I live long enough to know some of the answers.

Bob
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