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Genetic Differences Linked To Increased Risk Of Multiple Myeloma

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Published: Nov 28, 2011 3:58 pm

A team of British and German researchers have identified specific areas of the human genome that consistently differ between people with multiple myeloma and people who do not have the disease.

The new findings, summarized in a research article published yesterday, help explain why the risk of developing myeloma seems to be higher in some families than in others.

Moreover, by clearly identifying regions of the human genome linked to an increased risk of myeloma, the European research could lead to better treatments for myeloma and better tools for diagnosing the disease.

“This study is the first one to explore with enough statistical power the issue of genetic association and risk for myeloma,” Dr. Rafael Fonseca of the Mayo Clinic in Scottsdale, Arizona, told The Beacon.

“The study is very intriguing and has the potential to lead to new avenues for research [and] new therapeutic options,” added Dr. Fonseca, who was not directly involved in the recently published research.

Background And Design Of The Study

It has been known for some time that relatives of myeloma patients are several times more likely to develop the disease than members of the general population (see related Beacon resource article).  This finding has been viewed as strong evidence in favor of a genetic role in the development of myeloma.

It has not been clear, however, what genes are particularly associated with an increased risk for myeloma.

The German and British researchers therefore decided to see if such a link could be demonstrated through a “genome-wide association study.”

Genome-wide association studies compare the genetic makeup of people with a particular disease - for example, myeloma - to the genetic makeup of a control group of people who do not have the disease.

This comparison makes it possible to determine what genetic differences are most associated with the disease being investigated.

In the case of the newly published research, the study authors compared detailed genetic information for four samples of individuals – two samples of myeloma patients (one British and one German), and two “control” samples of people without any signs of myeloma (again, one British and one German).

Overall, the authors of the new study worked with DNA data for about 1,700 myeloma patients and almost 6,000 people without myeloma.

To determine which genetic differences were particularly associated with myeloma, the researchers took a three-step approach.

First, they looked for statistically significant genetic differences within each pair of national patient samples.  They compared the DNA of the British myeloma patients with the DNA of the British control group, and they compared the DNA of the German myeloma patients with the German control group.

Next, they did a combined comparison of data for all myeloma patients (German and British together) with data for all patients with no signs of myeloma (again, German and British patients from both countries).

These first two steps identified 19 very specific variations of the human genome that were different between the myeloma patients and control patient samples.  These 19 variations are all contained within three broad genetic regions known as 3p22.1, 7p15.3, and 2p23.3.

Finally, the researchers tested whether the 19 specific genetic variations they initially identified could be confirmed as statistically significant by a comparison of DNA data from two additional patient samples – another group of British myeloma patients, and a separate control group of British people without signs of myeloma.

Study Findings And Implications

In the end, the study authors found strong evidence that two of the original 19 genetic variations – one in the 3p22.1 region, the other in the 7p15.3 region – are associated with myeloma.

People with either of these genetic variations have a 30 to 40 percent greater chance of developing myeloma than people without the variations, according to the European researchers.

The researchers also believe there is “promising” data that a third genetic variation, in the 2p23.3 region, also is associated with myeloma.  The statistical evidence, however, is not quite as convincing in regard to this variation as it is for the other two.

Overall, the British and German researchers estimate that about 37 percent of myeloma patients of European heritage are likely to have one or more of the three genetic variations identified in their study.

The study authors caution, however, that this 37 percent statistic can be misleading.  It overstates the role of the three genetic variations in the increased risk for myeloma found within certain families.

In reality, the three genetic variations highlighted in the new study account for only 4 percent of the added risk family members of myeloma patients have of developing myeloma.  Other genetic and environmental factors account for the rest of the increased risk.

Nevertheless, the new findings are the first to tie specific variations in the human genome to an increased risk of myeloma.  The findings are likely to lead to more in-depth investigations of how the particular genetic variations identified by the study may play a role in the development, progression, and treatment of myeloma.

In addition, the findings can be expected to lead to additional “genome-wide association” studies – like the European study – to identify further genetic variations relevant to multiple myeloma.

For more information, please see the press release from the Institute of Cancer Research in the United Kingdom or the research study in Nature Genetics (abstract).

Photo by the National Institutes of Health on Wikipedia – some rights reserved.
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14 Comments »

  • Ben S. said:

    The research indicates that 63% of the patients of European heritage do not have any of the three gene variations. What are the other genetic variations, if any, that cause the 67% patients to have the disorder? Can those two or three genetic variations themselves be the result of some unknown, perhaps non-genetic, factors causing the patients to have the disorder in the first place? After call, the research showed ONLY that the 37% of the patients have the variations, but NOT that those variations caused the disorder.

  • Boris Simkovich said:

    Thanks for your questions, Ben. They highlight a number of important issues.

    Based on the data that they have and the statistical testing that they were able to do, the authors of this study could only say with reasonable certainty that the three genetic variations discussed in this article are associated with a higher risk of myeloma.

    The researchers did not list other genetic variations that might be common in myeloma patients because they could not demonstrate statistically that any other genetic variations were tightly enough associated with myeloma to be described as "linked" to the disease.

    This does not mean that other genetic variations don't play a role in the development of myeloma. In fact, there almost certainly are other genetic variations that do play a role

    However, with the data the researchers have right now, they just can't reasonably say that any other variation besides the three they've identified can be linked to myeloma.

    You are absolutely right that the results of this study do not prove that the variations identified by the researchers *cause* myeloma. This kind of study cannot prove that a genetic variation causes myeloma.

    All it can do is say that certain genetic characteristics are so much more common in people with myeloma than in people without myeloma that the difference almost certainly can't be the result of random fluctuations in the data.

    That's why these results are a first step rather than a final destination. They are clues rather than a solution to the mystery.

    Regarding your question as to whether the three variations discussed in this article might "themselves be the result of some unknown, perhaps non-genetic, factors causing the patients to have [myeloma]" ... Well, that's a good question. We wondered about it ourselves as we were writing up our review of the research.

    We believe the authors of the study are comfortable with the view that the genetic variations they've identified are hereditary variations rather than random mutations, and that the variations at least indirectly increase the risk of myeloma, rather than causation running the other way around (that is, myeloma causing the genetic variations).

    However, we've passed along the question to the study authors, and we'll let you know the response that we get.

    Best regards,

    Boris.

  • suzierose said:

    How does the European date correlate with US data?

    When we look at the demographics in Europe we find:

    In Europe, the highest rates are noted in the Nordic countries, the United Kingdom, Switzerland, Italy, and Israel. France, Germany, Austria, and Slovenia have a lower incidence, and developing countries have the lowest incidence.

    Yet when we look at the demographics in America we find:

    The annual incidence per 100,000 population is 6.5 among white men and 4.1 among white women. Among black men and women, the frequency doubles to 13.7 and 10.0, respectively, per 100,000 population. This racial difference is not explained by socioeconomic or environmental factors and is presumably due to unknown genetic factors.

    Would then the human genomic data for MM based on a primarily European population differ significantly from what would be found in the U.S. simply based on the variation of demographic incidence, alone?

  • Boris Simkovich said:

    Hi suzierose,

    Thanks for your question.

    The authors of the study actually touch on issues related to your question, writing "It will be intriguing to explore how our findings translate to non-European populations, which have a lower incidence of ... multiple myeloma."

    They then go on to note that the proportion of people with the three genetic variations identified in their study is very different in European, Chinese, Japanese, and African populations.

    This leads them to wonder whether differences among these ethnic groups in the 2p23.3, 3p22.1 and 7p15.3 genetic regions might actually account for some of the differences in the incidence of myeloma across the ethnic groups.

    But what I think you really are asking with your question is whether the results of this study would have been different if the research had been done with U.S. patients.

    I think the answer to that question is almost certainly "yes." Some of the same genetic variations might have been identified, but perhaps not all of them, and others not found to be significant in the European research might have been found to be significant in a U.S. study.

    I say this because this kind of research requires LOTS of patients to get consistent results. Even with the seemingly large numbers of patients that were included in this study, using a different group of patients would probably lead to somewhat different results.

    That would be particularly true if the different group of patients were U.S. patients, with a more varied genetic background than the British and German patients included in the current study.

    Even though the results might have been different with U.S. patients, that doesn't reduce the value or importance of the study's findings.

    Remember, the real value of this research is how it will help researchers better understand what causes myeloma and what makes the disease progress from one stage to the next. That sort of information is critical for developing new myeloma treatments and, eventually, finding a true cure for the disease.

  • suzierose said:

    Hi Boris,

    Thanks for your well thought out response and the additional details from the article as well . I was only able to look at the abstract which does not breakdown the ethnic groups.

    We know that the lowest incidence of MM globally occurs in Asia and Africa.

    I suspect as you infer, that the 19 variations contained within 3 broad genetic regions could change significantly based on a large population within the U.S .of European and African descent. As, historically, the US population, unlike the European countries, has considerable ethnic mixings of European ethnic groups along with African groups. What we generally refer to as the melting pot.

    I am hopeful that the research is valuable in helping to develop new MM therapies. It just makes me concerned when the database was from such a homogeneous genetic population (European) vs the heterogeneous genetic population that we have in America, given the globally variance of the incidence of MM. In this regard, will the data lead to new therapies or the pursuit of molecular venues that are not truly reflective of the genetics of North America which has a higher incidence of MM vs. Western Europe.

  • Boris Simkovich said:

    Hi Suzierose,

    I think the concerns you raise at the end of your last comment are valid ones. However, this study won't be the only one of its kind. The authors of the study have said that they plan on doing another larger study, and I'm sure other researchers are planning (or already carrying out) similar studies.

    So this study is far from the last word.

    Also, it might be worth mentioning that the researchers of this study explored over 400,000 genetic variations as they were looking for differences that might be linked to an increased risk of myeloma. So they were quite thorough!

    Take care,

    Boris.

  • Suzanne Gay said:

    YIKES! I am 100% Polish! Suzanne

  • Boris Simkovich said:

    Ben,

    We got some feedback from Prof. Richard Houlston in regard to the question you asked. Prof. Houlston designed the European study discussed in this article and was also joint senior author of the paper.

    Prof. Houlston explained that the genetic variations explored in this research are so-called "common" variations generally accepted to be hereditary variations.

    In fact, the title of the research paper is specifically "Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk."

    Thus, it is unlikely that the genetic variations identified during this research are unusual mutations due to (say) environmental factors.

    Similarly, because the paper explored "common" genetic variations, the most likely explanation is that there is some direct or indirect link running from the genetic variations to the myeloma, rather than the other way around (i.e., from the myeloma to the genetic variations).

    We hope that helps.

    And many thanks to Prof. Houlston for his prompt reply to our inquiry and for the valuable research he and his colleagues carried out.

  • Edward S said:

    Hi Boris,

    Does this indicate in your view that Myeloma is a hereditary cancer?

    Many thanks,

    Ed

  • Boris Simkovich said:

    Hi Edward S,

    I think this research is further evidence supporting the view that heredity plays a role in a person's risk of developing cancer.

    I would be very surprised, however, if heredity turns out to be the only factor creating a risk of developing myeloma. There is a lot of evidence that environmental factors also play a role.

    On these issues, let me recommend a few articles.

    First, there was an interesting paper published back in 2006 that looked at Swedish data on family-related risks for developing myeloma. The abstract is very readable and quite interesting:

    http://www.ncbi.nlm.nih.gov/pubmed/16753294

    As for environmental factors and the risk of developing myeloma, The Myeloma Beacon reviewed a number of studies on this issue not long after The Beacon launched. Here are links to a few of the articles:

    http://www.myelomabeacon.com/news/2008/11/20/long-term-exposure-to-benzene-may-increase-risk-of-multiple-myeloma/

    http://www.myelomabeacon.com/news/2009/05/18/formaldehyde-exposure-linked-to-increased-risk-of-multiple-myeloma/

    http://www.myelomabeacon.com/news/2008/11/13/occupation-and-chemical-exposure-linked-to-multiple-myeloma/

    http://www.myelomabeacon.com/news/2009/01/22/chemical-used-in-rubber-synthesis-increases-risk-of-myeloma/

    Best regards,

    Boris.

  • Ben S. said:

    Hi, Boris:

    Thanks for the following-up. Now I have more trust and admiration in the articles the Beacon has written and the fantastic work its staff has been doing.

    I am receptive to Professor Houlston's explanation on "common variations." While I undertand that experiments of this kind are inherently harder to carry out than lab-controlled physics experimentation, I still find the conclusion lacking by the fact that the genetic variations only cover about 37% of the patients, almost a super minority. Hope further researches can dig deeper and spread wider and be more conclusive on the genetic as well as non-genetic factors that play a role in triggering the disorder.

    Best regards.

  • Marti said:

    http://www.nature.com/bmt/journal/v38/n1/full/1705395a.html

    Perhaps someone could explain if the genes discussed in the above article about myeloma with amyloidosis would be inherited.
    Thanks...

  • Boris Simkovich said:

    @Ben S - Thanks for your feedback about the work we're doing here at The Beacon. That's very kind of you.

    As I suggested in some of my earlier comments, there's no question that there still is a lot of research to be done on this topic.

    Perhaps a useful way to think about all of this is to compare it to completing a puzzle.

    When you first start working on a puzzle, you'll have a few pieces connected to each other, but huge amounts of the puzzle will still be left undone. But, to complete the puzzle, you have to start somewhere.

    That's what this research is like. It's connecting some of the first pieces of the puzzle.

    @Marti - Not being an expert, I'm a bit hesitant to respond to your question. However, I believe it safe to say that the genes mentioned near the end of the section titled "Biology and genetics of AL amyloidosis" in the paper you link to are, in fact, genes that can be passed from one generation to another.

    That said, the section I just mentioned isn't discussing the kind of issues covered by the research reviewed in the article up above.

    Instead, the section is discussing two different issues. One issue is chromosomal mutations in plasma cells. The other issue is which genes in plasma cells are more or less active in myeloma patients with, or without, amyloidosis.

    It's not possible from the discussion of these two issues to determine which "common genetic variations" are associated with an increased risk of developing both myeloma and amyloidosis -- which, I think, is what you really want to know.

  • Marti said:

    Thanks so much for your reply...