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 ^[1] 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 ^[2] in the United Kingdom or the research study in Nature Genetics ^[3] (abstract).