Scientists at The Institute of Cancer Research in London have been the first to identify specific genes that may underlie inheritable risk in myeloma, in a study funded by Myeloma UK. This research, which was recently published in the prestigious journal Nature Genetics, takes a critical step forward in understanding how myeloma develops and provides opportunities for development of new anti-myeloma treatments.

The likelihood of anyone developing myeloma in the UK is about 4 in 100,000. In the last few years there have been a number of studies to show an increased risk of myeloma in relatives of patients with MGUS and myeloma. This evidence suggests that the risk for relatives is thought to be doubled, this increases the risk to about 8 in every 100,000.

Since the risk of developing myeloma still remains very low, even in relatives, it is unlikely that the findings from this study would ever be used to predict that a person will develop myeloma. Instead these data provide important insights into how myeloma arises and progresses, by identifying new and important biological pathways.

Population and genetic studies to date have shown that myeloma is likely to be influenced by a large number of gene mutations which individually have little impact, but together can have a significant impact on the onset and progression of myeloma.

Based on this understanding, the study recently published in Nature Genetics was designed to look at DNA variation across the whole genome (GWAS), giving the opportunity to make new associations between DNA mutations and myeloma.

Samples, including 1,371 from Myeloma IX patients were used for the study and compared to control samples from people who did not have myeloma. This important study has revealed biological pathways connected to myeloma which may send scientists in new research directions.

Specifically, two genetic mutations were found to be associated with myeloma. One of the genes implicated: ULK4, may be involved in cancer suppression, by a biological pathway that has not previously been connected to myeloma. Another of the genes CDCA7L, has not previously been connected to myeloma itself, but interacts with MYC, a molecule with a well established role in cancer progression.

Prof Richard Houlston who conducted this study said, “Compared to other cancer types, relatively little is known about the biological processes that cause myeloma. By identifying these genetic variants, we are closer to understanding how this cancer develops.”

Prof Gareth Morgan who oversees the Personalised Medicine Programme said, “This is a very exciting study, which allows us to start to understand the early events that lead to the development of myeloma, and in the future may be used to develop more effective treatments for patients.”

This study was part of a wider Myeloma UK funded research initiative at the Institute of Cancer Research looking at approaches for personalised medicine.

If you have any questions on this research or any other aspects of myeloma, please call our Infoline on 0800 980 3332, or speak to your consultant haematologist.

Q&A

What is GWAS?

GWAS stands for genome-wide association studies and is a method used in genetic research to find genetic variations linked to particular diseases. It involves the systematic scanning of the entire genetic material (genome) of individuals to search for specific genetic differences between different groups of people.

The human genome consists of all of our genes (made up of DNA) arranged in 23 pairs of chromosomes, which together make up the blueprint of life that determines how the body develops, grows and functions. While the human genome is mostly the same in everyone, slight differences exist across many of our genes that are passed from one generation to another. These are responsible for characteristic features or traits of an individual - some are obvious e.g. eye colour, others less so, e.g. the susceptibility to certain diseases.

GWAS is a method used to compare the genomes of two populations; people with a particular disease and people without the disease, to try to identify the genetic variations between them. If certain genetic variations are more frequent in people with the disease compared to people without the disease, then the genetic variations are said to be “associated” with the disease.

Why are genetic variations important in myeloma?

Many diseases such as cancer, asthma, heart disease and mental illness, are caused by a combination of genetic variations dotted throughout the genome. The same is true for myeloma but in myeloma the genetic variation from one myeloma patient to another is huge and is the reason why it is often described as being a very individual cancer.

However, certain variations may be common to all or subgroups of myeloma patients. These common variations may explain in part why some patients, for example: are at an increased risk of the cancer; are resistant to a particular treatment or are susceptible to a treatment side-effect. Identifying these genetic variations will lead to a better understanding of myeloma and possibly to the development of better ways of screening, diagnosing, treating or preventing it.

What is the significance of this GWAS?

This GWAS is significant for a number of reasons: 

• It is the first GWAS to be conducted specifically in myeloma patients
• It is the first time genetic variations have been linked to a significant increased risk of myeloma
• It has identified the potential involvement of new biological pathways in myeloma
• It may help to identify new targets for the development of novel treatments
• It may explain why the risk of developing myeloma seems to be higher in some families
• It provides the impetus for additional GWAS to identify further genetic variations relevant in myeloma

So does this mean that myeloma is an inherited cancer?

It does, but not in the traditional inherited disease sense where the inherited gene is actually the cause of the disease. It has been known for some time that there is a slightly greater incidence of myeloma in some families, but the reason for this has not previously been identified.

The results of this GWAS suggest that inherited genetic variations may be involved, but rather than causing the myeloma they appear to correlate with an increased risk instead. This means that other as yet unknown genetic variations which may or may not be inherited and/or other environmental factors are needed before myeloma develops.

How can patients get involved in future GWAS?

To carry out GWAS, researchers need to get hold of patient samples (blood, bone marrow biopsies) and this is one way in which patients can contribute to ongoing and future research.

This can be done in the context of a clinical study where everyone taking part may be asked if they wish to provide samples for genetic research. This is currently an option for all myeloma patients enrolled in the national Myeloma XI study.

Under normal circumstances, patients can also agree to have their samples used for research purposes. Once the patient has signed a consent form, samples are taken and may be sent to one of the major research centres such as The Institute of Cancer Research where a Myeloma Biobank has been set up specifically for the storage of samples from myeloma patients for future research.