Research Provides Insight Into Genetic Changes Responsible For Multiple Myeloma (EHA 2012)
In a recent study, an international research team reported several new genetic mutations that may be involved in multiple myeloma. Additionally, the researchers identified genetic changes associated with disease progression.
Dr. Niccolo Bolli from the University of Cambridge in the United Kingdom presented the findings last month at the 17th Congress of the European Hematology Association (EHA).
In multiple myeloma, as with all cancers, cells develop genetic abnormalities known as “mutations.” These mutations can lead to uncontrolled growth and survival of the cancer cells. In multiple myeloma, mutations typically result in the growth of white blood cells that produce abnormal antibodies, thus leading to a weakened immune system.
Genome sequencing can be used to determine the exact makeup of a patient’s genetic information (scientifically referred to as DNA). By comparing the genomic sequence of a healthy cell to the sequence of a cancerous cell, mutations can be identified and studied.
Once mutations associated with multiple myeloma are identified, researchers can develop new treatments targeted at those mutations.
Because myeloma patients generally have different combinations of mutations, the ability to identify a patient’s mutations along with the development of targeted treatments could ultimately lead to more individualized therapy for myeloma patients.
The full genome of a myeloma cell was first sequenced in 2009 (see related Beacon news). Since then, researchers have continued to sequence the genomes of myeloma cells from more patients to better understand which genetic mutations are responsible for multiple myeloma (see related Beacon news).
In the continued quest to better understand the genetic variances responsible for the onset and progression of myeloma, Dr. Bolli and his colleagues sequenced the genomes of 68 multiple myeloma patients. Additionally, multiple DNA samples from 17 of the patients were gathered at different time points, ranging from five to 18 months apart.
The researchers identified 1,803 genes that were mutated in the patients' myeloma cells; 292 of the genes were mutated in multiple patients, suggesting that they play a role in myeloma. The mutations included some of those previously identified by myeloma genome sequencing studies, but several new gene mutations also were identified as being involved in myeloma.
Overall, 97 percent of patients had at least two sets of myeloma cells with different genetic mutations at diagnosis. These results suggest that myeloma is not only a heterogeneous disease across patients, but that each patient has heterogeneous disease.
Of the patients who provided multiple DNA samples available, 80 percent demonstrated shifts over time in the amount of myeloma cells with certain genetic mutations. Additionally, 60 percent of patients acquired more chromosomal additions or deletions. Of these, 44 percent eventually showed evidence of a deleted region in chromosome 17 (known as 17p deletion). The 17p deletion is categorized as a high-risk abnormality that commonly leads to poorer survival outcomes. These results suggest that the new mutations in later samples play a role in disease progression.
For more information, particularly about the different types of genes that were mutated, please see abstract 571 on the EHA Meeting website.
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"Overall, 97 percent of patients had at least two sets of myeloma cells with different genetic mutations at diagnosis. The data suggests that myeloma is not only a heterogeneous disease across patients, but that each patient has heterogeneous disease."
Sooooo....in the first sentence above it's being said that "no two human fingerprints are identical" (analagously) in regard to the heterogeneity of gene expression in MM patients?
And the second sentence is telling us......the same thing?
What am I missing? If there's a practical difference between those two sentences, practical in terms of suggested research and treatment, past or present for MM patients, could someone please expand upon those implications for future research and treatment into MM?
Thanks,
S.
Please answer Steve's highly relevant question.
Steve
If we use your example of fingerprints ..what it means is that none of your 10 fingerprints match.
In addition no other person has your fingerprints. So not only do each of your fingerprints not match they do not match any other inndividual either.
The fact that no 2 of your fingerprints(mutations) match likely accounts 4 drug resistance and makes it far more difficult 2 find effective therapy for MM pts as a whole because the disease is also diverse within tiger group as well as within each individual.
This is different from other diseases where a single mutation is found for all individuals who have the disease. MM is different.
So the practical difference is different drugs would be needed to treat different MM pts since not all patients have the same mutations nor does any one patient have the same mutations in all their MMcells. The mutations are diverse within each individual cells not just between patients.
We see some of this with breasted cancer where some individuals have a HER2 oroothers could have estrogen receptors. The difference tho is that each patient with HER has all cells with HER on them or estrogen...but in MM the person can have neither both or both plus other receptors.
As u can see this makes the disease far more complex and no single target will impact all MM cells. Nor be effective necessarily in one individual.
Which means we may not even be seeing resistance as their are multiple clones & therapy kills off susceptible clones but never impacted the diversity of clones that were there from the start.
Please, explain if whese mutations are aquired after birth?
Thanks
Great questions, and great discussion.
To answer kira's question first: Yes, these mutations are acquired after birth. The mutations are in myeloma cells, not all of the cells of the body, so they are acquired later in life.
To provide further detail about the methodology used in this study and the heterogeneity found in the results:
The researchers analyzed one bone marrow sample from all of the myeloma patients included in the study. Some patients had multiple samples collected over time, each of which was analyzed.
Each sample, however, contained many myeloma cells. Researchers sequenced the genomes of several myeloma cells from each sample to see whether they contained the same mutations.
In a completely homogeneous cancer, every cancer cell (within a person's body as well as across patients) would have the same mutation (or set of mutations).
In a cancer that is heterogeneous across patients, some patients would have one mutation (or set of mutations) and others would have another. It doesn't necessarily have to mean that every patient has a set of mutations unique from every other patient, but certainly not everyone would have exactly the same mutations.
A cancer that is heterogeneous within a patient means that some of the patient's cancer cells have one mutation (or set of mutations) and others would have another. It doesn't necessarily mean that every cancer cell in the patient's body has a different set of mutations (that would be highly unlikely).
The scientific terminology for this is "subclones." As cells multiply, a cell makes a copy of its DNA, and then the cell divides into two, each of which includes a copy of the DNA from the original cell. Normally, both of the new cells contain exactly the same DNA. In some cases, a mistake occurs when the new copy of DNA is made, resulting in a mutation.
If a patient's cancer is homogeneous, the cancer cells pass along exactly the same DNA as the cells multiply and divide. A patient with this type of cancer has one "subclone."
If a patient's cancer is heterogenous, that means that at some point two or more of their cancer cells acquired different mutations. Let's suppose two. As those cells copy their DNA, divide, and multiply, there now exist two sets of cancer cells, with two sets of mutations. This patient has two "subclones."
The results from the current study showed that not only is myeloma heterogeneous across patients (not all patients have the same mutations, this has been known) but that each patient also has heterogeneous disease at diagnosis (each patient has more than one subclone).
As is already known, these results imply that the same myeloma treatment is not going to work for every patient.
These results also help to explain why a myeloma patient may partially respond to a myeloma therapy, but not achieve a complete response. And they also help to explain why a patient might relapse even after responding very well to myeloma therapy.
Since a patient has multiple types of myeloma cells, some of the cells, those with a certain set of mutations, may respond well to a given myeloma therapy, while other cells that have a different set of mutations do not respond to the therapy.
Likewise, most of a patient's cells may respond to a given therapy, but a few with a different set of mutations may persist, causing relapse. This can also explain why a new therapy may be needed at relapse, since the clone that causes relapse may be a different clone than what was predominate at diagnosis.
These results also help explain why combination therapies are often necessary to combat a patient's myeloma.
Thanks for the clarification, Beacon Staff!
However, to extrapolate the logic a bit further....if 97% have "at least two sets of myeloma cells with different genetic mutations at diagnosis", then that would seem to me to beg the question of whether additional myeloma cells might create still different genetic mutations in the same patient AND that a drug the patient had previously become refractory to could possibly become effective again with those new gentic mutations....yes...no?
Thanks,
Steve
This research seems to support the regimen that uses multiple, rather than single, agents in first-line treatment. It has the best chance to prevent clones from being left behind therefore leading to relapse and resistant diseases.
From abstract:
"Analysis of the clonal structure showed at least two subclones in 66/68 (97%) patients at diagnosis, suggesting that myeloma is a heterogeneous disease at presentation. The burden of at least some of the mutations changed over time in 12/15 patients (80%) with serial samples, highlighting ongoing clonal evolution. Interestingly, 2/2 NRAS mutations only appeared in the late sample, and 3/6 KRAS mutations increased their burden over time. Furthermore, copy number analysis showed that 9/15 (60%) patients also acquired additional chromosomal gain/deletions, with loss of 17p in 4/9 (44%). This suggests a role for RAS activation and TP53 loss in disease progression.
In conclusion, in our cohort of MM samples we show: 1) a comprehensive list of previously unreported variants, many of which are recurrent; 2) evidence of tumor heterogeneity at the time of diagnosis; 3) discernable genetic changes and shifts in the clonal structure of disease at the time of progression"
https://www.eventure-online.com/eventure/publicAbstractView.do?id=193790&congressId=5650
MM as a disease appears to be in a constant state of evolution, multiple clonal types at diagnosis and as it progresses it continues to become more heterogeneous. This means that any therapy will need to have multi-targets, as Ben notes, in order to derive the greatest benefits. If MM clones are evolving they aren't necessarily 'left behind' but rather may not have been present during induction and would not necessarily represent resistance either. MM is like cockroaches.
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