Only Your Genes Will Tell
Only Your Genes Will Tell
By
Cynthia Chmielewski
Molecular Groups of Multiple Myeloma
Multiple Myeloma is a cancer of the plasma cells found in
the bone marrow. We now know that Myeloma is not a single disease. Researchers
have identified several molecular subtypes. During the last 15 years, numerous
studies have pointed out the heterogeneity of both the phenotype and
chromosomal abnormalities of multiple myeloma.1 Using Gene
Expression Profiling of 414 newly diagnosed patients, Zhan et al. have
proposed a molecular classification of multiple myeloma into 7 groups. Read on
to discover how to determine to which molecular subgroup of multiple myeloma
you belong and why it’s important to know that information.
One Size Fits All
Until recently there weren’t many treatment options
available for individuals diagnosed with myeloma. Patients were prescribed the
treatment that showed the best efficacy when tested in the general myeloma
population. Most trials in the past did
not separate the myeloma population into molecular subtypes. In the last decade
many new myeloma drugs came to market. The challenge that we now have is how to
choose the right drug or combination of drugs, to be given at the right time,
in the right amounts with an acceptable side effect profile. The age of precision
medicine is upon us and we must embrace it so we can achieve the best possible
outcome.
We need to learn about “our myeloma” and share our data
about how our subgroup of myeloma responded to various treatments with others. We need to know more than I am IgG Kappa or
IgA Lambda. We need to know about the
genetics of our disease. We need to learn our molecular signature and how it
changes over time. Once we learn what’s driving our disease our doctors can
begin to search for appropriate therapies that will be aimed at disabling those
specific driver mutations.
There are several types of genetic testing available to
the myeloma patient. Some are common and
used at all clinics and others are more specialized and used at progressive
myeloma centers. I am by no means an
expert in genetic testing, but I am going to attempt to describe the different genetic
tests available.
Conventional
Cytogenetic Analysis
Bone marrow cells are taken
at the time of a bone marrow biopsy aspiration for conventional cytogenetic
analysis. These cells are grown in a culture, stained and then analyzed for
chromosomal abnormalities such as deletions or translocations. Only cells that are actively dividing are
examined (metaphase). Twenty cells are
typically reviewed.
According to Dr. Voorhees,
a Medical Advisor for the Myeloma Beacon, “Conventional cytogenetics is not an
analysis restricted to the myeloma cells. All bone marrow cells are analyzed.
So, many of the cells that are evaluated wind up not being plasma cells. If you
have a highly proliferative, aggressive myeloma (more myeloma cells actively
growing and dividing) you have a much higher likelihood of picking up a
chromosome abnormality in the myeloma cells by conventional cytogenetics. If the burden of disease is low and
proliferating at a slow rate (i.e. if there are few myeloma cells in the
metaphase of the cell cycle), conventional cytogenetics are likely to be
normal.” To me this means that conventional cytogenetics also referred to as
karyotyping leads to a lot of room for error. Cytogenetic
only offers clinically significant information in a fraction of patients.
iFISH
Testing (Interphase fluorescence
in situ hybridization)
iFISH testing is
currently the standard of care in myeloma genetic testing. There is a myeloma FISH panel. Interphase
FISH analysis is not intended to stand alone, but rather to provide
supplemental information to routine cytogenetic studies.
FISH studies are also performed
on bone marrow aspirates. In the lab the pathologist attaches a florescent
probe to specific markers for gene changes. The probe attaches to
a specific piece of DNA from your biopsy. The pathologist
shines an ultraviolet light on the cells. Under the microscope the gene that
matches the probe shows up as a bright glowing area. Compared
to standard cytogenetic testing, one advantage of FISH is that it can identify
genetic changes that are too small to be seen under a microscope. Another advantage
is that FISH doesn't have to be performed on cells that are actively dividing.
A disadvantage of FISH panel testing is it only shows abnormalities in the
genes that are probed. You only get results if you run the right probe, if you have a unique
mutation it might not be picked up by this panel. FISH testing becomes costly
and time consuming as increased numbers of probes are utilized.
At a recent meeting of the
International Myeloma Working Group (IMWG) in Copenhagen, Denmark, Dr. Gareth
Morgan said, “FISH Testing for myeloma is as dead as VAD treatment.” What’s VAD treatment you ask? VAD was the standard of care of treating
myeloma before the newer novel agents were approved. Now it is hardly ever used. The standard of
care for genetic testing in myeloma at present is iFISH testing. Dr. Morgan is suggesting that the FISH is now
belly-up and newer, better options are available. He said at that same meeting,
“It’s time to abandon iFISH technology and utilize a consensus next generation
sequencing panel that gives all the relevant information that is applied
routinely in clinic.” The task now before the IMWG is to develop that agreed
upon NGS gene mutation panel.
GENE EXPRESSION PROFILE (GEP)
When I reached out to Dr. Morgan to
seek his pearls of wisdom on genetic testing he said that patients should be
asking for GEP testing. Gene expression profiling is the measurement of the activity (the expression)
of many genes at once. An example of a
very popular GEP test which is clinically available for myeloma is MyPRS which
was developed by researchers at the University of Arkansas for Medical Sciences (UAMS) and
has been licensed to Signal Genetic. MyPRS (Myeloma Prognostic Risk Signature)
is a microarray-based gene expression profile (GEP). According to the Signal
Genetic website, “MyPRS provides each patient with a Prognostic Risk Score,
Molecular Subtype, and Chromosome imbalances unique to their disease.” When communicating with a representative from
UAMS I learned that the GEP informs of the different myeloma subgroups. UAMS has been able to identify and predict
which treatment strategies would be the most effective for the different
subgroups based on the large repository of research samples to which they have
access. MyPRS GEP is also done on a bone marrow aspirate.
MyPRS is not the only GEP test
available. Several other tests exist, each with its own unique gene panel. For
example, Dr. Pieter Sonneveld using a 70 gene
profile found 3 novel subsets of
multiple myeloma in addition to 7 clusters described in the UAMS
classification.2 A goal of
the IMWG is to develop a gene panel that is a consensus among its members that
would become standard of care for genetic testing using GEP.
NEXT GENERATION SEQUENCING (NGS)
In my communication
with MIRT, the Myeloma Institute, at UAMS Dr. Morgan also suggested that patients
should ask whether next generation sequencing and mutation analyses are available
as well. He said that these advanced diagnostic tests reveal information at the
molecular level about genetic patterns and mutations that enables us to design
individualized treatment approaches for each patient. It also enables us to
design methods for normalizing cell biology that has gone astray and develop
regimes based on altering the cell’s behavior to prevent treatment resistance
and relapse
NGS
is a technique used to determine the precise order of nucleotides within a DNA
molecule. Older techniques of sequencing DNA were more time consuming and less
accurate than NGS techniques for sequencing DNA. Increasing speed and accuracy
in sequencing DNA resulted in reduction in manpower and cost. NGS has significantly
decreased in price and now has a much quicker turnaround time since the first
genome was sequenced in 2003.
Myeloma
mutation panels are targeted panels that contain the most frequently mutated
genes and a selection of clinically relevant genes. In a mutation panel only
these specific genes are sequenced not the entire genome. Your entire genome
does not need to be sequenced in order to provide useful data for precision
medicine. Using a specific mutation panel instead of sequencing the entire
genome or exome further brings down the cost and turnaround time for this type
of genetic test. FoundationOne Heme is an example of clinical grade NGS
targeted panel that is currently available. There are other NGS Heme panels. In time it is my hope that there will be a
mutually agreed upon panel of genes to sequence that becomes the new standard
of care for genetic testing in myeloma. I also hope that this panel will be
updated as new information about myeloma genetics becomes available.
It is imperative that you
know the genetic signature of your myeloma. Request to have GEP or NGS testing
done when your next bone marrow biopsy is scheduled. Once you have that
information sharing your data about how your specific subtype responded to
treatment will help to accelerate a cure for myeloma. It is also important that
you consider entering appropriate clinical trials that will test therapies
based on genetic features. Once critical mass is obtained data scientists using
super computers like IBM’s Watson will be able to quickly analyzing these sets
of Big Data which may help determine which treatment path is best for you.
1.
Fonseca R, Barlogie B, Bataille R, Bastard C,Bergsagel PL, Chesi M, et al.(2004) Genetics and cytogenetics of multiple myeloma: a workshop
report.Cancer Res 64(4):1546–58.
2.
Sonneveld, P, et al. (2010) Gene
expression profiling for molecular classification of multiple myeloma in newly
diagnosed patients.
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