The Answer Could Be In Your Genes

Data sharing, precision medicine, genomics, genetic sequencing are the Buzz Words of hematology/oncology today.  But what do these words mean and how do they relate to treating and possibly curing multiple myeloma?

Genetics 101

Let’s start with a crash course in Genetics 101.  Our body is made up of cells. Almost every cell in our body, no matter where it is located, contains the SAME DNA.  All of the cells in our body started from a single cell at conception. That single cell then divided many, many times to turn into the 37.2 trillion cells that make up you. But how can cells that have very different functions in the body share the exact same DNA? Let’s explore this further.

In nucleus of our cells we have chromosomes. Chromosomes carry all the information that tells a cell to grow, survive and reproduce. Humans have 23 matched pair of chromosomes. One half of each chromosomal pair comes from mom and the other half from dad.

Each chromosome is covered with genes. Every cell in the human body contains about 20,000 genes which are distributed over our 23 pairs of chromosomes. Genes are strands of DNA. The DNA that makes up our genes is made up of four chemicals known as bases.  These bases are A, C, T, G (Adenine, Cytosine, Guanine, Thymine). These bases come in pairs since DNA is structured as a double helix. A is always paired with T and G is always paired with C. In humans, genes vary in size from a sequence of a few hundred DNA bases to a sequence containing more than 2 million bases. There are a total of 3 billion bases in your entire sequence of genes. Your whole genome is your entire sequence of all your genes and bases.

Gene

If order for a cell to work properly the gene must be turned on -”expressed”. Expressed genes form proteins to tell different cells to do their particular job. Thousands of proteins must be made for cells to work properly. Different sets of proteins make up our eyes and heart.  In our eyes the “seeing” genes are expressed and in our hearts the “pumping” genes are turned on. Even though ALL our cells contain the SAME genetic code (DNA), cells in various locations of our body are different depending on what part of that genetic code is expressed. I like to compare gene expression to a Christmas light display. There is a panel of lights but not all of them are turned on at any one time. Computers turn off and on lights in a particular sequence throughout the course of the display.  Depending on what lights are turned on (“expressed”) we see different scenes- a Christmas tree twinkling, snowflakes falling or Santa’s reindeer leaping over chimneys.

What is genetic sequencing?  Sequencing is any method or technology that is used to determine the order (sequence) of the four bases—A,C.G,T—in a strand of DNA. Sequencing can be done to a single gene, a panel of specific genes, entire chromosomes or the entire genome (all 20,000 genes found in a human cell).  In 2003 the human genome was first sequenced as the culmination of the 13 year Human Genome Project. By the end of the Human Genome Project it took 3-4 months to sequence the human genome and cost upwards of 50 million dollars. Today, thanks to advances in technology, sequencing a human genome can cost less than $5,000 and take only a day or two. This coupled with cloud computing, artificial intelligence and the many new targeted therapies available for use is allowing treatments for genetic diseases to become more personalized and precise. It is also giving pharmaceutical companies the tools to develop drugs faster and with greater chance of success. We have entered the era of Precision Medicine. Precision Medicine is the phrase that is used when information based on a person’s genetic profile, environment and lifestyle are used to diagnose and treat a disease.

gene map

Cancers such as multiple myeloma arise when there a copying error (mutation) in one or more sequences of DNA is found in our genes. Every time a cell divides, it needs to copy 6 billion letters of DNA. Sometimes an error in copying (replication) happens. Most of these errors are discovered and taken care of by our body. Sometimes these errors go unchecked. These unchecked errors may turn into cancer if they are involved in our cells life cycle regulation genes. All cells in our body are programmed to die. Cancer cells lose their ability to die and replicate out of control. It’s likely that most cancers involve several gene mutations. Each cancerous tumor has its own unique set of genetic alterations (mutations)- its own genetic profile.

In 2009, as part of the Multiple Myeloma Genomics Initiative (MMGI), the Multiple Myeloma Research Foundation (MMRF) sequenced the first human tumor genome, that of multiple myeloma. They did parallel sequencing of the patient’s myeloma tumor’s DNA and a sample of that same patient’s normal DNA which was derived from their peripheral blood. The results from this parallel sequencing were compared. (Remember ALL the cells of our body have the same DNA. Any differences that were found in the tumor’s DNA compared to the matched peripheral blood sample were mutations.) The MMGI goal was to molecularly sequence 500 relapsed and refractory myeloma patients. After only 38 myeloma tissue samples were sampled the MMRF discovered an unexpected finding- 4 patients had a mutation in the BRAF gene.  Although this mutation had been linked to melanoma in the past it was the first time the BRAF mutation was liked to myeloma. The BRAF mutation is an actionable mutation since it is known to cause cancer and there are approved BRAF inhibitors. Screening future myeloma patients for the BRAF mutation may lead them to existing treatment.

By sequencing over 200 myeloma genomes the MMRF discovered that multiple myeloma is not just a single disease, but one of at least 10 subtypes identified by their unique genetic signature of mutations. Currently all these subtypes are treated the same way in clinical practice. Analyzing the data on how these various myeloma subtypes respond to treatment may lead to a more personalized, precise way to treat myeloma. MMRF’s CoMMpass Study is doing this now.

The MMRF describes the CoMMpass Study as being about patients helping patients to put new treatment options within reach. The CoMMpass Study has enrolled 1,000 newly diagnosed myeloma patients. All participants had bone marrow biopsy at diagnosis. Their biopsies were sequenced and compared to matched samples of their normal DNA found in their peripheral blood to determine genetic alterations in their tumor cells. Patients then proceeded to follow the treatment plan their doctor prescribed. Their genomic profiles were mapped to their clinical outcomes. At the time of maximum response to treatment each participant agreed to another bone marrow biopsy which was again sequenced to determine genetic alterations. Finally the participants had/will have their bone marrow biopsies sequenced at relapse. This pattern of sequencing at maximum response to treatment and relapse will continue for 8 years. By providing their data CoMMpass participants are advancing the science by enabling researchers to track how myeloma progresses, changes and reacts to treatment over time. They are building the basis for Precision Treatment for myeloma patients.

The MMRF CoMMpass Study is in 100 sites. What is unique about this study is that it encourages data sharing.  After the member institutions have priority access to the data they collected then it is put in an open access public domain portal called the MMRF Researcher Gateway for all interested to analyze. Here is a link to the Researcher’s Gateway https://research.themmrf.org/  The MMRF also created the CoMMunity Gateway for patients to encourage data sharing. According to their website the key features of the MMRF CoMMunity Gateway include the ability to collect and store health and treatment information, and the ability to find, connect, and share information with other patients.

In its newest initiative, the Molecular Profiling Initiative (MPI), the MMRF partnered with the University of Michigan. Their goal is to determine if a relapsed/refractory myeloma patient would benefit from available drugs depending on actionable mutations as determined by clinical grade genetic sequencing. Actionable mutations drive cancer and are potentially responsive to targeted therapy.  If a patient exhibits an actionable mutation they will be matched to a specific therapy. The  Molecular Profiling Initiative (MPI) has a timeline of two years and hopes to perform free clinical-grade genomic sequencing (CLIA) on bone marrow and matched peripheral blood samples from 500 relapsed and refractory multiple myeloma patients. The data will then be evaluated for alterations in 1,700 cancer-related genes. This data will also be added to the MMRF’s publicly accessible portal.

Our genomic DNA data may save our lives, but the only way this will happen is if we get tested and share our data.  It’s important to build critical mass.  The data set needs to be large enough to draw conclusions. It’s imperative for patients to get genetically tested, and to join clinical trials, studies and registries.

What can you do? Ask your doctors about what genetic testing may be right for you, get a copy of your test results, share that information, and educate yourself on treatment options and clinical trials that may work for you based on your genetic signature.

The cure to our cancer lies in our genes.  We just need to get to know them better and how they work.


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Cindy Chmielewski Precision Medicine Advocate

Cindy Chmielewski Precision Medicine Advocate

Cynthia Chmielewski was diagnosed with multiple myeloma, a blood cancer, in 2008. Cindy’s induction therapy stopped working after a few cycles and she proceeded with a stem cell transplant which failed to put her into remission. Depressed and scared she continued her fight using newly FDA-approved targeted therapies which eventually put her in remission. Cynthia continues treatment with a maintenance protocol.  Cynthia is using her passion for education to teach a new group of “students” – myeloma patients, their caregivers and others interested in myeloma.  She is a trained mentor, advocate and Patient Ambassador.
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