What are point mutations in genes? How do they differ from chromosomal mutations? Consequences?

Point mutations, also known as gene mutations, involve a change in a single nucleotide base in the DNA sequence. They are called point mutations because they occur at one specific location. In contrast, chromosomal mutations affect larger segments of DNA or even entire chromosomes, leading to changes in chromosome structure or number. In this Health Tree University lesson, you will learn more about point mutations, point mutations associated with multiple myeloma, and how these mutations are identified. What is a point mutation? How do they differ from mutations in chromosomes? As much of the audience may know, when you're diagnosed with multiple myeloma and when you get a bone marrow biopsy done, often there is this FISH cytogenetic testing that is done, which is basically looking at large changes in the chromosomes. We all have 23 pairs of chromosomes. One of the hallmarks of most cancers, including multiple myeloma, is that there are significant changes within those chromosomes as a part of becoming cancer. These are not genetic alterations that are passed on to children, heritable, but they're genetic alterations which makes a cancer cell cancer. For instance, in multiple myeloma, some patients may have what is called as deletion 17. That means that a piece of the 17th chromosome is deleted or missing. That's normally patients have an intact 17th chromosome, two pairs of it, but in patients with multiple myeloma, maybe about 10% or so when they're diagnosed, they may have a small piece of the 17th chromosome entirely missing. And that's associated with higher risk disease, for instance. Similarly, there are patients in whom we have something called translocation, which means that a piece of chromosome, one chromosome, is translocated or moves to a different chromosome. So one common one is translocation 414. That means that a piece of chromosome 4 has migrated to chromosome 14 and vice versa, a piece from chromosome 14 has gone to chromosome 4. So these kinds of genetic alterations are gross changes across the chromosome and they've been cataloged for multiple myeloma for many decades. Now we identify some of these translocations, deletions, genetic alterations to be associated with higher risk disease. Now point mutations or genetic alterations are referred to a more detailed or in-depth look of this. So we have 23 pairs of chromosomes, but each of these chromosomes have thousands of genes, maybe 20,000 plus genes. And there may be alterations within those specific genes. These cannot be identified by doing FISH or cytogenetics, which looks at the entire chromosome, but these can be identified by sequencing different genes. So some institutions and hospitals do targeted sequencing, which look at a few 500, 400, 600 genes that are of interest for cancer or multiple myeloma. Others may do what's called as whole exome sequencing, which would be sequencing the entire exome, which is the parts of the chromosomes that are functional, if you will, or make proteins that are functional, or whole genome, which is sequencing the entire genome, all 20,000 genes, if you will. And depending on what technology you use, you might find more and more mutations. There are certain genes and mutations we know are important for cancer cell and cancer biology. So for instance, a gene called TP53, which resides on chromosome 17, is a very critical tumor suppressor gene that suppresses tumors. If you lose that gene or if you have a mutation on that gene, that may lead to cells becoming more cancerous or more proliferated. So with the advent of technologies like sequencing, we're now able to catalog these mutations in any given patient in great detail. That has been noted to be very important in certain other cancers where identification of these point mutations will allow doctors to use very precise drugs that target those mutations. In myeloma, we don't yet have such precise targeted treatments quite yet. There are small exceptions. So for instance, there's a gene called BRAF, which about 4% of patients with multiple myeloma may have a mutation. There is no FDA-approved treatment for BRAF mutations in multiple myeloma. However, there are FDA-approved treatments for BRAF mutations in melanoma, for instance, a different kind of cancer. So sometimes if there are no other treatment options and a patient has a BRAF mutation, we can identify that using sequencing. Their doctors may want to try a BRAF inhibitor as an off-label use to see if targeting that specific mutation may help. Our hope is the kinds of efforts that our center here, others are doing in cataloging all the different mutations that are seen in any given patient will allow us to develop more targeted treatments that are geared towards targeting specific mutations and alterations even within myeloma. And the kinds of drugs we can use for targeting these mutations are also expanding. Genes and mutations we thought were not targetable, for instance, RAS, which is a common genetic alteration across many cancers. Point mutations or alterations in RAS genes historically have been considered as being undruggable, as in you can't develop drugs. Now we have drugs that targets RAS mutations which are being used and approved for the treatment of lung cancer. So similarly, the hope is that the genetic field will progress both within myeloma and outside such that we can identify these mutations more easily and then hopefully we can target those mutations as well with effective drugs. Can you have a point mutation in the P53 gene but not of a deletion of 17p chromosomal mutation? So P53 or TP53 is the gene that resides in chromosome 17. So if the chromosome 17 or the specific part of chromosome 17 is deleted, then you don't have P53 on that chromosome. But again, all patients have two alleles, so there's two 17th chromosomes. You could, for instance, have different combinations. Both of the 17th chromosome looks normal. That's one out. So that means that the 17th chromosome and P53 is not affected. A piece of 17th chromosome is deleted, the piece that where P53 or TP53 gene resides in one chromosome and the other one is intact. That would be called as deletion 17. That would be identified by FISH cytogenetic testing. But then you may also have a patient in whom on one chromosome 17p is deleted. On the other chromosome, there's a point mutation in the P53 gene. So that point mutation cannot be identified by FISH. So if you did only a FISH testing, you would only know about the deletion but not this point mutation on the other side. But if you do a FISH and sequencing, you're now able to identify both of the alterations. And finally, the only alterations you might see with P53 could be point mutation. So one or both alleles, there's no deletion, but there's point mutations. If you did a FISH testing, the results would come back saying P53 is normal or 17p is normal. But if you now do sequencing, you may be able to identify these point mutations that would have a prognostic implication and prognostic effect on how we consider the patient's multiple myeloma. So the more sensitive testing you use, the more genetic information you get, including for genes like P53, which then in turn will eventually help us figure out about risk stratification, about prognosis, about the risk of progression, about treatment options for patients, et cetera. Understanding the genetics of your myeloma is crucial. Knowing your risk status can help guide your decisions about treatment and maintenance therapy and it may also reveal a targetable mutation. To track your genetic profile, sign up for Health Tree Cure Hub. Once your medical records are connected, you can view your genetic profile by clicking the Track My Disease button on your dashboard. The Health Tree Cure Hub AI algorithm will then use this information to suggest treatment options and relevant clinical trials.