Genetic predisposition to MDS: clinical features and clonal evolution
Inherited Gene Variations Reveal Precision Therapy Potential For Rare Cancer Syndrome
An international team of researchers led by The Hospital for Sick Children (SickKids) have, for the first time, developed strategies to diagnose and treat an aggressive syndrome that leads to cancer in almost all cases.
Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare genetic condition. Children who inherit the syndrome are considered "predisposed" to cancer, meaning they have a high likelihood of developing many different types of cancer – most commonly in the brain, digestive system and blood. In the past, these patients rarely survived to adulthood.
Research into CMMRD published in The Lancet Oncology studied more than 330 malignant tumours from 201 patients with the syndrome from the International Replication Repair Deficiency Consortium (IRRDC). The research team, including PhD student Ayse Ercan, observed that patients with CMMRD develop a new tumour every two years, suggesting the condition is the most aggressive human cancer predisposition syndrome.
The researchers also discovered that the type and severity of CMMRD is dependent on the specific inherited gene variation. Currently, there are four major genes associated with CMMRD: MLH1, MSH2, MSH6 and PMS2.
"All patients with CMMRD are not the same, and how we approach their care is dependent on many factors. Developing targeted therapies based on gene-specific cases could help patients with CMMRD have better health outcomes," said Dr. Anirban Das, co-lead author of the paper, Staff Physician in the Division of Haematology/Oncology and Project Investigator in the Genetics & Genome Biology program at SickKids.
Findings inform a more targeted screening protocol for patients with CMMRDAll day, cells in the human body are dividing and multiplying – it's a process essential to life. Occasionally, a change during cell division can cause a slight variation in genetic material. A process called the DNA mismatch repair system clears these errors to maintain regular function in cells. In patients with CMMRD, the DNA mismatch repair system is unable to clear errors. As a result, genetic variations can accumulate and can lead to cancer.
In order to identify cancers as early as possible, many individuals with CMMRD undergo regular screening to stay on top of cancers that might be developing. The research team found that 90 per cent of patients with CMMRD will develop at least one cancer by the age of 18 and if they survive to the age of 40, all will develop multiple cancers.
Preventative monitoring can be very successful, but new findings suggest that this screening protocol has the highest impact among patients with variations in the MLH1 or MSH2 genes. In addition, patients with variations in MSH6 and PMS2 received the greatest benefit from treatment with immunotherapy.
"Until now, it was not known that the type and severity of CMMRD was predictable based on the specific gene affected," says Dr. Uri Tabori, co-lead author of the paper, Section Head of the Neuro-Oncology and a Senior Scientist in the Genetics and Genome Biology program.
"We show how the different links between affected genes and variant types determine the type of cancer, onset and outcome for each patient. Knowing these variations will help inform the future individualization of patient care through Precision Child Health," Tabori says.
Global collaboration informs care in real timeThe IRRDC, a collaborative network of physicians, scientists, policy makers, patients and families from more than 50 countries, was established in 2007 by Tabori and other SickKids physicians including Dr. Eric Bouffet, Director, Paediatric Neuro-Oncology Program and Dr. Carol Durno.
Now run by Das and Tabori, the IRRDC hosts weekly rounds to discuss global patient cases and manage more than 150 patients participating in active immunotherapy under the expertise of a SickKids-led team.
"Global collaboration is an essential part of learning more about CMMRD and developing future care. The consortium allows us to help patients in real time from diagnosis to treatment," says Das.
By sharing data and patient stories, the international team has worked together to see patients with CMMRD live past university age for the first time. Future research on the syndrome may further improve the diagnosis, management and prognosis for those with CMMRD.
Genetic Mutation
Genes are the inherited material you get from both your parents that are made from strands of molecules called DNA. Long stretches of DNA are packed with other materials, like proteins, to make 46 chromosomes. Genes contain the information, or "code", needed so your body can make the many proteins it needs to function. A genetic mutation is an alteration in the genetic code found in DNA.
A mutation changes the specific instructions of the gene, coded through small components of DNA. Because a genetic mutation changes the genetic coding, the resulting protein might not work the way it was initially supposed to, which can lead to disease.
Some mutations are present from birth. You can inherit some gene mutations that first occurred in one of your parents, grandparents, or an older ancestor. Other genetic mutations happen as a natural part of aging, and some happen after exposure to substances that cause damage to your DNA.
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The types of genetic mutations are complicated because scientists conceptualize genetic mutations in different ways. They can be classified by the type of molecular genetic change, whether they're inherited vs. Acquired, or if they're dominant vs. Recessive. Type of Molecular Genetic Change Some mutations change just one tiny part of the genetic code, making it "incorrect." This might lead to a change in the effectiveness of the protein for which it codes. The protein might have missing parts, a part that doesn't work as well, a part in the wrong place, or it might not be made at all. Other types of mutations affect longer stretches of DNA and even more than one gene. For example, part of one gene might connect to the wrong part of the DNA sequence. This sometimes causes an abnormal combined protein to form. This kind of change can happen in some cancers. In some cases, large stretches of DNA are affected, and the mutation impacts multiple genes. Many genes might be completely absent, or there might be an extra copy of a long stretch of genes. One example is Down syndrome, in which the person has an extra copy of the genes found in chromosome 21. Not all mutations make a difference. Some "silent" mutations don't change how the protein functions, so they don't cause any problems. Inherited vs. Acquired Mutations You might inherit a mutated gene from one or both of your parents, meaning your parents had the mutation in their DNA and it became part of your DNA. In that case, you'd have the gene mutation in all your cells from conception. This might be important if the mutation directly causes a disease or greatly increases your risk of disease. A mutation like this might be passed down from generation to generation. The actual event that changed the DNA might have happened a very long time ago. In contrast, an acquired mutation occurs at some point later in life. It affects some of your cells, not all the cells in your body. It's normal to acquire new mutations as part of aging, and most of them don't make a difference. However, some acquired mutations can lead to cancer or other medical conditions. Scientists are still finding different types of gene mutations and determining how they are connected to certain diseases. Some related terminology is "germline" versus "somatic" mutation. A mutation in the germline affects the genes in the cells that one's children receive, so it can be transmitted across generations. However, mutations in other types of cells in the body, called "somatic cells," can't affect future generations. Dominant vs. Recessive Gene Mutations For some gene mutations that can cause disease, it matters whether you get a copy from just one or from both of your parents. Some diseases require you to have gene mutations from both of your parents in order for the disease to develop. Anyone can have a single gene mutation that doesn't cause illness; this is known as being a "carrier." For dominant gene mutations, having only one copy of the abnormal mutation can give you the disease. You can inherit it from either of your parent's DNA. For recessive gene mutations, you need to get copies of the mutation from both sides of your family to get the disease. Inheritance is also more complicated for mutations on the sex chromosomes (e.G., the "X" or "Y" chromosome). Depending on one's biological sex, you might need to inherit a gene from just one or from both parents to get the associated disease. You get inherited mutations from your parents. Even though the actual mutation occurred in your family's DNA long ago, scientists still refer to them as "mutations" if they result in certain diseases. Acquired mutations are caused by more recent changes to the DNA during one's lifetime. Getting some acquired mutations is a normal part of aging, but exposure to substances that can alter your DNA can increase your risk of getting more of them. Substances that increase the risk of such mutations can increase your risk of cancer. Examples include tobacco products, ultraviolet radiation from the sun, X-rays from medical imaging, radioactive substances (like radon), and many different chemicals. Scientists think that people inherit roughly 50,000 different genes, half from each parent. A genetic mutation can occur in any of these genes. The impact of a mutation varies widely based on the type of protein it affects and what that protein normally does. A mutation might affect your muscles, heart, digestive system, brain, blood, or any other body part. Because some proteins are expressed in more than one system, some mutations affect multiple areas. Some mutations are so severe that the fetus does not survive until birth. In cases of spontaneous miscarriage, at least half of fetuses carry a genetic mutation. These are typically severe chromosomal mutations involving many genes. Genetic Diseases vs. Multifactorial Diseases Some genetic mutations directly cause disease. For these kinds of diseases, sometimes called "genetic diseases," you need to inherit one (dominant) or two (recessive) copies of the abnormal mutation to get the disease. However, many diseases are multifactorial, meaning they have both genetic and environmental components causing them. Having variations of certain genes (i.E., having certain gene mutations) can increase your risk of a disease, but a lot more is involved. For example, having a certain gene mutation might slightly increase your risk of getting Alzheimer's disease. However, you wouldn't necessarily get Alzheimer's disease if you have this mutation, and some people without the mutation also get the disease. Harmful, Neutral, and Beneficial Mutations Most new mutations are neutral or harmful. However, some gene mutations cause advantageous protein changes. If so, that genetic mutation may eventually become widespread in the population. Mutations are a part of how species adapt to the environment over very long periods of time through the process of evolution. Thousands of different genetic disorders can affect human beings. Although they range from somewhat uncommon to exceedingly rare, together they affect around 1 in 12 people. Genetic diseases caused by inherited abnormal mutations include: Sickle cell disease (SCD): SCD causes a person's hemoglobin (a protein in red blood cells) not to form correctly, causing their red blood cells to form a "sickle" shape. It can cause anemia, repeated pain crises, and organ damage. Inherited thrombophilia: Sometimes called hereditary thrombophilia, this greatly increases your risk of abnormal blood clots that can affect the legs, lungs, or other parts of the body. A mutation in the prothrombin gene is a common cause of this condition. Hemophilia: This can cause frequent and severe bleeding. It is caused by mutations in genes such as FVIII which help make clotting factors to stop your body from bleeding. Familial hypercholesterolemia: Results from a genetic mutation can lead to very high levels of LDL-type cholesterol and can lead to heart attacks at a very young age. Cystic fibrosis (CF): CF is caused by mutations in the CFTR gene, which makes a protein responsible for the regulation of the chloride ion in cells. It leads to thick mucus build-up in the body, affecting the lungs, digestive tract, and other organs. Huntington's disease: Caused by mutations in the HD gene, this disease causes the nerves in the brain to break down. This can lead to involuntary movements and cognitive decline, among other symptoms. Duchenne muscular dystrophy: This condition generally affects males. It's caused by mutations in the DMD gene on the X chromosome and causes progressive muscle and skeletal weakness. Tay Sachs disease: This causes a build-up of fatty acids in the brain that progressively destroys cells in the nervous system. It results from a mutation on chromosome 15. Autosomal dominant polycystic kidney disease (ADPKD): Caused by mutations in the PKD1 or PKD2 gene, it causes abnormal cysts in the kidneys, which can cause kidney failure. Fragile X syndrome: This results from abnormalities in the FMR1 gene, leading to mental disability and other symptoms. Down syndrome: This causes mental disability and an increased risk of heart defects and digestive problems due to mutations leading to extra genes from chromosome 21. Cancer Acquired genetic mutations are part of what causes cancer. However, inheriting certain genes can increase your risk of developing these acquired mutations and, in turn, getting cancer. This is sometimes just a small increased risk, but the risk can be greater with some genes. For example, "BRCA" proteins are involved in DNA repair. Having a mutation in the BRCA1 or BRCA2 genes dramatically increases your risk of breast, ovarian, and some other cancers, and it increases your risk of getting these cancers at a younger age. Therefore, it sometimes makes sense to test for these mutations as part of preventive medical care, especially if you have a family member (such as your mother, aunt, or grandmother) who had breast or ovarian cancer. These tests are not part of routine preventative medical care. Individuals are selectively screened for risks and then tested based on their personal and family history. Genetic counseling is a good idea if you've been diagnosed with a genetic disease, have a known genetic disease in your family, or if you're displaying symptoms of a genetic disease. A specialist in genetics can talk to you about your risks of a certain condition in your specific medical context. Genetic testing is often needed to get a clear picture. To perform genetic testing, your healthcare provider will collect your DNA by swabbing your cheek or taking a sample of blood or saliva. Then your DNA will be examined in a laboratory to see if you have specific disease-causing mutations. Treatment for genetic mutations varies a great deal based on the mutation and the specific disease it causes. For example, treatment for muscular dystrophy varies quite a bit from treatment for a genetic problem that abnormally increases your cholesterol levels. Historically, healthcare providers haven't been able to directly treat the mutation itself. Instead, they focused on reducing symptoms and improving your day-to-day function. Depending on the situation, this might involve medications, changes in diet, and exercise, among other treatments and lifestyle factors. For acquired mutations leading to cancer, the focus is mostly on removing the unhealthy cells (e.G., through surgery, chemotherapy, or radiation). Newer technologies are making it possible to treat some genetic conditions at a deeper level. In a stem cell transplant, the approach is to wipe out your unhealthy blood-forming stem cells (containing the mutation). Then, you receive a stem donation from someone without the mutation, which eliminates disease symptoms. However, this isn't possible for all genetic conditions. Researchers have also developed gene therapies. These work by replacing or deactivating disease-causing mutations. This is a newer treatment area with potential risks, but it may eventually provide radically improved management for various genetic diseases, such as cystic fibrosis, hemophilia, and sickle cell disease. Although you can't always prevent getting a potentially harmful mutation or passing one on to your children, you may be able to reduce your risks. Preventing New Genetic Mutations in Yourself You can take steps to reduce your risk of getting potentially harmful mutations, including the following: Avoid tobacco products, all of which increase your risk of cancer and other disease Protect your skin from radiation from the sun by limiting exposure during the middle of the day and using sunscreen and coverups Eat a high-fiber diet with lots of fruits and vegetables Only get medical tests using radiation when truly needed, such as X-rays and especially CT scans Limit your consumption of alcohol Preventing Passing Down a Harmful Genetic Mutation In some diseases, parents can pass the disease to their children even if they don't have symptoms themselves. Genetic tests can show if you have a certain mutation that might cause disease in your child, so consult with an expert such as a genetic counselor. People who are carriers of disease-causing mutations have some options. For example, some people can use genetic testing paired with in vitro fertilization (IVF) to make sure their child won't have the disease mutation. You can also use genetic testing during pregnancy to see if a developing fetus carries specific gene mutations. Gene mutations can impact your health significantly. Depending on where they occur and their type, mutations can cause a broad range of disorders and diseases. When mutations occur in genes responsible for making important proteins, they can disrupt normal cell functions. Genetic mutations are classified in different ways, including the type of molecular genetic change, if they're inherited or acquired, or if they're dominant or recessive. Some genetic mutations directly cause disease while some require both genetic and environmental components in order to mutate. It is possible to develop thousands of genetic disorders, each very different from the last. You may be able to reduce your risk of developing a genetic disorder through some modifiable lifestyle factors. Genetic testing can also help your healthcare providers determine if you have certain gene mutations, if you're a carrier, or if your child is at risk of inheriting a mutation.Understanding The Genetics And Inheritance Of ALS
Most people with ALS don't have a family history of it. Still, some cases of ALS are linked to inheriting specific gene mutations. Even nonfamilial cases can be linked to sporadic gene mutations that are not inherited.
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder that causes your muscles to weaken over time. Most people who develop ALS do not have a family history of the condition.
Still, ALS can be hereditary. Familial ALS is a less common form of the condition that's passed on genetically from parent to child.
There's still a lot we don't know about genetic risk factors for ALS. This article provides an overview of current research into ALS genes and inheritance.
Around 5% to 10% of people with ALS have a family history of the condition. Familial ALS is often linked to known inherited genetic mutations, but there are cases where there isn't a recognized genetic mutation.
The remainder of ALS cases are sporadic, meaning they occur at random. But even though sporadic ALS isn't hereditary, it still has a genetic component.
Genes are inherited from parent to child, but sometimes a genetic mutation can develop due to unknown factors. Experts believe this to be the case with nonfamilial forms of ALS.
Around 10% of people with sporadic ALS show mutations in the same genes as people with familial ALS, even if they don't have a family history of the condition. In these cases, the family history may not be fully known, or the genetic mutation is occurring for the first time.
With sporadic ALS, environmental factors likely also play a role in triggering certain genetic changes. For example, exposure to agricultural chemicals, heavy metals, or radiation might interact with genes and lead to the development of ALS.
ALS is a motor neuron disease. Motor neurons are a type of cell found in the spinal cord. They are responsible for controlling muscles and movement.
In people with ALS, motor neurons slowly die, causing the muscles to weaken and waste away. The loss of motor neurons can sometimes be linked to a genetic mutation.
Researchers have identified dozens of gene mutations that can lead to the development of familial ALS. Some of the most common include:
Familial ALS is most often inherited in an autosomal dominant pattern.
"Autosomal" refers to genes on one of the regular 22 pairs of chromosomes found in human cells. (The 23rd pair consists of sex chromosomes.) When a condition is autosomal dominant, it means you only need one copy of the gene to develop that condition.
In other words, if one of your parents has familial ALS, you have a 50% chance of also developing the condition.
Autosomal recessive forms of ALS are less common. In these cases, you would have to inherit an ALS-associated gene from both parents to have the condition. Your parents would not have the disease if they each only had one recessive gene for ALS.
There's also at least one known X-linked form. These cases involve a mutated gene on the X chromosome, one of the two sex chromosomes.
X-linked inheritance usually affects males, as they only have one X chromosome and do not have another copy of the gene to override or compensate for the mutated gene.
If both you and a close family member have ALS, the condition is likely inherited. A doctor might suggest genetic testing to see whether you have a mutation associated with ALS.
Genetic testing is an optional procedure that can provide more information about genes involved in ALS. However, not everyone who has received a diagnosis of familial ALS tests positive for a genetic mutation.
If genetic tests do reveal a mutation associated with ALS, your family members might decide to get tested, too. But some people decide they would prefer not to know whether they have the ALS mutation.
A genetic counselor can help you learn more about the risks and benefits of genetic testing.
Is ALS inherited from your grandparents?It's possible to inherit familial ALS if your grandparents had it. But if you don't have a parent with ALS, you aren't likely to develop it.
That's because familial ALS typically has an autosomal dominant inheritance pattern. Such patterns don't usually skip a generation. However, rarer autosomal recessive and X-linked forms can skip a generation.
If you have the ALS gene, will you get ALS?If you have a first-degree relative (like a parent, sibling, or child) with ALS and testing reveals you also have the gene, you have a significant chance of developing the condition. However, not everyone with a known mutation will develop ALS.
Will I get ALS if my parent has it?Most people who have a first-degree relative with sporadic ALS do not go on to develop the condition. If you have a parent or sibling with sporadic ALS, you have a 1% chance of also developing ALS.
At what age does ALS usually start?ALS typically develops in middle age, with the age of onset ranging from 55 to 75 years. Familial ALS generally tends to appear earlier than sporadic ALS.
Most people with ALS don't inherit the condition. These cases are known as sporadic ALS. But in some cases, ALS can be familial, meaning it's passed through genetic mutations from parent to child.
Scientists have identified several specific genes involved in familial ALS. These genes typically pass on in an autosomal dominant inheritance pattern. That means if one of your parents has the gene mutation, you have a 50% chance of also having the mutation.
Genetic testing is one way to pinpoint whether ALS is due to a genetic mutation known to be associated with the condition. If you have ALS, consult with a healthcare professional to learn more about the advantages and disadvantages of genetic testing.
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