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A Family Discovers an Unexpected Cancer Risk in Their Genes

Source: Memorial Sloan Kettering - On Cancer
Date: 07/19/2018
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When his younger brother, Mitchell, was found to have urothelial cancer in 2011, Elliot Katz never expected that diagnosis might save his own life.

Mitchell, now 64, initially had surgery with then-MSK urologic surgeon Raul Parra to remove a tumor in his kidney. A short time later, the cancer came back, and he had genetic testing with MSK-IMPACT™. In addition to looking for 468 mutations that are known to drive tumor growth, the test can reveal cancer-related mutations in the normal tissue that someone with cancer may have inherited.

Mitchell’s test results showed that he had a hereditary condition called Lynch syndrome. Lynch syndrome is associated with a genetic predisposition to a number of different cancer types. It’s most commonly linked to colon and rectal cancers but is also known to increase the risk of developing uterine, urothelial, ovarian, and other gastrointestinal cancers.

A Cancer Risk That Runs in Families

Families that carry one of the genes for Lynch syndrome usually have many members, spanning several generations, who have had cancer, especially colorectal cancer. Elliot and Mitchell’s father died of lymphoma when he was in his early 40s, but their family didn’t have a cancer history otherwise. Their mother lived to her 90s.

After Mitchell learned he had Lynch syndrome in 2015, he met with MSK genetic counselor Meg Sheehan, who explained the risks to him and recommended that other family members get tested. “I was very surprised to find out I had this condition,” he says. “Once I knew, it was important to me that my family have testing too, just in case they had the same thing.”

Elliot, now 66, met with Janice Berliner, a genetic counselor who works at MSK Basking Ridge, to get tested. Elliot was found to share his brother’s mutation for Lynch syndrome.

Focusing on More-Frequent Cancer Screenings

Because he was over age 50, Elliot had already begun undergoing screening colonoscopies, but only one polyp — a sign of possible precancer — had ever been found. Once he learned he had Lynch, he began undergoing colonoscopies every two years. The standard recommendation for the general population is every ten years. In October 2017, a few small polyps were found in Elliot’s colon. “Because I knew about Lynch, I decided not to wait,” he says. “I went back in six months.”

At that next exam, Elliot was found to have an early-stage colorectal cancer. “I’m lucky,” he says. “If I hadn’t known about Lynch, I would have waited much longer to have my next colonoscopy. I probably would have missed the boat.”

In April 2018, MSK surgeon José Guillem performed laparoscopic surgery to remove the tumor and a portion of Elliot’s colon. Dr. Guillem also removed a number of lymph nodes to determine whether the cancer had spread. They were all clear, which indicated that Elliot would not need any follow-up chemotherapy or radiation.

In addition to being a surgeon, Dr. Guillem is Director of MSK’s Hereditary Colorectal Cancer Family Registry. This registry allows researchers to learn more about the genetic causes of colorectal cancer and to develop new ways to prevent, diagnose, and treat cancers of the colon and rectum. It also makes it easier for people who have inherited this risk to undergo more regular monitoring.

Lynch mutations are autosomal dominant, which means a person with Lynch has a 50% chance of passing it down to a child. Elliot and his wife don’t have any children, but Mitchell’s two daughters, ages 29 and 34, were also found to carry a mutation for Lynch syndrome. Despite their young age, they began undergoing annual colonoscopy screenings to check for polyps or other signs of colorectal cancer. This is an action they never would have known to take otherwise.

“Very few centers provide patients with information about inherited risk at the same time their tumors are genetically screened,” comments geneticist Kenneth Offit, who directs MSK’s Niehaus Center for Inherited Cancer Genomics. “The experience of the Katz family shows the potential benefit of genomic sequencing, not only to offer targeted therapy but also to empower prevention and early detection.”

Mitchell is receiving an immunotherapy drug called atezolizumab (Tecentriq®) for his urothelial cancer. This drug has been found to work well for many people with Lynch syndrome. He continues to see MSK medical oncologist Gopa Iyer for his treatment and has had no evidence of disease in the four years since he started receiving the drug.

Elliot is recovering from his surgery and doing very well. He’s walking for exercise almost every day and has resumed most of his other daily activities. He says he has lost weight, and his blood pressure is better than it’s been in years. He now plans to follow up with colonoscopies every year.

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Study Suggests More People with Kidney Cancer Should Be Screened for Hereditary Cancer Genes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/06/2018
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Kidney cancer, also called renal cell carcinoma (RCC), is a relatively common cancer. It’s diagnosed in nearly 65,000 people in the United States every year. Yet despite its frequency, very little is known about what causes it, beyond two broad factors linked to many common cancers: smoking and obesity.

That’s now starting to change for one advanced form of the disease, called non-clear cell RCC. Recent research from a collaborative team at Memorial Sloan Kettering found that more than 20% of people with this type of RCC have disease that is driven by inherited cancer mutations. Many of the types of mutations that were found indicated that the tumors might respond to targeted therapies that would not otherwise be prescribed for kidney cancer.

“These findings suggest that everyone with advanced non-clear cell RCC should be referred for genetic counseling,” says medical oncologist Robert Motzer, one of the authors of the study, published in July in JAMA Oncology. “Beyond a rare inherited condition called von Hippel-Lindau syndrome, as well as a few other uncommon disorders, we haven’t previously known that kidney cancer had this strong hereditary component.”

Non-clear cell RCC makes up about one-quarter of RCC cases. For clear cell RCC, the more common type, the study found that only about 2% of tumors were caused by inherited cancer genes. Before this study, the rate for all kidney cancers was expected to be about 5%.

A Surprising Finding about a Diverse Group of Cancers

Over the past decade, a number of targeted drugs and immunotherapies have changed the outlook for many people with clear cell RCC. Dr. Motzer and his team have led many of the clinical trials that have resulted in US Food and Drug Administration approval for these drugs, including sunitinib (Sutent®), sorafenib (Nexavar®), axitinib (Inlyta®), and nivolumab (Opdivo®). Thanks to these new drugs, even people with advanced kidney cancer can live for many years, often with very few side effects from their treatments.

Non-clear cell RCC has been a different story. Many of the drugs approved to treat clear cell RCC do not have the same efficacy against non-clear cell tumors. “Non-clear cell” is a catch-all term that applies to several types of cancer including papillary, chromophobe, and collecting-duct tumors.

In this current research, investigators looked at 254 people who had been treated for advanced RCC at MSK. Each person had undergone MSK-IMPACT™ testing to look for mutations in their cancer. As part of this test, both normal tissue and tumor cells are analyzed. This enables doctors to detect cancer-related mutations that someone may have inherited.

Unexpectedly, about 20% of people with non-clear cell RCC carried inherited mutations. The study found the most frequently inherited mutation in people with non-clear cell RCC was in a gene called CHEK2. Mutations in this gene have previously been connected to an increased risk of breast and colon cancer, but the link to RCC was not known. The researchers found mutations in other cancer-linked genes not previously known to play a role in kidney cancer as well.

The team also found several people with non-clear cell RCC who had inherited mutations in a gene called FH. Mutations in FH have already been linked to a condition called hereditary leiomyomatosis and renal cell cancer. But they were more common than what would have been expected in a group of people with RCC.

“Once we know that someone has one of these hereditary gene mutations, we can help make sure they get the right treatment,” says Maria Carlo, a clinical geneticist and medical oncologist on the Genitourinary Service and first author of the study. “In addition, we can offer them screening tests for other cancers that may be linked to the same mutation.”

Discoveries Lead to Changes in the Clinic

At the American Society of Clinical Oncology (ASCO) meeting in June, Dr. Carlo presented similar findings from people being treated for advanced bladder cancer at MSK. About 16% were found to have inherited mutations. Some of these mutations suggested that they might benefit from targeted therapies that are not usually given for bladder cancer.

Learning that someone has an inherited cancer gene has important implications for his or her close relatives as well. MSK’s genetic counselors are able to offer them genetic tests. If any of them are found to have the same mutation, they can participate in screening programs for cancer as well.

In fact, due in large part to the findings reported in the JAMA Oncology and ASCO studies, Dr. Carlo is now leading a Genitourinary Cancer Genetics Program within MSK’s Clinical Genetics Service. The program offers genetic testing and screening services to people with hereditary prostate, kidney, and bladder cancers and their families.

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New Framework for Categorizing Inherited Cancer Genes Will Have Wide-Ranging Impact

Source: Memorial Sloan Kettering - On Cancer
Date: 11/01/2018
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Every gene is made up of thousands of As, Cs, Gs, and Ts, which spell out the instructions for making all the proteins in our cells. Errors in those instructions — known as mutations or variants — can occur anywhere in these long strings of code.

For genes linked to diseases, including cancer, researchers are focused on determining which mutations matter. Some don’t affect risk, but others actually change the functions of proteins and could have a negative effect in the body.

“Understanding the significance of the variants we find in cancer genes is important,” says Memorial Sloan Kettering clinical geneticist Michael Walsh. “We need to know if they are harmless or harmful, so when we learn that someone has inherited one of them, we can tell them what it means. Should they have more frequent cancer screenings? Should their family members get tested as well?” In addition, for those who already have cancer, inherited gene variants may influence what treatments they are given.

The Tremendous Task of Finding Meaning in Gene Variants

The field of cancer genomics took off in the early 1990s. At that time, scientists, including geneticists Mary-Claire King and MSK’s Kenneth Offit, began to report details on some of the first genes connected to cancer. These genes, BRCA1 and BRCA2, are associated with an increased chance of developing certain cancers, especially breast cancer and ovarian cancer. But what predisposes people to cancer are specific alterations in the genes. These changes can cause the proteins to malfunction in such a way that cancer may develop.

As genomic sequencing has become easier and less expensive, it has become much more commonplace. Huge amounts of data are now being generated. New cancer genes and variants are frequently being discovered. When the dozens of variants in hundreds of genes linked to cancer are taken into account, the task of determining which variants are significant may seem Sisyphean.

To help address that challenge, a few years ago the American College of Medical Genetics and Genomics (ACMG) released recommendations on how to classify the variants found in inherited cancer genes. Variants found in any gene may be classified in one of five categories: benign, likely benign, uncertain, likely pathogenic, or pathogenic. What remains a problem are the many variants that fall under the “uncertain” grouping, also called “variant of unknown significance.”

Now the ACMG is releasing an updated framework for classifying inherited variants in cancer genes. It focuses on integrating both tumor data and biomarker data. Dr. Walsh, a member of MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics, is the lead author of the new guidelines, which were published November 1, 2018, in the journal Human Mutation.

“In the past, the ACMG has provided guidance for testing labs, saying that people who get their genomes sequenced should be informed about which of their genes harbor variants. But in some ways that was like putting the cart before the horse,” Dr. Walsh says. “We didn’t know enough to determine what many of these variants meant.”

He explains that researchers are starting to make some headway in pulling together all the tumor and biomarker data that’s being collected. There may now be evidence about whether certain previously unknown variants cause harm.

A Rapidly Changing Field with Real Consequences

As the new guidelines are adopted by labs around the country, variants will continue to be reclassified. As a result, earlier genomic screening will need to be revisited on a regular basis.

“As labs begin to apply these new rules, there will be some people who had testing in the past who will need to be contacted with updated results,” Dr. Walsh says.

Even as the guidelines are still being phased in, the issues that they are expected to bring up are already apparent. A recent study from investigators at the University of Texas Southwestern Medical Center in Dallas found that nearly one-quarter of the variants that had originally been classified as being of “unknown significance” were later reclassified as being either likely or unlikely to be associated with cancer. The investigators reviewed the results from 1.45 million people who were screened for cancer genes with a test developed by Myriad Genetic Laboratories.

Dr. Walsh says that people who have had testing in the past should consider contacting the labs and clinics where the testing was performed. The incremental change in rule classification will impact few people overall, so it is important that appropriate channels are established between patients and providers, he adds. MSK encourages people who have been tested here to contact their doctor or genetic counselor at regular intervals to see if there are any updates pertaining to the tests they had.

“Communicating is key and delivery of information needs to be in such a way that the information is useful and not frightening,” Dr. Walsh notes. “These changes in gene classification can have meaningful implications for people’s lives.” Some people who learn that gene variants they carry are linked to cancer will likely want to explore questions surrounding screening guidelines, risk-reducing surgeries, and even family planning. Others who learn that their variants are harmless after months or years of worry may be able to breathe a sigh of relief.

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There’s an App for That: When the Meaning of a BRCA Mutation Isn’t Clear-Cut

Source: Memorial Sloan Kettering - On Cancer
Date: 02/11/2019
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Many people have heard that mutations in the genes BRCA1 and BRCA2 increase the risk of developing certain cancers, especially breast cancer and ovarian cancer. What they may not know is that the connection is not always clear-cut.

The reason is that there are many possible mutations in these genes, not just one. Not all of these changes, also known as variants, result in the same risk of developing cancer: For about 40% of BRCA mutations, the health effects are unclear. This can be confusing and stressful for the people who carry them.

To address these unknowns, clinical genetics experts from Memorial Sloan Kettering and other institutions around the world have launched the BRCA Exchange. This online database shares data about BRCA mutations and what they actually mean for cancer risk. It is also available as a mobile app. People can search the database for information on BRCA1 and BRCA2 variants and how experts classify the risks of different mutations in real time. The creators hope that opening up the database to others in the field will lead to better classification of the variants that have an unknown risk.

“One of the nice features of the mobile app is that users can elect to receive notifications when classifications change in the future,” says Kenneth Offit, Chief of MSK’s Clinical Genetics Service and a member of BRCA Challenge, the international group that created the BRCA Exchange. The database is open sourced, but as Dr. Offit points out, it is intended primarily for those with genetic training who are interpreting results for people who have been tested.

Coping with the Unknown

When a gene contains a mutation, that means that its instructions for how to make a protein have been altered. But not all genetic mistakes lead to the same outcome. Some may dramatically change the shape of the resulting protein, leading to a severe disruption in how the protein functions. Others may have little or no effect.

There are five categories of gene variants: benign, likely benign, uncertain, likely pathogenic, or pathogenic. Benign mutations are not cancer causing, and pathogenic ones are cancer causing. The problem is the many variants in the uncertain group. These are also called variants of unknown significance.

When a person learns they have a pathogenic BRCA mutation, doctors and genetic counselors usually recommend that they take measures to protect themselves. This often means undergoing more frequent cancer screenings. Many women with these mutations take medication to reduce their cancer risk. They may also choose to have surgery to remove their breasts, ovaries, or both.

But when a person learns they have a BRCA variant of unknown significance, the next steps are less clear. People are advised to turn to experts in cancer genetics for guidance. “Now, through the BRCA Exchange, experts as well as members of the informed public will have increased access to this important information,” says Mark Robson, a clinical geneticist and Chief of MSK’s Breast Cancer Medicine Service.

Concerns about how to classify variants go beyond the BRCA genes. Other genes linked to cancer are at issue as well. Last year, MSK clinical geneticist Michael Walsh led the development of new guidelines for using tumor genetic testing to classify the meaning of variants in hereditary cancer genes.Back to top 

A Growing Popularity and a Growing Need for Research

The BRCA Exchange was established as a resource so doctors can review the classifications and help people understand their risk. A panel of experts in cancer genes developed the classifications. The database also provides information on gene variants to researchers, data scientists, patients, and patient advocacy groups. It already includes more than 20,000 BRCA1 and BRCA2 variants. As genetic testing becomes more widespread, that number will continue to grow.

Additionally, as more people get genetic testing, it is becoming increasingly important to make sure that people understand what the results mean for their own cancer risk, as well as understanding the limits of the tests themselves. To figure out the best way for people to receive this kind of health information, a team of clinical genetics experts recently launched the BRCA Founder Outreach (BFOR) study. The study is being spearheaded by MSK and three other cancer centers.

Dr. Offit is one of the leaders of BFOR. He says it’s important to get genetic testing done by healthcare providers who can help interpret the results rather than a direct-to-consumer test offered by companies like 23 and Me. In the BFOR study, individuals of Ashkenazi Jewish ancestry who are more likely to carry certain BRCA mutations are offered testing for those mutations at no cost. They access the study via a website and can choose to receive their results from their own doctor or another expert.  

“Together, projects like the BRCA Exchange and the BFOR study are using the power and reach of the internet to empower both experts and healthcare providers to make more accurate and more accessible genetic information available,” Dr. Offit concludes.

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Genomic Research Connects Juvenile and Adult Forms of Arthritis

Source: Brigham and Women's Hospital - On a Mission
Date: 12/23/2019
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Traditionally, juvenile idiopathic arthritis (JIA) has been considered a distinct condition from the types of arthritis seen in adults. But increasingly, research is showing that juvenile and adult forms of arthritis represent a continuum.

“One of the central themes of my recent work has been pointing out the similarities between juvenile and adult forms of arthritis,” said Peter A. Nigrovic, MD, director of the Center for Adults with Pediatric Rheumatic Illness (CAPRI) at Brigham and Women’s Hospital. “The big picture is that these diseases are much more similar than they are different. I think the differences in nomenclature between the two types have been a hindrance rather than a help in understanding disease biology.”

Studying the Genetics of Arthritis

JIA is a blanket term that covers several different subtypes of arthritis. Like adult forms of the disease, it is characterized by symptoms that include pain and swelling of the joints, stiffness and, in systemic JIA, also rashes and fever. In some cases, it can also affect the eyes or internal organs. A case of arthritis is defined as “juvenile” if it appears before the age of 16. Once it develops, however, JIA can continue into adulthood.

At the Brigham, Dr. Nigrovic cares for adults who have JIA. He also sees children with the disease as an attending physician in the Boston Children’s Hospital rheumatology program. Some of his recent research has looked at the genetics of arthritis.

“One of the strongest pieces of evidence that these diseases are similar has to do in particular with the HLA locus on chromosome 6,” said Dr. Nigrovic, who also directs a lab that uses both human specimens and mouse models to study the basic immune mechanisms of arthritis and other rheumatic diseases. “Proteins encoded at this locus control how peptides are presented to T cells, including autoantigens that can trigger arthritis.”

He noted that the particular HLA genes that carry arthritis risk change with the type of arthritis, but are largely shared between adult-onset and childhood-onset forms of the disease. Risk genes outside of the HLA locus are also shared.

In a paper published in Nature Genetics in July 2018, Dr. Nigrovic and his team used a new technique termed SNP-seq to test thousands of candidate genetic variants linked to JIA risk by genome-wide association studies (GWAS). Through this work, they identified 148 candidate functional single nucleotide polymorphisms (fSNPs) that may modulate the binding of regulatory proteins. For fSNPs near the CD40 and STAT4 genes, they were able to confirm the fSNPs and identify specific transcription factors that likely modulate these genes differentially in individuals who carry protective gene variants compared with those who carry variants associated with enhanced disease risk.

“We believe that this approach will allow us to identify particular pathways that drive disease biology,” he said. “And we expect to find the same sets of pathways in children and adults.” He added that once these pathways are fully characterized, it could eventually enable the development of better targeted treatments for disease subtypes in both children and adults.

Developing a ‘Fingerprint’ Would Be Key

One of Dr. Nigrovic’s long-term goals is to identify drugs that would target pathways engaged by the new protein-DNA interactions identified in his lab. By understanding which variants each individual carries, it may be possible to develop a “fingerprint” that will help determine what treatments will be best for each individual with arthritis, irrespective of age of onset.

“We hope to use GWAS data to identify these common pathogenic pathways,” he said. “We’re not there yet, and we’ll need many patient samples to achieve this goal. But between the large volume of patients that we see—as well as our expertise in other related areas of research at both the Brigham and its related institutions—we are well-positioned to make important contributions in this field.”

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BabySeq project explores impacts of genetic disease testing in newborns

Source: Cell Press
Date: 01/03/2019
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In the 1960s, doctors began screening newborns for a metabolic condition called phenylketonuria (PKU). Since then, dozens of other diseases have been added to the panel of tests given to newborns, most looking for inherited genetic disorders. (The exact number of tests varies by state.)

In the era of increasingly common genomic sequencing, an effort called the BabySeq Project aims to explore the medical, behavioral, economic, and ethical impacts of adding genetic testing to the roster of newborn screenings. Some of the first findings from the project are being reported January 3 in the American Journal of Human Genetics.

“Traditional newborn screening uses biochemical analysis on a small drop of blood to look for a small number of conditions that can benefit from early intervention,” says senior author Alan Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital and one of the principal investigators for BabySeq. “In contrast, genomic sequencing has the ability to simultaneously analyze thousands of genes that are known to cause disease.

“But the specificity and sensitivity of genetics tests are uncertain and relatively low, and not all of the diseases that we may find are treatable,” he says. “This leads to a potentially complex package of information about a baby. It’s important to look at how people view this information and what the outcomes of having it are.”

The BabySeq study, led by Beggs and Robert C. Green, of Brigham and Women’s Hospital, together with Amy L. McGuire and collaborators at the Baylor College of Medicine, included sequencing of 159 newborns; 127 were healthy, and 32 were being treated in neonatal intensive care units, although not necessarily for genetic conditions. Parents who consented to have their babies tested filled out questionnaires including questions related to family history.

The investigators report that 15 of the babies (9.4%) carried mutations that revealed a risk of diseases that could arise or be managed in childhood, including cardiomyopathy and hearing loss. The investigators say this number was surprising, because none of these results were anticipated based on the infant’s clinical or family history.

“In this study, we focused on reporting gene variants that had substantive evidence to confer risk for disease” says first author Ozge Ceyhan-Birsoy, a clinical molecular geneticist, now at Memorial Sloan Kettering Cancer Center.

With additional parental consent, 85 babies were also tested for certain conditions that arise later in life but for which at-risk individuals could benefit from early screenings and other interventions. Three of them were found to carry gene variants that put them at a higher-than-average risk of adult-onset cancers. Two had variants in BRCA2, and one tested positive for Lynch syndrome.

“This part of the testing was very different from the component that looked at childhood diseases,” Beggs says. “In this case, it alerted the parents that they should also get tested because they were the ones who had more imminent risk. One of the aspects that’s important to highlight with this kind of research is that genetic testing has implications for the whole family.” This is in contrast to other medical testing, he notes, which only informs you about the health of the person having the test.

The BabySeq project aims to look at issues that arise with this kind of testing. The investigators are not proposing that it become part of standard newborn screening at this time. “There are many considerations with offering these tests to individuals,” says co-author Casie Genetti, a genetic counselor at Boston Children’s Hospital. “We plan to follow these babies, as well as their parents and their doctors, to look at how this information gets used and how it impacts health and well-being long term. It will help us to get a pulse on whether this kind of testing is feasible on a larger scale.”

Another aspect to note is that, unlike other definitive screening tests, genetic results are rarely cut and dried. Genomic sequencing can reveal variants in disease-associated genes that confer higher levels of risk, but in some cases, this might lead only to unnecessary worry, as the absolute risk would still be small. In addition, many gene variants have unknown significance, making predictions of their eventual effects difficult. In the current study, the investigators only reported variants that were pathogenic or likely pathogenic if a child was healthy, but variant classifications may change over time as researchers continue to collect long-term data on people who carry them.

“This is one of the reasons it’s important to continue to follow the participants in this study,” Ceyhan-Birsoy concludes.

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The BabySeq Project is jointly funded by the National Institutes of Health’s Human Genome Research Institute and its National Institute of Child Health and Human Development. This research was supported by the National Institutes of Health.

The American Journal of Human Genetics, Ceyhan-Birsoy et al. “Interpretation of genomic sequencing results in healthy and ill newborns: Results from the BabySeq Project.” https://www.cell.com/ajhg/fulltext/S0002-9297(18)30424-5

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Researchers identify a gene linked to needing less sleep

Source: Cell Press
Date: 08/28/2019
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The genetics of circadian rhythms have been well studied in recent years, but much less is known about other types of genes that play a role in sleep, specifically those that regulate how much sleep our bodies require. Now, by studying a family with several members who require significantly less sleep than average, a team of researchers has identified a new gene that they believe has a direct impact on how much someone sleeps. They report their findings on August 28 in the journal Neuron.

“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” says Louis Ptáček, a neurologist at the University of California, San Francisco (UCSF), and one of the paper’s two senior authors. “This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”

The family whose DNA led to the identification of this gene is one of several that Ptáček and UCSF geneticist Ying-Hui Fu, the paper’s other senior author, are studying and includes several members who function normally on only six hours of sleep. The gene, ADRB1, was identified using genetic linkage studies and whole-exome sequencing, which revealed a novel and very rare variant.

The first step in deciphering the role of the gene variant involved studying its protein in the test tube. “We wanted to determine if these mutations caused any functional alterations compared with the wild type,” Fu says. “We found that this gene codes for ß1-adrenergic receptor, and that the mutant version of the protein is much less stable, altering the receptor’s function. This suggested it was likely to have functional consequences in the brain.”

The researchers then conducted a number of experiments in mice carrying a mutated version of the gene. They found that these mice slept on average 55 minutes less than regular mice. (Humans with the gene sleep two hours less than average.) Further analysis showed that the gene was expressed at high levels in the dorsal pons, a part of the brain stem involved in subconscious activities such as respiration and eye movement as well as sleep.

Additionally, they discovered that normal ADRB1 neurons in this region were more active not only during wakefulness, but also during REM (rapid eye movement) sleep. However, they were quiet during non-REM sleep. Furthermore, they found that the mutant neurons were more active than normal neurons, likely contributing to the short sleep behavior.

“Another way we confirmed the role of the protein was using optogenetics,” Fu explains. “When we used light to activate the ADRB1 neurons, the mice immediately woke up from sleep.”

Ptáček acknowledges some limitations of using mice to study sleep. One of these is that mice exhibit different sleep patterns than humans, including, for example, sleeping in a fragmented pattern, rather than in a single continuous period. “But it’s challenging to study sleep in humans, too, because sleep is a behavior as well as a function of biology,” he says. “We drink coffee and stay up late and do other things that go against our natural biological tendencies.”

The investigators plan to study the function of the ADRB1 protein in other parts of the brain. They also are looking at other families for additional genes that are likely to be important. “Sleep is complicated,” Ptáček notes. “We don’t think there’s one gene or one region of the brain that’s telling our bodies to sleep or wake. This is only one of many parts.”

Fu adds that the work may eventually have applications for developing new types of drugs to control sleep and wakefulness. “Sleep is one of the most important things we do,” she says. “Not getting enough sleep is linked to an increase in the incidence of many conditions, including cancer, autoimmune disorders, cardiovascular disease, and Alzheimer’s.”

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This work was funded by the National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics, the National Institutes of Health (NIH), and the William Bowes Neurogenetics Fund.

Neuron, Shi et al. “A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors.” https://www.cell.com/neuron/fulltext/S0896-6273(19)30652-X

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Important gene variants found in certain African populations

Source: Cell Press
Date: 10/31/2019
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In the nearly 20 years since the Human Genome Project was completed, experts in genetic variants increasingly have raised concerns about the overemphasis on studying people of European descent when performing large population studies. A study appearing October 31 in the journal Cell aims to address some of this disparity by focusing on populations living in rural Uganda, thus revealing several new genetic variants related to human health.

“This study highlights the high level of diversity in African populations that remains undiscovered despite large numbers of gene sequences that have been generated from Europeans,” says co-senior author Manjinder Sandhu, who studies genomic diversity at the University of Cambridge in the UK. “We found that more than a quarter of the genetic variation we observed in the Ugandan population had not been discovered.”

The participants in the study came from 25 villages in a rural part of southwestern Uganda. Using blood samples, the investigators generated genotypes from about 5,000 individuals and conducted whole-genome sequencing on about 2,000 individuals. The researchers collected information through electronic questionnaires; carried out physical measurements such as blood pressure, height, and weight; and tested the blood samples for medically important markers such as cholesterol and glucose.

The investigators made several findings related to genetic variants and health. “We found many new associations with blood traits, liver function tests, and glucose-related traits,” Sandhu says. “Most of these relate to genetic variants that are either unique to Africans or rare in non-Africans. They may not have been readily discovered even in very large studies of non-African populations.”

Specifically, they found that height is less genetically determined among rural Ugandans relative to what’s been seen in European studies. In contrast, LDL cholesterol levels appear to be more genetically determined relative to Europeans.

“We think this might relate to differences in the impact of diet and nutrition relative to genetic influences between African and European populations,” says co-first author Deepti Gurdasani, a career development fellow at Queen Mary’s University of London. “For example, the genetic influences on height might be more limited by malnutrition in early childhood in these populations. On the other hand, so-called Western dietary patterns possibly have a lower influence on cholesterol levels, making these more genetically determined.”

The researchers also found an association between a genetic variant that causes alpha-thalassemia among Africans and levels of glycated hemoglobin. This genetic variant, found in 22% of Africans, protects against severe malaria. It is rare in populations where malaria isn’t endemic. “Because glycated hemoglobin is commonly used to diagnose diabetes, this finding suggests that it needs careful evaluation as a test for diabetes in relevant populations,” says co-senior author Ayesha Motala, of KwaZulu Natal University in South Africa.

The study also revealed important findings about human history and migration. “Uganda is a melting pot of different cultures and languages, and we wanted to understand the genetic structure and history of populations within the country,” says Pontiano Kaleebu, the Director of Uganda Virus Research Institute and Director of the MRC/UVRI & London School of Hygiene and Tropical Medicine Uganda Research Unit, who co-led the project. “These studies highlight the extensive movement and population expansions that have occurred within and into Africa over the past few thousand years.”

Analysis revealed that the genomes of Ugandans are a mosaic of many ancestries, likely reflecting the extensive migration from surrounding regions spanning hundreds to thousands of years. It also showed that significant Eurasian ancestry has entered the region at multiple time points, ranging from a few hundred years ago to about 4,000 years ago.

Although the researchers identified new genetic variants associated with disease, they say much more research is needed to understand how these genetic variants affect disease traits. This will require not just looking at genomes but also at functional effects of genomes on gene expression and protein levels.

In the future, they also plan to look at individuals from other parts of Africa, especially indigenous hunter-gatherer populations such as the Khoe-San populations in Namibia and South Africa and the rainforest hunter-gatherer populations in central Africa.

“This study confirms that genetic causes of disease may be different in Africans and provides opportunities to identify new genes associated with disease that would not be identified in European studies,” Gurdasani concludes. “This kind of research will allow us to identify new targets for therapies that could potentially be useful for all populations.”

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This work was funded by the Wellcome Trust, the Wellcome Sanger Institute, the UK Medical Research Council, and the Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine Uganda Research Unit core funding. This work was funded in part by IAVI with the generous support of the United States Agency for International Development and other donors.

Cell, Gurdasani et al. “Uganda Genome Resource enables insights into population history and genomic discovery in Africa” https://www.cell.com/cell/fulltext/S0092-8674(19)31120-1