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Largest Study of Its Kind Reveals New Targetable Genetic Causes of the Rare Blood Disorder Histiocytosis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/04/2019
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Histiocytoses are a group of blood diseases that are diagnosed in only a few hundred people in the United States every year. Despite that rarity, researchers at Memorial Sloan Kettering have extensive experience with histiocytosis. MSK doctors care for more adults with histiocytosis than doctors at any other hospital in the country.

In recent years, MSK investigators have led a number of studies on the specific gene mutations that cause different types of histiocytoses (also called histiocytic neoplasms). On November 25, in Nature Medicine, an international team led by MSK reported findings from the largest study of its kind. They identified mutations for nearly all of the 270 people included in the study.

“We’ve known for some time that most cases of this disease are driven by a single mutation,” says MSK neurologist and histiocytosis expert Eli Diamond, one of the paper’s two senior authors. “In the past, we’ve been able to define those mutations for about 70% of patients.”

“Through the more extensive sequencing that we’ve done in this study, we can now define the mutations driving the disease in close to 100% of patients,” adds MSK physician-scientist Omar Abdel-Wahab, the paper’s other senior author. “For most of these mutations, we already have drugs to target them.”

Previous Success with Targeted Therapies

Histiocytosis occurs when the body makes an unusually large amount of abnormal white blood cells, referred to as histiocytes. These cells can build up and form tumors, which can grow in any part of the body. The bones and skin are most commonly affected.

The most common types of histiocytoses are Erdheim-Chester disease, which occurs mostly in adults; Langerhans cell histiocytosis and Rosai-Dorfman disease, which can affect both children and adults; and juvenile xanthogranuloma, which is found almost exclusively in children. All of these types were included in the study, as well as some other, rarer forms of the disease.

Thanks to earlier research done at MSK and elsewhere, experts already knew about the mutations driving many of these subtypes. That understanding has led to targeted therapies that are effective in treating them.

In 2017, vemurafenib (Zelboraf®) was the first drug approved for people with Erdheim-Chester disease. Vemurafenib targets mutations in a gene called BRAF. In October 2019, the US Food and Drug Administration announced that it had granted a Breakthrough Therapy Designation for the drug cobimetinib (Cotellic®) to treat histiocytosis with mutations in the genes MEK1 and MEK2. This designation indicates that the agency believes the drug is particularly promising. The clinical trials for both of these drugs were led by investigators at MSK.

“Another thing that’s important to note is that unlike treatment with most targeted therapies, where the tumors eventually become resistant to the drugs, when histiocytosis is treated with these therapies, patients’ responses tend to be long-lasting,” Dr. Diamond says. “Many people have remained on these drugs for years with durable benefits and few side effects.”

The new study opens up opportunities for even more people to be treated with targeted therapies. The researchers uncovered mutations in the RET, ALK, and NTRK genes. All of these mutations can be targeted with drugs that are already approved or are in clinical trials for other types of cancer with these mutations.

The study also reported for the first time that the gene CSF1R is implicated in certain cases of histiocytosis. CSF1R was already known to be important in the formation of a type of white blood cell called a macrophage.

“One of the strengths of this study is that it included all subtypes of histiocytosis. We have enough data to make these correlations between specific gene mutations and specific forms of histiocytosis,” says Dr. Abdel-Wahab, who leads a lab in MSK’s Human Oncology and Pathogenesis Program.

New Details about the Causes of Histiocytosis

The study revealed valuable information about the underlying origins of these diseases as well.

For example, doctors observed twins with histiocytosis. The investigators found that the common mutation driving the disease came not from the twins’ parents but from a mutation in the very early embryo that affected how their blood cells developed. These findings have implications for understanding how histiocytosis forms in many people.

Many of the patients whose data were included in the study were treated at MSK, but people treated at hospitals in Europe and other parts of the United States were included, too. Investigators from several other institutions were co-authors on the paper.

One way that the team was able to collect so many samples is through Make-an-IMPACT. This MSK initiative provides individuals with rare cancers the opportunity to receive genomic testing of their tumors at no cost. Histiocytosis is one of the cancer types included in this program.

“It’s very important that everyone who has histiocytosis gets their tumor sequenced,” Dr. Abdel-Wahab says. “It not only can help them but can also make important contributions to research.”

This work was supported by grants from the Histiocytosis Association, the Erdheim-Chester Disease Global Alliance, the American Society of Hematology, the Leukemia and Lymphoma Society, the Pershing Square Sohn Cancer Research Alliance, the Functional Genomics Initiative at MSK, The Society of Memorial Sloan Kettering, a Translational and Integrative Medicine Award from Memorial Sloan Kettering, the Geoffrey Beene Cancer Research Center at MSK, the Frame Family Fund, the Joy Family West Foundation, the Nonna’s Garden foundation, the Flanders Institute for Biotechnology in Belgium, and the National Institutes of Health (K08CA218901, UL1TR001857, P30CA008748, and 1R01CA201247).

This work was also supported by Cycle for Survival, MSK’s rare cancer fundraising program. Make-an-IMPACT is also funded by Cycle for Survival.

Dr. Abdel-Wahab has received grants from H3 Biomedicine and personal fees from H3 Biomedicine, Foundation Medicine, Merck, and Jansen unrelated to this manuscript.

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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

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Simulations suggest embryo selection based on traits like height or IQ is still far off

Source: Cell Press
Date: 11/21/2019
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There have been concerns about the idea of “designer babies” for almost as long as in vitro fertilization and technology to screen embryos for inherited disorders have existed. While the recent live births resulting from human embryonic CRISPR editing have heightened global attention to these issues, currently, the most practical approach to genetic “enhancement” of embryos is preimplantation genetic screening of IVF embryos. But according to a study publishing November 21 in the journal Cell, the ability to select for traits that are brought about by multiple genes–rather than genetic diseases caused by a single mutation–is more far off and complicated than most people probably realize.

“The ability to do genomic sequencing of embryos is much easier than it was even five years ago, and we know many more gene variants linked to certain traits,” says co-corresponding author Shai Carmi, of the Hebrew University of Jerusalem. “But selecting embryos for particular traits is very controversial except when it relates to a serious disease like cystic fibrosis. It raises many issues related to eugenics and unequal opportunities.”

Carmi’s team looked at the feasibility of selecting embryos based on each of two traits caused by multiple genes–IQ and height–as a kind of thought experiment. While there are many traits determined by multiple genes that the researchers could have investigated, they chose to focus on IQ because it is frequently brought up in concerns regarding eugenics and on height because it is objectively measurable and a lot is known about the complex genetics influencing height. Their findings suggest that our current knowledge of the genetics of these types of traits may not be enough to generate a substantial increase in the desired traits in an IVF embryo selection scenario.

In the study, the researchers ran computer simulations using genomic sequences from real people to model genomic profiles of hypothetical embryos that would result from pairs of those people–some actual couples and some artificially paired. In the simulations, they assumed that each couple would have ten embryos to choose from. They then predicted the IQ or adult height for each of the offspring based on the gene variants present in the genomes of the simulated embryos. Their experiments were based on the assumption that the embryo with the top score could then be selected for implantation.

They found that expected advantages to these theoretical offspring would be relatively small. For IQ, the most it increased above the average of the embryos was three points. For height, the most it increased above the average was three centimeters.

And even if some people might believe that those increases were great enough to warrant using the technology, they are not guaranteed.

“There is much about these traits that is unpredictable,” Carmi says. “If someone selected an embryo that was predicted to have an IQ that was two points higher than the average, this is no guarantee it would actually result in that increase. There is a lot of variability that is not accounted for in the known gene variants.”

There are several other limitations, Carmi notes, that would make it challenging to accurately select embryos for desired traits.

For one, the researchers conducted their simulations using ten embryos from each couple, but in reality, many couples get far fewer viable embryos when they do in vitro fertilization. For example, with five embryos, the gain would be reduced to 2.5 IQ points or 2.5 cm. When they based the simulation on 50 or 100 embryos, they found that the benefit per embryo decreased as the number of embryos increased, indicating diminishing returns even with large numbers of hypothetical embryos to choose from.

In addition, what is known about the gene variants linked to traits like height and IQ–as well as other health-related traits like blood pressure and cholesterol–applies mainly to people of European descent. They would be much less applicable for people from other parts of the world. Finally, attempting to maximize more than one trait, a potential future scenario, would make embryo selection far more complicated: an embryo that ranked highest for IQ may rank lowest for height, for example.

Furthermore, the researchers used real-world data to confirm that predictions about traits made using what’s currently known about gene variants are not always accurate. They reported on an analysis of 28 families with up to 20 children who have grown to adulthood–and found that the offspring they would have selected for having the greatest height based on gene variants was not always the tallest one in adulthood.

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This research was supported by the Abisch-Frenkel Foundation, the National Institutes of Health, and the James S. McDonnell Centennial Fellowship in Human Genetics.

Cell, Karavani et al.: “Screening human embryos for polygenic traits has limited utility” https://www.cell.com/cell/fulltext/S0092-8674(19)31210-3