In a bid to detect cancers early and in a non-invasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to accurately identify more than half of 138 people with relatively early-stage colorectal, breast, lung and ovarian cancers. The test, the scientists say, is novel in that it can distinguish between DNA shed from tumours and other altered DNA that can be mistaken for cancer biomarkers. “This study shows that identifying cancer early using DNA changes in the blood is feasible and that our high accuracy sequencing method is a promising approach to achieve this goal,” says Victor Velculescu, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center. Blood tests for cancer are a growing part of clinical oncology, but they remain in the early stages of development. To find small bits of cancer-derived DNA in the blood of cancer patients, scientists have frequently relied on DNA alterations found in patients’ biopsied tumour samples as guideposts for the genetic mistakes they should be looking for among the masses of DNA circulating in those patients’ blood samples. To develop a cancer screening test that could be used to screen seemingly healthy people, scientists had to find novel ways to spot DNA alterations that could be lurking in a person’s blood but had not been previously identified. “The challenge was to develop a blood test that could predict the probable presence of cancer without knowing the genetic mutations present in a person’s tumour,” says Velculescu. The goal, adds Jillian Phallen, a graduate student at the Johns Hopkins Kimmel Cancer Center who was involved in the research, was to develop a screening test that is highly specific for cancer and accurate enough to detect the cancer when present, while reducing the risk of “false positive” results that often lead to unnecessary over-testing and overtreatments. The task is notably complicated, says Phallen, by the need to sort between true cancer-derived mutations and genetic alterations that occur in blood cells and as part of normal, inherited variations in DNA. As blood cells divide, for example, Velculescu says there is a chance these cells will acquire mistakes or mutations. In a small fraction of people, these changes will spur a blood cell to multiply faster than its neighbouring cells, potentially leading to pre-leukemic conditions. However, most of the time, the blood-derived mutations are not cancer-initiating. His team also ruled out so-called “germline” mutations. While germline mutations are indeed alterations in DNA, they occur as a result of normal variations between individuals, and are not usually linked to particular cancers. To develop the new test, Velculescu, Phallen and their colleagues obtained blood samples from 200 patients with breast, lung, ovarian and colorectal cancer. The scientists’ blood test screened the patients’ blood samples for mutations within 58 genes widely linked to various cancers. Overall, the scientists were able to detect 86 of 138 (62 percent) stage I and II cancers. More specifically, among 42 people with colorectal cancer, the test correctly predicted cancer in half of the eight patients with stage I disease, eight of nine (89 percent) with stage II disease, nine of 10 (90 percent) with stage III and 14 of 15 (93 percent) with stage IV disease. Of 71 people with lung cancer, the scientists’ test identified cancer among 13 of 29 (45 percent) with stage I disease, 23 of 32 (72 percent) with stage II disease, three of four (75 percent) with stage III disease and five of six (83 percent) with stage IV cancer. For 42 patients with ovarian cancer, 16 of 24 (67 percent) with stage I disease were correctly identified, as well as three of four (75 percent) with stage II disease, six of eight (75 percent) with stage III cancer and five of six (83 percent) with stage IV disease. Among 45 breast cancer patients, the test spotted cancer-derived mutations in two of three (67 percent) patients with stage I disease, 17 of 29 (59 percent) with stage II disease and six of 13 (46 percent) with stage III cancers. They found none of the cancer-derived mutations among blood samples of 44 healthy individuals. Despite these initial promising results for early detection, the blood test needs to be validated in studies of much larger numbers of people, say the scientists.
John Hopkins Medicinehttp://tinyurl.com/yd8vb763
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Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signalling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity. The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years. “Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years. The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection. “There’s been a great deal of controversy and confusion surrounding myalgic encephalomyelitis (ME) CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.” Many, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them. The sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down. To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the centre has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the centre is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signalling models, and more on a massive scale. This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph. The scientists analysed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years. Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease. When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumour growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory. TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link. One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.
Stanford Medicinehttp://tinyurl.com/y7agngxn
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A new Pathology Atlas has been launched with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns of individual cancers observed in the study strongly reinforces the need for personalized cancer treatment based on precision medicine. In addition, the systems level approach used to construct the Pathology Atlas demonstrates the power of “big data” to change how medical research is performed. The dream of personalized treatment for cancer patients takes a major step forward with the launch by Swedish researchers of the Human Pathology Atlas. The Atlas is based on the analysis of 17 main cancer types using data from 8,000 patients. In addition, a new concept for showing patient survival data is introduced, called Interactive Survival Scatter plots, and the atlas includes more than 400,000 such plots. A national supercomputer centre was used to analyse more than 2.5 petabytes of underlying publicly available data from the Cancer Genome Atlas (TCGA) to generate more than 900,000 survival plots describing the consequence of RNA and protein levels on clinical survival. The Pathology Atlas also contains 5 million pathology-based images generated by the Human Protein Atlas consortium. Professor Mathias Uhlen, Director of the Human Protein Atlas consortium and leader of the Pathology Atlas effort says: “This study differs from earlier cancer investigations, since it is not focused on the mutations in cancers, but the downstream effects of such mutations across all protein-coding genes. We show, for the first time, the influence of the gene expression levels demonstrating the power of “big data” to change how medical research is performed. It also shows the advantage of open access policies in science in which researchers share data with each other to allow integration of huge amounts of data from different sources.” The article reports several important findings related to cancer biology and treatment. Firstly, a large fraction of genes is differentially expressed in cancers – and in many cases – have an impact on overall patient survival. The research also showed that gene expression patterns of individual tumours varied considerably, and could exceed the variation observed between different cancer types. Shorter patient survival was generally associated with up-regulation of genes involved in mitosis and cell growth, and down-regulation of genes involved in cellular differentiation. The data allowed the researchers to generate personalized genome-scale metabolic models for cancer patients to identify key genes involved in tumour growth. The work depends heavily on the supercomputing power available to the Human Protein Atlas consortium through the Science for Life Laboratory (SciLifeLab). According to Dr. Adil Mardinoglu, SciLifeLab Fellow and leader of the systems biology effort in the project: “We are now in possession of incredibly powerful systems biology tools for medical research, allowing, for the first time, genome-wide analysis of individual patients with regards to the consequence of their expression profiles for clinical survival.” The Pathology Atlas is available via an interactive open-access database.
EurekAlerthttp://tinyurl.com/y6ubo3qb
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Autism spectrum disorder affects approximately one out of every 68 children in the United States. Despite expansive study, the origin and risk factors of the complex condition are not fully understood. To better understand the root causes, an international team led by researchers at OHSU in Portland, Oregon, has applied a new systematic analysis to a cohort of 2,300 families who have a single child affected with autism. The study focused on identifying and characterizing low-lying genetic mutations that may have been missed in previous research, given these mutations are only present in a fraction of the bulk DNA of an individual. Known as postzygotic mosaic mutations, or PMMs, these genetic changes occur after the conception of the human zygote during the development cycle of a foetus. An individual will contain a mosaic – or assortment – of mutated and non-mutated cells with the level of mosaicism depending on the time and location of the mutation’s occurrence. This emerging class of genetic risk factors has recently been implicated in various neurologic conditions, however, their role in more complex disorders, such as autism, has been unclear. By comparing genetic sequencing data of these families — part of the Simons Simplex Collection, a permanent repository of precisely characterized genetic samples — the research team determined that approximately 11 percent of previously reported new mutations affecting a single DNA base, which were thought to have be present at the time of human conception, actually show evidence of the mutation occurring during the development process. “This initial finding told us that, generally, these mosaic mutations are much more common than previously believed. We thought this might be the tip of a genetic iceberg waiting to be explored,” said the study’s principal investigator Brian O’Roak, Ph.D., an assistant professor of molecular and medical genetics in the OHSU School of Medicine. To investigate this possibility, a custom approach — leveraging next generation sequencing and molecular barcodes– was developed to both identify these low-level mutations, and also validate that they are, in fact, real and not technological artifacts. With this more sensitive method, the rate of potentially PMMs increased to 22 percent of the new mutations present in children. The researchers then compared the rates of PMMs that result in different predicted effects on the genome in affected children and their unaffected siblings. This lead to an unexpected finding that so-called “silent” mosaic mutations were enriched in the affected children, contributing risk to approximately 2 percent of the individuals with autism in this cohort. These types of mutations are generally believed to be neutral, as they don’t alter the genetic coding of proteins. However, the team found evidence that these mutations might actually be altering how genetic messages are stitched together. The study also found preliminary evidence that mosaic mutations that alter the protein code of genes essential for development, or genes that resist mutations, are also enriched in individuals with autism. This contributes risk to an additional 1 to 2 percent of individuals with autism. Many of the PMMs occurred in some of the most highly validated autism risk genes identified to date, further suggesting that these mutations are contributing to autism genetic risk. Due to this, the research team believes that overall, mosaic mutations may contribute to autism risk in 3 to 4 percent of this cohort.
OHSU School of Medicine news.ohsu.edu/2017/08/31/study-identifies-new-genetic-risk-factor-for-developing-autism-spectrum-disorder
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Cancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown. This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body. With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these "liquid biopsies" will be offered to patients within the next five years. Circulating tumour cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumours, but new methods are bringing their diagnostic value ever closer to patient care. Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumours and travel through the body in the bloodstream. This is how metastases, or satellite tumours elsewhere in the body, are thought to form. "The tumours were constantly shedding cells even when they were small — that’s one thing we learned," Nagrath said. "Although we define the tumours as early stage, already they are disseminating cells in the body." Early-stage lung cancer patients, whose tumours may only measure a few millimetres in diameter, are typically treated with surgical removal of the tumour, but the study results suggest that this may not be enough. A handful of patients had tumours that were shedding hundreds or thousands of tumour cells into the lung. "Even though you removed the tumour, you left behind these hundreds and hundreds of cells," Nagrath said. "If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?" With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumour will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumour cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumour cells appearing in clusters. "Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection," said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.
University of Michigan www.mcancer.org/news/archive/blood-test-can-predict-early-lung-cancer-prognosis
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A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease. Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment. Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material. TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK. Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development. As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. "Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease," said Crowther. While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. "The end result is the same. In both cases, there is too little full-length TREM protein on microglia," said Haass. "This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy."
Extending non-invasive prenatal screening to all 24 human chromosomes can detect genetic disorders that may explain miscarriage and abnormalities during pregnancy, according to a study by researchers at the National Institutes of Health and other institutions. Because of the way data have been analysed, typical genomic tests performed during pregnancy have targeted extra copies of chromosomes 21, 18 and 13, but rarely evaluated all 24 chromosomes. The study findings may ultimately improve the accuracy of these tests, including by explaining why some give false-positive results. Women often request non-invasive screening tests to detect genetic conditions. These tests, however, typically focus only on Down syndrome and other common trisomies. A trisomy is a condition in which there are three instances of a certain chromosome instead of the standard two. "Extending our analysis to all chromosomes allowed us to identify risk for serious complications and potentially reduce false-positive results for Down syndrome and other genetic conditions," said Diana W. Bianchi, M.D., senior author of the study and chief of the Prenatal Genomics and Therapy Section at NIH’s National Human Genome Research Institute (NHGRI). Dr. Bianchi is also the director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The investigators analysed DNA sequence data from nearly 90,000 samples of maternal plasma, the liquid portion of blood after all cells have been removed. Of these samples, 72,972 came from a U.S. cohort and 16,885 came from an Australian cohort. For each, researchers calculated a normalized chromosome denominator quality (NCDQ), which measures the likelihood that a sample has the standard two copies of each chromosome. Those with an NCDQ of 50 or below were flagged for further evaluation. In the U.S. cohort, 328 (0.45 percent) samples were flagged and ultimately classified as abnormal. In the Australian cohort, 71 (0.42 percent) samples were deemed abnormal, 60 of which contained a rare trisomy. Trisomy 7 was observed most frequently in both study cohorts, followed by trisomies 15, 16 and 22. Pregnancy and other outcome data were available for 52 of the 60 cases of rare trisomies found in the Australian cohort. Notably, researchers linked 22 samples with early miscarriage (occurring before 11 or 12 weeks gestation), including 13 of 14 samples with trisomy 15 and 3 of 5 samples with trisomy 22. "We found that pregnancies at greatest risk of serious complications were those with very high levels of abnormal cells in the placenta," said Mark D. Pertile, Ph.D., co-first author of the study and head of the division of reproductive genetics at Victorian Clinical Genetics Services, part of Murdoch Childrens Research Institute in Melbourne, Australia. "Our results suggest that patients be given the option of receiving test results from all 24 chromosomes."
The National Human Genome Research Institute (NHGRI) www.genome.gov/27569418/2017-news-relase-sequencing-all-24-human-chromosomes-uncovers-rare-disorders/
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Malaria is a leading cause of death for children living in Sub-Saharan Africa. Many children in rural areas seek care at local community health clinics, but these clinics lack reliable tests to distinguish severe and uncomplicated malaria. Working at a health centre in rural Uganda, researchers from the University of North Carolina at Chapel Hill demonstrated for the first time the potential of using a low-cost, routinely available rapid diagnostic test to detect severe malaria in children. “In many areas of rural areas of sub-Saharan Africa, malaria is inevitable. Children will be infected,” said Ross Boyce, M.D., MS.c., study author and a fellow in the UNC Division of Infectious Diseases. “Ensuring that those with the most severe form of the disease are quickly identified and treated, even when hours from the nearest hospital, is critically important to reducing the number of deaths.” Over a period of six months, a total of 2,678 children with fever underwent testing for malaria using a rapid diagnostic test at the Bugoye Level III Health Center in the Kasese District of Western Uganda. Nearly half tested positive for malaria and 83 satisfied criteria for severe malaria. The sensitivity and specificity of the rapid diagnostic test for detecting severe malaria was 97.6 percent. The test was especially sensitive for children less than 5 years of age. Knowing when a child is suffering from severe malaria allows for a referral to a health centre better equipped to handle the disease’s grave manifestations. “Rapid diagnostic tests have been around for awhile, and are generally considered standard of care in most malaria-endemic settings,” said Boyce. “However, what we’ve done is show that these relatively simple tests can be used in new ways to provide important information beyond just a positive or negative result. While it’s not perfect, the approach could help first-line healthcare workers – many of who have no formal medical training – make potentially lifesaving triage decisions.” Boyce said further work is needed to validate and operationalize diagnostic and treatment algorithms so as not to overwhelm fragile referral networks.
University of North Carolina globalhealth.unc.edu/2017/08/rapid-diagnostic-test-malaria/
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Vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme. “We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of Perlmutter Cancer Center. Changes in the genetic code, or mutations, that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages. Along with these diseases, new tests suggest that about 2.5 percent of all United States cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumours, say the authors. The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context. These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them. The back-and-forth attachment and removal of methyl groups also fine tunes gene expression in stem cells, which can mature, specialize, and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection. The enzyme studied in this report TET2, enables a change in the molecular structure, or oxidation, of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a countdown toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Dr. Neel. To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off. Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene. Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.
NYU Langone Healthhttp://tinyurl.com/y8pvrxso
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Using fragments of circulating tumour DNA in blood, University of California San Diego School of Medicine researchers were able to identify theoretically targetable genetic alterations in 66 percent of patients with cancer of unknown primary (CUP), a rare disease with seven to 12 cases per 100,000 people each year. In order to plan treatment for cancer in general, physicians first attempt to pinpoint the primary cancer — where the tumour first developed. In CUP, despite its spread throughout the body, the origin remains unknown, making treatment more difficult. The current standard of care is platinum-based combination chemotherapies with a median survival time of six to eight months. In a study, researchers report that by sequencing circulating tumour DNA (ctDNA) derived from blood samples in 442 patients with CUP, they were able to identify at least one genetic alteration linked to cancer in 290 — 66 percent — of patients. Researchers used a screening test developed by Guardant Health that evaluates up to 70 genes. Based on known carcinogenic mutations, 99.7 percent of the 290 patients who had detectable tumour DNA in their bloodstream had genomic alterations that could hypothetically be targeted using existing FDA-approved drugs (as off-label use) or with therapies currently under investigation in clinical trials. “By definition, CUP does not have a definite anatomical diagnosis, but we believe genomics is the diagnosis,” said Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at Moores Cancer Center at UC San Diego Health and senior author. “Cancer is not simple and CUP makes finding the right therapy even more difficult. There are multiple genes and abnormalities involved in different areas of the body. Our research is the first to show that evaluating circulating tumour DNA from a tube of blood is possible in patients with CUP and that most patients harbour unique and targetable alterations.” “Another advantage of the liquid biopsy is that the location of the cancer does not matter,” said Shumei Kato, MD, assistant professor of medicine at UC San Diego School of Medicine and first author. “With a blood sample, we can analyse the DNA of tumours throughout the body to find targetable alterations. With tissue biopsies, we can only see genomic changes that are in that one site and that may not be the same as what is in different sites not biopsied, such as the lung or bone.”
Moores Cancer Centerhttp://tinyurl.com/y9lffvh3
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Blood test spots tumour-derived DNA in people with early-stage cancer
, /in E-News /by 3wmediaIn a bid to detect cancers early and in a non-invasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to accurately identify more than half of 138 people with relatively early-stage colorectal, breast, lung and ovarian cancers. The test, the scientists say, is novel in that it can distinguish between DNA shed from tumours and other altered DNA that can be mistaken for cancer biomarkers.
“This study shows that identifying cancer early using DNA changes in the blood is feasible and that our high accuracy sequencing method is a promising approach to achieve this goal,” says Victor Velculescu, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center.
Blood tests for cancer are a growing part of clinical oncology, but they remain in the early stages of development. To find small bits of cancer-derived DNA in the blood of cancer patients, scientists have frequently relied on DNA alterations found in patients’ biopsied tumour samples as guideposts for the genetic mistakes they should be looking for among the masses of DNA circulating in those patients’ blood samples.
To develop a cancer screening test that could be used to screen seemingly healthy people, scientists had to find novel ways to spot DNA alterations that could be lurking in a person’s blood but had not been previously identified.
“The challenge was to develop a blood test that could predict the probable presence of cancer without knowing the genetic mutations present in a person’s tumour,” says Velculescu.
The goal, adds Jillian Phallen, a graduate student at the Johns Hopkins Kimmel Cancer Center who was involved in the research, was to develop a screening test that is highly specific for cancer and accurate enough to detect the cancer when present, while reducing the risk of “false positive” results that often lead to unnecessary over-testing and overtreatments.
The task is notably complicated, says Phallen, by the need to sort between true cancer-derived mutations and genetic alterations that occur in blood cells and as part of normal, inherited variations in DNA.
As blood cells divide, for example, Velculescu says there is a chance these cells will acquire mistakes or mutations. In a small fraction of people, these changes will spur a blood cell to multiply faster than its neighbouring cells, potentially leading to pre-leukemic conditions. However, most of the time, the blood-derived mutations are not cancer-initiating.
His team also ruled out so-called “germline” mutations. While germline mutations are indeed alterations in DNA, they occur as a result of normal variations between individuals, and are not usually linked to particular cancers.
To develop the new test, Velculescu, Phallen and their colleagues obtained blood samples from 200 patients with breast, lung, ovarian and colorectal cancer. The scientists’ blood test screened the patients’ blood samples for mutations within 58 genes widely linked to various cancers.
Overall, the scientists were able to detect 86 of 138 (62 percent) stage I and II cancers. More specifically, among 42 people with colorectal cancer, the test correctly predicted cancer in half of the eight patients with stage I disease, eight of nine (89 percent) with stage II disease, nine of 10 (90 percent) with stage III and 14 of 15 (93 percent) with stage IV disease. Of 71 people with lung cancer, the scientists’ test identified cancer among 13 of 29 (45 percent) with stage I disease, 23 of 32 (72 percent) with stage II disease, three of four (75 percent) with stage III disease and five of six (83 percent) with stage IV cancer. For 42 patients with ovarian cancer, 16 of 24 (67 percent) with stage I disease were correctly identified, as well as three of four (75 percent) with stage II disease, six of eight (75 percent) with stage III cancer and five of six (83 percent) with stage IV disease. Among 45 breast cancer patients, the test spotted cancer-derived mutations in two of three (67 percent) patients with stage I disease, 17 of 29 (59 percent) with stage II disease and six of 13 (46 percent) with stage III cancers.
They found none of the cancer-derived mutations among blood samples of 44 healthy individuals.
Despite these initial promising results for early detection, the blood test needs to be validated in studies of much larger numbers of people, say the scientists.
John Hopkins Medicinehttp://tinyurl.com/yd8vb763
Biomarkers associated with chronic fatigue syndrome severity
, /in E-News /by 3wmediaResearchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signalling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
“Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years.
The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.
“There’s been a great deal of controversy and confusion surrounding myalgic encephalomyelitis (ME) CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”
Many, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.
The sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down.
To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the centre has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the centre is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signalling models, and more on a massive scale.
This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph.
The scientists analysed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years.
Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease.
When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumour growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory.
TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link.
One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.
Stanford Medicinehttp://tinyurl.com/y7agngxn
Atlas maps genes in cancer to accelerate progress in personalized medicine
, /in E-News /by 3wmediaA new Pathology Atlas has been launched with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns of individual cancers observed in the study strongly reinforces the need for personalized cancer treatment based on precision medicine. In addition, the systems level approach used to construct the Pathology Atlas demonstrates the power of “big data” to change how medical research is performed.
The dream of personalized treatment for cancer patients takes a major step forward with the launch by Swedish researchers of the Human Pathology Atlas. The Atlas is based on the analysis of 17 main cancer types using data from 8,000 patients. In addition, a new concept for showing patient survival data is introduced, called Interactive Survival Scatter plots, and the atlas includes more than 400,000 such plots. A national supercomputer centre was used to analyse more than 2.5 petabytes of underlying publicly available data from the Cancer Genome Atlas (TCGA) to generate more than 900,000 survival plots describing the consequence of RNA and protein levels on clinical survival. The Pathology Atlas also contains 5 million pathology-based images generated by the Human Protein Atlas consortium.
Professor Mathias Uhlen, Director of the Human Protein Atlas consortium and leader of the Pathology Atlas effort says: “This study differs from earlier cancer investigations, since it is not focused on the mutations in cancers, but the downstream effects of such mutations across all protein-coding genes. We show, for the first time, the influence of the gene expression levels demonstrating the power of “big data” to change how medical research is performed. It also shows the advantage of open access policies in science in which researchers share data with each other to allow integration of huge amounts of data from different sources.”
The article reports several important findings related to cancer biology and treatment. Firstly, a large fraction of genes is differentially expressed in cancers – and in many cases – have an impact on overall patient survival. The research also showed that gene expression patterns of individual tumours varied considerably, and could exceed the variation observed between different cancer types. Shorter patient survival was generally associated with up-regulation of genes involved in mitosis and cell growth, and down-regulation of genes involved in cellular differentiation. The data allowed the researchers to generate personalized genome-scale metabolic models for cancer patients to identify key genes involved in tumour growth.
The work depends heavily on the supercomputing power available to the Human Protein Atlas consortium through the Science for Life Laboratory (SciLifeLab). According to Dr. Adil Mardinoglu, SciLifeLab Fellow and leader of the systems biology effort in the project: “We are now in possession of incredibly powerful systems biology tools for medical research, allowing, for the first time, genome-wide analysis of individual patients with regards to the consequence of their expression profiles for clinical survival.”
The Pathology Atlas is available via an interactive open-access database.
EurekAlerthttp://tinyurl.com/y6ubo3qb
Study identifies new genetic risk factor for developing autism spectrum disorder
, /in E-News /by 3wmediaAutism spectrum disorder affects approximately one out of every 68 children in the United States. Despite expansive study, the origin and risk factors of the complex condition are not fully understood.
To better understand the root causes, an international team led by researchers at OHSU in Portland, Oregon, has applied a new systematic analysis to a cohort of 2,300 families who have a single child affected with autism. The study focused on identifying and characterizing low-lying genetic mutations that may have been missed in previous research, given these mutations are only present in a fraction of the bulk DNA of an individual.
Known as postzygotic mosaic mutations, or PMMs, these genetic changes occur after the conception of the human zygote during the development cycle of a foetus. An individual will contain a mosaic – or assortment – of mutated and non-mutated cells with the level of mosaicism depending on the time and location of the mutation’s occurrence. This emerging class of genetic risk factors has recently been implicated in various neurologic conditions, however, their role in more complex disorders, such as autism, has been unclear.
By comparing genetic sequencing data of these families — part of the Simons Simplex Collection, a permanent repository of precisely characterized genetic samples — the research team determined that approximately 11 percent of previously reported new mutations affecting a single DNA base, which were thought to have be present at the time of human conception, actually show evidence of the mutation occurring during the development process.
“This initial finding told us that, generally, these mosaic mutations are much more common than previously believed. We thought this might be the tip of a genetic iceberg waiting to be explored,” said the study’s principal investigator Brian O’Roak, Ph.D., an assistant professor of molecular and medical genetics in the OHSU School of Medicine.
To investigate this possibility, a custom approach — leveraging next generation sequencing and molecular barcodes– was developed to both identify these low-level mutations, and also validate that they are, in fact, real and not technological artifacts. With this more sensitive method, the rate of potentially PMMs increased to 22 percent of the new mutations present in children.
The researchers then compared the rates of PMMs that result in different predicted effects on the genome in affected children and their unaffected siblings. This lead to an unexpected finding that so-called “silent” mosaic mutations were enriched in the affected children, contributing risk to approximately 2 percent of the individuals with autism in this cohort. These types of mutations are generally believed to be neutral, as they don’t alter the genetic coding of proteins. However, the team found evidence that these mutations might actually be altering how genetic messages are stitched together.
The study also found preliminary evidence that mosaic mutations that alter the protein code of genes essential for development, or genes that resist mutations, are also enriched in individuals with autism. This contributes risk to an additional 1 to 2 percent of individuals with autism. Many of the PMMs occurred in some of the most highly validated autism risk genes identified to date, further suggesting that these mutations are contributing to autism genetic risk. Due to this, the research team believes that overall, mosaic mutations may contribute to autism risk in 3 to 4 percent of this cohort.
OHSU School of Medicine
news.ohsu.edu/2017/08/31/study-identifies-new-genetic-risk-factor-for-developing-autism-spectrum-disorder
A blood test can predict early lung cancer prognosis
, /in E-News /by 3wmediaCancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown.
This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body.
With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these "liquid biopsies" will be offered to patients within the next five years.
Circulating tumour cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumours, but new methods are bringing their diagnostic value ever closer to patient care.
Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumours and travel through the body in the bloodstream. This is how metastases, or satellite tumours elsewhere in the body, are thought to form.
"The tumours were constantly shedding cells even when they were small — that’s one thing we learned," Nagrath said. "Although we define the tumours as early stage, already they are disseminating cells in the body."
Early-stage lung cancer patients, whose tumours may only measure a few millimetres in diameter, are typically treated with surgical removal of the tumour, but the study results suggest that this may not be enough. A handful of patients had tumours that were shedding hundreds or thousands of tumour cells into the lung.
"Even though you removed the tumour, you left behind these hundreds and hundreds of cells," Nagrath said. "If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?"
With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumour will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumour cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumour cells appearing in clusters.
"Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection," said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.
University of Michigan
www.mcancer.org/news/archive/blood-test-can-predict-early-lung-cancer-prognosis
Stabilizing TREM2 — a potential strategy to combat Alzheimer’s disease
, /in E-News /by 3wmediaA gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.
Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.
Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.
TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.
Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.
As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. "Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease," said Crowther.
While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. "The end result is the same. In both cases, there is too little full-length TREM protein on microglia," said Haass. "This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy."
EurekAlert
www.eurekalert.org/pub_releases/2017-08/e-st-083017.php
Sequencing all 24 human chromosomes uncovers rare disorders
, /in E-News /by 3wmediaExtending non-invasive prenatal screening to all 24 human chromosomes can detect genetic disorders that may explain miscarriage and abnormalities during pregnancy, according to a study by researchers at the National Institutes of Health and other institutions. Because of the way data have been analysed, typical genomic tests performed during pregnancy have targeted extra copies of chromosomes 21, 18 and 13, but rarely evaluated all 24 chromosomes. The study findings may ultimately improve the accuracy of these tests, including by explaining why some give false-positive results.
Women often request non-invasive screening tests to detect genetic conditions. These tests, however, typically focus only on Down syndrome and other common trisomies. A trisomy is a condition in which there are three instances of a certain chromosome instead of the standard two.
"Extending our analysis to all chromosomes allowed us to identify risk for serious complications and potentially reduce false-positive results for Down syndrome and other genetic conditions," said Diana W. Bianchi, M.D., senior author of the study and chief of the Prenatal Genomics and Therapy Section at NIH’s National Human Genome Research Institute (NHGRI). Dr. Bianchi is also the director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
The investigators analysed DNA sequence data from nearly 90,000 samples of maternal plasma, the liquid portion of blood after all cells have been removed. Of these samples, 72,972 came from a U.S. cohort and 16,885 came from an Australian cohort. For each, researchers calculated a normalized chromosome denominator quality (NCDQ), which measures the likelihood that a sample has the standard two copies of each chromosome. Those with an NCDQ of 50 or below were flagged for further evaluation.
In the U.S. cohort, 328 (0.45 percent) samples were flagged and ultimately classified as abnormal. In the Australian cohort, 71 (0.42 percent) samples were deemed abnormal, 60 of which contained a rare trisomy. Trisomy 7 was observed most frequently in both study cohorts, followed by trisomies 15, 16 and 22.
Pregnancy and other outcome data were available for 52 of the 60 cases of rare trisomies found in the Australian cohort. Notably, researchers linked 22 samples with early miscarriage (occurring before 11 or 12 weeks gestation), including 13 of 14 samples with trisomy 15 and 3 of 5 samples with trisomy 22.
"We found that pregnancies at greatest risk of serious complications were those with very high levels of abnormal cells in the placenta," said Mark D. Pertile, Ph.D., co-first author of the study and head of the division of reproductive genetics at Victorian Clinical Genetics Services, part of Murdoch Childrens Research Institute in Melbourne, Australia. "Our results suggest that patients be given the option of receiving test results from all 24 chromosomes."
The National Human Genome Research Institute (NHGRI)
www.genome.gov/27569418/2017-news-relase-sequencing-all-24-human-chromosomes-uncovers-rare-disorders/
Rapid diagnostic test distinguish between severe and uncomplicated malaria
, /in E-News /by 3wmediaMalaria is a leading cause of death for children living in Sub-Saharan Africa. Many children in rural areas seek care at local community health clinics, but these clinics lack reliable tests to distinguish severe and uncomplicated malaria. Working at a health centre in rural Uganda, researchers from the University of North Carolina at Chapel Hill demonstrated for the first time the potential of using a low-cost, routinely available rapid diagnostic test to detect severe malaria in children.
“In many areas of rural areas of sub-Saharan Africa, malaria is inevitable. Children will be infected,” said Ross Boyce, M.D., MS.c., study author and a fellow in the UNC Division of Infectious Diseases. “Ensuring that those with the most severe form of the disease are quickly identified and treated, even when hours from the nearest hospital, is critically important to reducing the number of deaths.”
Over a period of six months, a total of 2,678 children with fever underwent testing for malaria using a rapid diagnostic test at the Bugoye Level III Health Center in the Kasese District of Western Uganda. Nearly half tested positive for malaria and 83 satisfied criteria for severe malaria. The sensitivity and specificity of the rapid diagnostic test for detecting severe malaria was 97.6 percent. The test was especially sensitive for children less than 5 years of age. Knowing when a child is suffering from severe malaria allows for a referral to a health centre better equipped to handle the disease’s grave manifestations.
“Rapid diagnostic tests have been around for awhile, and are generally considered standard of care in most malaria-endemic settings,” said Boyce. “However, what we’ve done is show that these relatively simple tests can be used in new ways to provide important information beyond just a positive or negative result. While it’s not perfect, the approach could help first-line healthcare workers – many of who have no formal medical training – make potentially lifesaving triage decisions.”
Boyce said further work is needed to validate and operationalize diagnostic and treatment algorithms so as not to overwhelm fragile referral networks.
University of North Carolina
globalhealth.unc.edu/2017/08/rapid-diagnostic-test-malaria/
Vitamin C may encourage blood cancer stem cells to die
, /in E-News /by 3wmediaVitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.
Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.
“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of Perlmutter Cancer Center.
Changes in the genetic code, or mutations, that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.
Along with these diseases, new tests suggest that about 2.5 percent of all United States cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumours, say the authors.
The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context. These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.
The back-and-forth attachment and removal of methyl groups also fine tunes gene expression in stem cells, which can mature, specialize, and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection.
The enzyme studied in this report TET2, enables a change in the molecular structure, or oxidation, of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a countdown toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Dr. Neel.
To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.
Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.
Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.
NYU Langone Healthhttp://tinyurl.com/y8pvrxso
Blood biopsy reveals unique, targetable genetic alterations in patients with rare cancer
, /in E-News /by 3wmediaUsing fragments of circulating tumour DNA in blood, University of California San Diego School of Medicine researchers were able to identify theoretically targetable genetic alterations in 66 percent of patients with cancer of unknown primary (CUP), a rare disease with seven to 12 cases per 100,000 people each year.
In order to plan treatment for cancer in general, physicians first attempt to pinpoint the primary cancer — where the tumour first developed. In CUP, despite its spread throughout the body, the origin remains unknown, making treatment more difficult. The current standard of care is platinum-based combination chemotherapies with a median survival time of six to eight months.
In a study, researchers report that by sequencing circulating tumour DNA (ctDNA) derived from blood samples in 442 patients with CUP, they were able to identify at least one genetic alteration linked to cancer in 290 — 66 percent — of patients. Researchers used a screening test developed by Guardant Health that evaluates up to 70 genes. Based on known carcinogenic mutations, 99.7 percent of the 290 patients who had detectable tumour DNA in their bloodstream had genomic alterations that could hypothetically be targeted using existing FDA-approved drugs (as off-label use) or with therapies currently under investigation in clinical trials.
“By definition, CUP does not have a definite anatomical diagnosis, but we believe genomics is the diagnosis,” said Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at Moores Cancer Center at UC San Diego Health and senior author. “Cancer is not simple and CUP makes finding the right therapy even more difficult. There are multiple genes and abnormalities involved in different areas of the body. Our research is the first to show that evaluating circulating tumour DNA from a tube of blood is possible in patients with CUP and that most patients harbour unique and targetable alterations.”
“Another advantage of the liquid biopsy is that the location of the cancer does not matter,” said Shumei Kato, MD, assistant professor of medicine at UC San Diego School of Medicine and first author. “With a blood sample, we can analyse the DNA of tumours throughout the body to find targetable alterations. With tissue biopsies, we can only see genomic changes that are in that one site and that may not be the same as what is in different sites not biopsied, such as the lung or bone.”
Moores Cancer Centerhttp://tinyurl.com/y9lffvh3