In a new study, researchers from the University of Copenhagen and EMBL in Heidelberg have learned how a specific genetic mutation affects the maturation of blood cells in mouse models. Leukaemia patients often have a mutation in this gene, often seen before the disease sets in. The researchers are working on a strategy for treating the mutation.
In the veins, stem cells constantly mature and develop into different blood cells that are necessary for the body to work properly. Now researchers from the University of Copenhagen and EMBL in Heidelberg have discovered exactly how a specific mutation in the stem cells in the blood can obstruct this maturation process.
In a new study, the researchers show what happens at the molecular level in blood cells from mice when the TET2 gene is neutralised. A lot of patients with leukaemia and other disorders often have TET2 mutations, which neutralise the gene.
‘A lot of researchers have been interested in this mutation, because it appeared to play a main role in several blood disorders. But we have taken an important step now, as we are able to reveal exactly what happens at the molecular level with this unhealthy gene mutation. In the long term, this knowledge can help us develop treatments for a host of haematological disorders’, says Postdoc Kasper Dindler Rasmussen, who participated in the study at the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, but is now a Principal Investigator at the University of Dundee.
The researchers have studied the molecular events on the DNA in blood cells from mice with the TET2 gene mutation. They used ultramodern gene sequencing techniques to map the molecular and genetic modifications. They measured more than 1,000 so-called transcription factors at once, which help stem cells develop into functional cells. This way, the researchers can determine exactly which genes are affected by the loss of TET2.
The researchers point out that one of the main challenges in several types of cancer is that the disease can transform into various subclones. However, if you are able to target this mutation, which appears to be common to a large fraction of patients suffering from blood disorders, you can treat these patients with the same treatment.
‘Understanding how TET2 mutations can lead to leukaemia holds great potential. This knowledge is an important step on the way to developing new drugs for effective treatment of leukaemia, because we often find this mutation in leukaemia patients before the disease sets in. This can make treatment possible’, says Head of the Study Kristian Helin, Professor at BRIC and Director, Center for Epigenetics Resarch at Memorial Sloan Kettering Cancer Center.
University of Copenhagen https://tinyurl.com/yxtd2ekr

Levels of a gene that helps the immune system differentiate the good cells from the bad could be a good indicator of prognosis in people with colorectal cancers, Medical College of Georgia researchers report.
Looking at 15 genes known to be associated with colorectal cancers — eight associated with lower survival rates and seven with higher — the researchers found that one gene, CCR4, was present in higher levels in patients with a good prognosis, even in those diagnosed with late stage disease.
The gene is part of the chemokine family, which is involved in trafficking the body’s white blood cells, which then fight off invaders. Through genetic analysis, MCG researchers found that patients with higher levels had responded better to treatment, had more incidences of remission and lived longer, says second-year MCG student Chance Bloomer.
“If the cancer is expressing this gene, it makes it easier for the immune system to attack those cells,” he says. “There is no good type of colorectal cancer, but if you’re going to have it, you want higher levels of this gene.” Bloomer is presenting his findings at the American Association for Cancer Research Annual Meeting this week in Atlanta.
Bloomer worked with Dr. Ravindra Kolhe, molecular pathologist and director of MCG’s Georgia Esoteric & Molecular Laboratory, to design the two genetic panels — one that he hoped could be used to predict good outcomes and one for poorer outcomes. They started by combing through cBioPortal for Cancer Genomics, which houses large-scale cancer genomics data sets.
“Essentially this was raw data,” Bloomer says. “There are thousands of gene expression levels for thousands of patients with all types of cancers. I was looking for genes that had been shown to be associated with better survival rates.”
Bloomer started with nearly 800 genes — all with known and strong associations to cancer progression — and narrowed those down to 38 with significant associations to increased or decreased survival rates for colon cancer. He narrowed the group further by grouping those with similar mechanisms — whether they were involved in immune system response, rates of tumour growth or treatment response, for example. “I wanted a holistic approach that looked at tumour genetics and how these genes worked,” he says.
After settling on an eight gene panel he hoped would help determine decreased survival rates, and a seven gene panel to determine better survival rates, they analysed tissue samples of 750 colorectal cancer patients from the Georgia Cancer Center. Patients were grouped by tumour stage, determined by using its size and/or whether it has spread; whether they survived less than or more than three years; tumour grade, a measure of how quickly it is likely to grow and spread; and age — over or under age 76.
While the entire panel did not work as well as Bloomer had hoped, increased levels of CCR4 did show multiple significant associations with better prognosis, even in patients with stage 4 cancer. Patients with stage 3 cancer and better survival rates also had higher levels of CCR4 than those with stage 1 tumours and poorer survival rates. Young patients with better survival rates also had higher levels than those with worse survival rates.
“We’re not entirely sure what the association is, but those are next steps,” Bloomer says. “If we are able to design a panel that can predict prognosis, and we are able to tell people they may have a worse prognosis, maybe that helps justify the more aggressive treatments, which can be uncomfortable and come with worse side effects. It’s important, though, that we tell patients that their results are not a certainty. They indicate, not ensure.”
Medical College of Georgia https://jagwire.augusta.edu/archives/63148

A new study has found that genes cause about 1 in 10 cases of chronic kidney disease in adults, and that identifying the responsible genes has a direct impact on treatment for most of these patients.
“Our study shows that genetic testing can be used to personalize the diagnosis and management of kidney disease, and that nephrologists should consider incorporating it into the diagnostic workup for these patients,” says Ali Gharavi, MD, chief of nephrology at Columbia University Vagelos College of Physicians and Surgeons and a co-senior author of the study.
It’s estimated that 1 in 10 adults in the United States have chronic kidney disease. Yet, for 15 percent of patients with chronic kidney disease, the underlying cause of kidney failure is unknown.
“There are multiple genetic causes of chronic kidney disease, and treatment can vary depending on the cause,” says Gharavi. “And because kidney disease is often silent in the early stages, some patients aren’t diagnosed until their kidneys are close to failing, making it more difficult to find the underlying cause.”
DNA sequencing has the potential to pinpoint the genetic culprits, but has not been tested in a wide range of patients with chronic kidney disease.
“Our study identifies chronic kidney disease as the most common adult disease, outside of cancer, for which genomic testing has been demonstrated as clinically essential,” says David Goldstein, PhD, director of Columbia University’s Institute for Genomic Medicine and a co-senior author of the study.
Nearly 1 in 10 patients have a genetic kidney disorder
In this study, researchers used DNA sequencing to look for genetic kidney disorders in 3,315 individuals with various types of chronic or end-stage kidney disease. For 8.5 percent of these individuals, clinicians had not been able to identify the cause of disease.
The researchers found that a genetic disorder was responsible for about 9 percent of the participants’ kidney problems, and DNA testing reclassified the cause of kidney disease in 1 out of 5 individuals with a genetic diagnosis. In addition, DNA testing was able to pinpoint a cause for 17 percent of participants for whom a diagnosis was not possible based on the usual clinical workup.
DNA results had a direct impact on clinical care for about 85 percent of the 168 individuals who received a genetic diagnosis and had medical records available for review. “For several patients, the information we received from DNA testing changed our clinical strategy, as each one of these genetic diagnoses comes with its own set of potential complications that must be carefully considered when selecting treatments,” Gharavi says.
About half of the patients were diagnosed with a kidney disorder that also affects other organs and requires care from other specialists. A few (1.5 percent) individuals learned they had medical conditions unrelated to their kidney disease, In all of these cases, the incidental findings had an impact on kidney care. “For example, having a predisposition to cancer would modify the approach to immunosuppression for patients with a kidney transplant,” adds Gharavi.
“These results suggest that genomic sequencing can optimize the development of new medicines for kidney disease through the selection of patient subgroups most likely to benefit from new therapies,” says Adam Platt, PhD, Head of Global Genomics Portfolio at AstraZeneca and a co-senior author of the study.
Irving Medical Centerhttps://tinyurl.com/y2xct8uo

Messe Düsseldorf will participate in the AACC Clinical Lab Expo 2019 in order to promote its “MEDICAlliance” program of regional and international medical trade fairs organized around the globe.  At AACC booth 2653, visitor and exhibitor information for MEDICA 2019, World Forum for Medicine, and COMPAMED 2019, High tech solutions for medical technology (held currently from November 18 – 21, 2019 in Düsseldorf, Germany), MEDICAL FAIR CHINA 2019 (September 5 – 7, 2019 in Suzou), MEDICAL FAIR THAILAND 2019 (September 11 – 13, 2019 in Bangkok) as well as MEDICAL FAIR ASIA 2020 and MEDICAL MANUFACTURING ASIA 2020 (held concurrently from September 9 – 11, 2020 in Singapore) and Meditech 2020 (July 14 – 17, 2020 in Bogota, Colombia) will be available.
As the No. 1 international medical trade fair worldwide, MEDICA reflects the status of the medical market. Every year, over 5,200 exhibitors from 66 nations present the complete range of new products, systems and services for high-quality in-patient and out-patient care to about 120,000 visitors from around the globe. Over 70% of the MEDICA exhibitors usually come from nations other than Germany, including more than 400 companies from the U.S. As in the past, Messe Düsseldorf North America will again organize two U.S. Pavilions at MEDICA 2019. Congresses, various theme parks, forums and numerous special events will complement the exhibits. www.medicalliance.global www.medica-tradefair.com

Researchers at the Johns Hopkins Kimmel Cancer Center have developed a simple new blood test that can detect the presence of seven different types of cancer by spotting unique patterns in the fragmentation of DNA shed from cancer cells and circulating in the bloodstream.
In a proof-of-concept study, the test, called DELFI (DNA evaluation of fragments for early interception), accurately detected the presence of cancer DNA in 57% to more than 99% of blood samples from 208 patients with various stages of breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancers in the U.S., Denmark and the Netherlands.
DELFI also performed well in tests of blood samples from 215 healthy individuals, falsely identifying cancer in just four cases. The test uses machine learning, a type of artificial intelligence, to identify abnormal patterns of DNA fragments in the blood of patients with cancer. By studying these patterns, the investigators said they could identify the cancers’ tissue of origin in up to 75% of cases.
Blood tests, or so-called “liquid biopsies” for cancer detection typically look for mutations, which are changes in the DNA sequence within a cancer cell, or for methylation, a chemical reaction in which a methyl group is added to DNA, says senior study author Victor E. Velculescu, M.D., Ph.D., professor of oncology and co-director of the Cancer Biology Program at the Johns Hopkins Kimmel Cancer Center. But not all cancer patients have changes that are detectable using these methods, he says, and there is a great need for improved methods for early detection of cancer.  
DELFI, he says, takes a different approach, studying the way DNA is packaged inside the nucleus of a cell by looking in the blood at the size and amount of DNA from different regions across the genome for clues to that packaging.  
Alessandro Leal, M.D., a lead author of the study and a Ph.D. candidate at the Johns Hopkins University School of Medicine, explains that the nuclei of healthy cells package DNA like a well-organized suitcase in which different regions of the genome are carefully placed in various compartments. By contrast, the nuclei of cancer cells are more like disorganized suitcases, with items from across the genome thrown in haphazardly.   
 “For various reasons, a cancer genome is disorganized in the way it’s packaged, which means that when cancer cells die they release their DNA in a chaotic manner into the bloodstream,” says Jillian Phallen, Ph.D., a lead author on the study and a Johns Hopkins Kimmel Cancer Center postdoctoral fellow. “By examining this cell-free DNA (cfDNA), DELFI helps identify the presence of cancer by detecting abnormalities in the size and amount of DNA in different regions of the genome based on how it is packaged.”  
The researchers caution that the test’s potential must be further validated in additional studies, but if that happens it could be used to screen for cancer by taking a tube of blood from an individual, extracting the cfDNA, studying its genetic sequences and determining the fragmentation profile of the cfDNA. The genome-wide fragmentation pattern from an individual can then be compared with reference populations to determine if the pattern is likely healthy or derived from cancer.  
Robert B. Scharpf, Ph.D., a senior author on the study and an associate professor of oncology, says that because the genome-wide fragmentation patterns may reveal differences associated with specific tissues, these patterns, when found to be derived from cancer, can also indicate the source of the cancer, such as from the breast, colon or lung.  
DELFI simultaneously analyses millions of sequences from hundreds to thousands of regions in the genome, identifying tumour-specific abnormalities from minute cfDNA amounts, says Scharpf.   
Using DELFI, investigators found that genome-wide cfDNA fragmentation profiles are different between cancer patients and healthy individuals. Stephen Cristiano, a lead author on the study and a Ph.D. candidate in the Johns Hopkins Bloomberg School of Public Health, says that in cancer patients, fragmentation patterns in cfDNA appear to result from mixtures of DNA released from both blood and tumour cells, and show multiple distinct genomic differences with increases and decreases in fragment sizes at different regions.
John Hopkins Medicinehttps://tinyurl.com/yyph9y6e