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UC San Francisco Scientists Discover Antibodies That Appear in Multiple Sclerosis Patients Years before Symptoms Occur

Findings may lead to new clinical laboratory biomarkers for predicting risk of developing MS and other autoimmune diseases

Scientists continue to find new clinical laboratory biomarkers to detect—and even predict risk of developing—specific chronic diseases. Now, in a recent study conducted at the University of California San Francisco (UCSF), researchers identified antibodies that develop in about 10% of Multiple Sclerosis (MS) patients’ years before the onset of symptoms. The researchers reported that of those who have these antibodies, 100% develop MS. Thus, this discovery could lead to new blood tests for screening MS patients and new ways to treat it and other autoimmune diseases as well.

The UCSF researchers determined that, “in about 10% [of] cases of multiple sclerosis, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge,” Yahoo Life reported, adding that “when [the patients] are tested at the time of their first disease flare, the antibodies show up in both their blood and cerebrospinal fluid.”

That MS is so challenging to diagnose in the first place makes this discovery even more profound. And knowing that 100% of a subset of MS patients who have these antibodies will develop MS makes the UCSF study findings quite important.

“This could be a useful tool to help triage and diagnose patients with otherwise nonspecific neurological symptoms and prioritize them for closer surveillance and possible treatment,” Colin Zamecnik, PhD, scientist and research fellow at UCSF, told Yahoo Life.

The researchers published their findings in the journal Nature Medicine titled, “An Autoantibody Signature Predictive for Multiple Sclerosis.”

“From the largest cohort of blood samples on Earth, we obtained blood samples from MS patients years before their symptoms began and profiled antibodies against self-autoantibodies that are associated with multiple sclerosis diagnosis,” Colin Zamecnik, PhD (above), scientist and research fellow at UCSF, told Yahoo Life. “We found the first molecular marker of MS that appears up to five years before diagnosis in their blood.” These findings could lead to new clinical laboratory tests that determine risk for developing MS and other autoimmune diseases. (Photo copyright: LinkedIn.)

UCSF Study Details

According to the MS International Foundation Atlas of MS, there are currently about 2.9 million people living with MS worldwide, with about one million of them in the US. The disease is typically diagnosed in individuals 20 to 50 years old, mostly targeting those of Northern European descent, Yahoo Life reported.

To complete their study, the UCSF scientists used the Department of Defense Serum Repository (DoDSR), which is comprised of more than 10 million individuals, the researchers noted in their Nature Medicine paper.

From that group, the scientists identified 250 individuals who developed MS, spanning a period of five years prior to showing symptoms through one year after their symptoms first appeared, Medical News Today reported. These people were compared to 250 other individuals in the DoDSR who have no MS diagnosis but who all had similar serum collection dates, ages, race and ethnicities, and sex.

“The researchers validated the serum results against serum and cerebrospinal fluid results from an incident MS cohort at the University of California, San Francisco (ORIGINS) that enrolled patients at clinical onset. They used data from 103 patients from the UCSF ORIGINS study,” according to Medical News Today. “They carried out molecular profiling of autoantibodies and neuronal damage in samples from the 500 participants, measuring serum neurofilament light chain measurement (sNfL) to detect damage to nerve cells.

“The researchers tested the antibody patterns of both MS and control participants using whole-human proteome seroreactivity which can detect autoimmune reactions in the serum and CSF,” Medical News Today noted.

Many who developed MS had an immunogenicity cluster (IC) of antibodies that “remained stable over time” and was not found in the control samples. The higher levels of sNfL in those with MS were discovered years prior to the first flare up, “indicating that damage to nerve cells begins a long time before symptom onset,” Medical News Today added.

“This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes,” the UCSF scientists wrote in Nature Medicine.

“We believe it’s possible that these patients are exhibiting cross reactive response to a prior infection, which agrees with much current work in the literature around multiple sclerosis disease progression,” Zamecnik told Yahoo Life.

It “validates and adds to prior evidence of neuro-axonal injury occurring in patients during the MS preclinical phase,” the researchers told Medical News Today.

Implications of UCSF’s Study

UCSF’s discovery is a prime example of technology that could soon work its way into clinical use once additional studies and research are done to support the findings.

The researchers believe their research could lead to a simple blood test for detecting MS years in advance and discussed how this could “give birth to new treatments and disease management opportunities,” Neuroscience News reported.

Current MS diagnosis requires a battery of tests, such as lumbar punctures for testing cerebrospinal fluid, magnetic resonance imaging (MRI) scans of the spinal cord and brain, and “tests to measure speed and accuracy of nervous system responses,” Medical News Today noted.

“Given its specificity for MS both before and after diagnosis, an autoantibody serology test against the MS1c peptides could be implemented in a surveillance setting for patients with high probability of developing MS, or crucially at a first clinically isolated neurologic episode,” the UCSF researchers told Medical News Today.

“It would also be interesting to see whether these antibodies could be a marker of disease severity and explain some of the MS course heterogeneity,” epidemiologist Marianna Cortese, MD, PhD, senior research scientist at Harvard T.H. Chan School of Public Health, told Medical News Today.

The UCSF discovery is another example of nascent technology that could work its way into clinical use after more research and studies. Microbiologists, clinical laboratories, and physicians tasked with diagnosing MS and other autoimmune diseases should find the novel biomarkers the researchers identified most interesting, as well as what changed with science and technology that enabled researchers to identify these biomarkers for development.

—Kristin Althea O’Connor

Related Information:

An Autoantibody Signature Predictive for Multiple Sclerosis

Signs of Multiple Sclerosis Can Be Detected in Blood 5 Years before Symptoms Appear, New Study Finds. Here’s Why This Breakthrough Is Important.

Signs of MS May Be Visible in Blood Years Before First Flare-Up of Symptoms

Blood Test Predicts Multiple Sclerosis Years Before Symptoms Appear

University of Ghent Belgium Research Team Finds Stool Transplants Improve Motor Symptoms in Early-stage Parkinson’s Disease Patients

Findings could lead to clinical laboratory tests that help physicians identify microbes lacking in the microbiomes of their Parkinson patients

Microbiologists and clinical laboratory scientists know that gut microbiome can be involved in the development of Parkinson’s disease, a progressive neurological disorder that affects the nervous system due to damage caused to nerve cells in the brain. There is no cure for the illness. But a new treatment developed by researchers at the VIB Center for Inflammation Research at the University of Ghent in Belgium, may help to alleviate the symptoms.

During a clinical trial, VIB Center for Inflammation Research (VIB-IRC) scientists discovered that fecal microbiota transplantation (FMT), also known as a stool transplant, can improve motor skills in some Parkinson’s patients, according to Neuroscience News.

Parkinson’s disease (PD) develops when a protein called alpha-synuclein misfolds and forms into bundled clusters damaging nerve cells in the brain that produce dopamine. These formations, which are believed to appear in the gastrointestinal wall in the early stages of PD, then reach the brain via the vagus nerve leading to typical PD symptoms in patients.

Dopaminergic medication, deep brain stimulation, and speech and occupational therapy are some of the treatments currently available to people with Parkinson’s disease, but researchers are constantly on the lookout for more and better treatments,” Medical News Today reported.

The scientists published their findings in eClinicalMedicine titled, “Safety and Efficacy of Fecal Microbiota Transplantation in Patients with Mild to Moderate Parkinson’s Disease (GUT-PARFECT): A Double-Blind, Placebo-Controlled, Randomized, Phase 2 Trial.”

“Our study provides promising hints that FMT can be a valuable new treatment for Parkinson’s disease,” Roosmarijn Vandenbroucke, PhD (above), Principal Investigator, VIB-UGent Center for Inflammation Research and full professor, UGent Department of Biomedical molecular biology, Faculty of Sciences, told Neuroscience News. “More research is needed, but it offers a potentially safe, effective, and cost-effective way to improve symptoms and quality of life for millions of people with Parkinson’s disease worldwide.” Clinical laboratories will likely be involved in identifying the best microbes for the FMT treatments. (Photo copyright: University of Ghent.)

Correlation between Gut Microbiome and Neurogenerative Disease

To perform their clinical study—referred to as GUT-PARFECT—the IRC researchers first recruited patients with early-stage PD and healthy donors who provided stool samples to the Ghent Stool Bank. The PD patients received the healthy stool via a tube inserted into the nose which led directly into the small intestine.

The FMT procedures were performed on 46 patients with PD between December 2020 and December 2021. The participants in this group ranged in ages from 50 to 65. There were 24 PD patients in the placebo group, and a total of 22 donors provided the healthy stool. Clinical evaluations were performed at baseline, three, six, and 12 months.

After 12 months, the group that received the transplants showed a reduction in symptoms compared to the placebo group. Their motor score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) improved by a mean of 5.8 points. The improvement registered on the same scale for the placebo group was 2.7 points.

Developed in the 1980s, the MDS-UPDRS is a scale utilized to evaluate various aspects of PD by measuring patient responses via a questionnaire rating several issues (such as cognitive impairment, apathy, depression, and anxiousness) common in PD patients from normal to severe. It is divided into four parts:

  • Part I: Non-motor experiences of daily living.
  • Part II: Motor experiences of daily living.
  • Part III: Motor examination.
  • Part IV: Motor complications.

During the final six months of the research, the improvement in motor symptoms became even greater. To the VIB-IRC researchers this implied that an FMT may have long-lasting effects on PD patients. The FMT study group also experienced less constipation, a condition that can be bothersome for some PD patients.

“Our results are really encouraging!” said the study’s first author, Arnout Bruggeman, MD, PhD student, VIB-UGent Center for Inflammation Research, in a UGent News release. “After twelve months, participants who received the healthy donor stool transplant showed a significant improvement in their motor score, the most important measure for Parkinson’s symptoms.”

Findings Could Lead to Other Targeted Therapies for PD

The VIB-IRC researchers believe there is a correlation between the gut microbiome and Parkinson’s disease.

“Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages,” the IRC researchers wrote in eClinicalMedicine.  

“Our next step is to obtain funding to determine which bacteria have a positive influence. This could lead to the development of a ‘bacterial pill’ or other targeted therapy that could replace FMT in the future,” Debby Laukens, PhD, Associate Professor, Ghent University, told Neuroscience News.

According to the Parkinson’s Foundation website, nearly one million people in the US live with PD. It is second only to Alzheimer’s disease in the category of neurodegenerative diseases.

More research and studies are needed before the VIB-IRC’s stool transplant treatment can be used in clinical care. As researchers learn more about which specific strains of bacteria are doing the beneficial work in PD patients, that data could eventually lead to clinical laboratory tests performed to help physicians identify which microbes are lacking in the microbiomes of their PD patients, and if fecal transplants could help those patients.

—JP Schlingman

Related Information:

Fecal Bacteria Transplant May Improve Parkinson’s Symptoms

Safety and Efficacy of Fecal Microbiota Transplantation in Patients with Mild to Moderate Parkinson’s Disease (GUT-PARFECT): A Double-Blind, Placebo-Controlled, Randomized, Phase 2 Trial

Stool Transplantation Shows Promise For Parkinson’s Disease

Fecal Microbiota Transplant Eases Parkinson’s Symptoms in Trial

Stool Transplant Could Improve Motor Symptoms in Parkinson’s Disease

In Conversation: Why Parkinson’s Research is Zooming in on the Gut

University of Chicago Study Determines Certain Gut Bacteria Can Help Prevent Food Allergies and Other Gastrointestinal Illnesses

With further research, clinical laboratories may soon be performing macrobiotic testing to measure certain bacterial levels in patients’ gut bacteria

New insights from the University of Chicago (UChicago) into how human microbiota (aka, gut bacteria) play a role in food allergies has the potential to change the way a number of gastrointestinal health conditions are diagnosed and treated. This would give microbiologists and clinical laboratories a greater role in helping physicians diagnose, treat, and monitor patients with these health issues.

Past research has shown that certain gut bacteria can prevent antigens that trigger allergic reactions from entering the bloodstream. For example, Clostridium bacteria in the stomach produce a short-chain fatty acid known as butyrate, a metabolite that promotes the growth of healthy bacteria in the gut. This helps keep the microbiome in balance.

One way butyrate is created in the gut is through the fermentation of fiber. However, a lack of fiber in the diet can deplete the production of butyrate and cause the microbiome to be out of balance. When this happens, a state known as dysbiosis occurs that disrupts the microbiome and can lead to food allergies. 

Without butyrate, the gut lining can become permeable and allow food to leak out of the gastrointestinal tract and into the body’s circulatory system. This reaction can trigger a potentially fatal anaphylactic response in the form of a food allergy. Thus, eating enough fiber is critical to the production of butyrate and to maintaining a balanced microbiome.

But today’s western diet can be dangerously low in soluble fiber. Therefore, the scientists at the University of Chicago have developed “a special type of polymeric molecule to deliver a crucial metabolite produced by these bacteria directly to the gut, where it helps restore the intestinal lining and allows the beneficial bacteria to flourish. … these polymers, called micelles, can be designed to release a payload of butyrate, a molecule that is known to help prevent food allergies, directly in the small and large intestines,” according to a UChicago news release.

This will be of interest to microbiologists, in particular. It’s another example of researchers connecting a specific species of bacteria in the human microbiome to a specific benefit.

The University of Chicago scientists published their findings in the journal Nature Biomedical Engineering titled, “Treatment of Peanut Allergy and Colitis in Mice via the Intestinal Release of Butyrate from Polymeric Micelles.”

Cathryn Nagler, PhD

“It’s very unlikely that butyrate is the only relevant metabolite, but the beauty of this platform is that we can make polymers with other microbial metabolites that could be administered in conjunction with butyrate or other therapies,” said Cathryn Nagler, PhD (above), Bunning Family Professor in the Biological Sciences Division and Pritzker School of Molecular Engineering at UChicago and a senior author of the study. “So, the potential for the polymer platform is pretty much wide open.” As further research validates these findings, clinical labs are likely to be doing microbiomic testing to monitor these therapies. (Photo copyright: University of Chicago.)

Restoring Butyrate in the Gut

One way to treat this anomaly has been through a microbiota transplant—also called a fecal biota transplant—where the administration of a solution of fecal matter is transplanted from a donor into the intestinal tract of the recipient. This transplant alters the recipient’s gut microbial composition to a healthier state, but it has had mixed results. 

So, the UChicago researchers went in another direction (literally). They created an oral solution of butyrate and administered it to mice in the lab. The purpose of the solution was to thwart an allergic reaction when the mice were exposed to peanuts. 

But there was a problem with their oral solution. It was repulsive.

“Butyrate has a very bad smell, like dog poop and rancid butter, and it also tastes bad, so people wouldn’t want to swallow it,” Shijie Cao, PhD, Postdoctoral Scientist at the Pritzker School of Molecular Engineering at UChicago and one of the researchers who worked on the project, told Medical News Today.

The researchers developed a new configuration of polymers that masked the butyrate. They then delivered these polymer micelles directly into the digestive systems of mice that lacked healthy gut bacteria or a proper gut linings.

The treatment restored the microbiome by increasing the production of peptides that obliterate harmful bacteria. This allowed more of the beneficial butyrate-producing bacteria to emerge, which protected the mice from an anaphylactic reaction to peanuts and even reduced the symptom severity in an ulcerative colitis model. 

“We were delighted to see that our drug both replenished the levels of butyrate present in the gut and helped the population of butyrate-producing bacteria to expand,” said Cathryn Nagler, PhD, Bunning Family Professor in the Biological Sciences Division and Pritzker School of Molecular Engineering at the University of Chicago and a senior author of the study, in the press release. “That will likely have implications not only for food allergy and inflammatory bowel disease (IBD), but also for the whole set of non-communicable chronic diseases that have been rising over the last 30 years, in response to lifestyle changes and overuse of antibiotics in our society.”

Future Benefits of UChicago Treatment

According to data from the Asthma and Allergy Foundation of America, about 20 million Americans suffered from food allergies in 2021. This includes approximately 16 million (6.2%) of adults and four million (5.8%) of children. The most common allergens for adults are shellfish, peanuts, and tree nuts, while the most common allergens for children are milk, eggs, and peanuts. 

The best way to prevent an allergic reaction to a trigger food is strict avoidance. But this can be difficult to ensure outside of the home. Therefore, scientists are searching for ways to prevent food allergies from happening in the first place. The micelle technology could be adapted to deliver other metabolites and molecules which may make it a potential platform for treating allergies as well as other inflammatory gastrointestinal diseases

“It’s a very flexible chemistry that allows us to target different parts of the gut,” said Jeffrey Hubbell, PhD, Eugene Bell Professor in Tissue Engineering and Vice Dean and Executive Officer at UChicago’s Pritzker School of Molecular Engineering and one of the project’s principal investigators, in the UChicago news release. “And because we’re delivering a metabolite like butyrate, it’s antigen-agnostic. It’s one agent for many different allergic indications, such as peanut or milk allergies. Once we begin working on clinical trials, that will be a huge benefit.”

Nagler and Hubbell have co-founded a company called ClostraBio to further the development of butyrate micelles into a commercially available treatment for peanut and other food allergies. They hope to begin clinical trials within the next 18 months and expand the technology to other applications as well.  

Further research and clinical trials are needed to prove the validity of using polymer micelles in the treatment of diseases. But it is possible that clinical laboratories will be performing microbiomic testing in the future to help alleviate allergic reactions to food and other substances.

—JP Schlingman

Related Information:

Peanut and Food Allergies May Be Reversed with Compound Produced by Healthy Gut Bacteria

Time Release Polymers Deliver Metabolites to Treat Peanut Allergy and Colitis

Food Allergies: Reversing the Old, Preventing the New with Gut Bacteria

Scientists Reverse Food Allergies by Targeting the Microbiome

Polymers Help Protect Mice from Anaphylactic Reaction to Peanuts, UChicago Research Finds

Treatment of Peanut Allergy and Colitis in Mice via the Intestinal Release of Butyrate from Polymeric Micelles

New American Gastroenterological Association Guidelines for Managing Crohn’s Disease Suggest More Clinical Laboratory Tests and Fewer Colonoscopies

As doctors become more familiar with using biomarkers to monitor Crohn’s disease, clinical laboratories may play a greater role in that process

New evidence-based guidelines from the American Gastroenterological Association (AGA) that call for using specific biomarkers to help manage Crohn’s disease (CD) may decrease the number of invasive procedures patients must undergo and increase the role clinical laboratories play in monitoring the disease.

The new AGA guidelines “recommend using the C-reactive protein (CRP) biomarker in blood and the fecal calprotectin (FCP) biomarker in stool to measure inflammation levels and assess whether Crohn’s disease is in remission or active,” Medical News Today reported.

Crohn’s disease is a chronic inflammatory bowel disease (IBD) that causes inflammation in the digestive tract, primarily in the small and large intestine. The cause of the disease is unknown, but genetics may play a role.

Typically, CD patients must undergo repeated colonoscopies to monitor the disease’s progression or remission. This has long been standard practice. Now, however, “AGA recommends the use of biomarkers in addition to colonoscopy and imaging studies,” according to an AGA news release. This hints at a greater role for clinical laboratories in helping physicians manage patients with Crohn’s Disease.

“Patients’ symptoms do not always match endoscopic findings, so biomarkers are a useful tool to understand and monitor the status of inflammation and guide decision making in patients with Crohn’s disease,” said gastroenterologist Siddharth Singh, MD, Assistant Professor of Medicine at UC San Diego Health and a co-author of the new AGA guidelines.

The AGA’s new guidelines demonstrate how medical science is generating new insights about how multiple biomarkers can be associated for diagnosis/management of a disease in ways that change the standard of care, particularly if it can reduce invasive procedures for the patient by the use of less invasive methods (such as a venous blood draw instead of a colonoscopy).

The AGA published its new guidelines in the journal Gastroenterology titled, “AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Crohn’s Disease.”

Ashwin Ananthakrishnan MD

“Based on this guideline, biomarkers are no longer considered experimental and should be an integral part of inflammatory bowel disease care,” Ashwin Ananthakrishnan MD (above), a gastroenterologist at Massachusetts General Hospital and co-author of the guidelines, told Medical News Today. Under the new AGA guidelines, clinical laboratories will play a greater role in helping patients monitor their disease. (Photo copyright: Massachusetts General Hospital.)

Patient’s Needs Determine Biomarker vs Endoscopy Monitoring

AGA’s new guidelines could give patients a more comfortable, cost-effective, and possibly more efficient treatment plan to manage their Crohn’s disease. That’s even true if a patient’s Crohn’s disease is in remission.

With these new guidelines, Crohn’s disease patients in remission would only need their biomarkers to be checked every six to 12 months. Patients with active symptoms would need their biomarkers checked roughly every two to four months.

Biomarker testing can be seen as a useful addition to Crohn’s disease care rather than a full replacement of other forms of care. For example, the new AGA guidelines do not fully omit imaging studies and colonoscopies from treatment. Rather, they are recommended in treatment plans based on the patient’s needs.

In their Gastroenterology paper, the AGA authors wrote, “A biomarker-based monitoring strategy involves routine assessment of symptoms and noninvasive biomarkers of inflammation in patients with CD in symptomatic remission to inform ongoing management. In this situation, normalization of biomarkers is an adequate treatment target—asymptomatic patients with normal biomarkers would continue current management without endoscopy, whereas those with elevated biomarkers would undergo endoscopy.”

Fecal Matter Biomarkers

In speaking with Medical News Today on the benefits of using fecal biomarkers to assess a patient’s disease maintenance, gastroenterologist Jesse Stondell, MD, an Associate Clinical Professor at UC Davis Health, said, “If we start a patient on therapy, they’re not responding appropriately, they’re still having a lot of symptoms, we can check that fecal calprotectin test and get a very quick sense of if things are working or not.

“If the calprotectin is normal, it could be reassuring that there may be other reasons for their symptoms, and that the medicine’s working. But if they have symptoms, and a calprotectin is elevated, that’s a signal that we have to worry the medicine is not working. And that we need to change therapy in that patient,” he added.

“This is a win for Crohn’s disease patients,” Ashwin Ananthakrishnan, MD, a gastroenterologist at Massachusetts General Hospital and co-author of the AGA’s new guidelines, told Medical News Today. “Biomarkers are usually easier to obtain, less invasive, more cost-effective than frequent colonoscopies, and can be assessed more frequently for tighter disease control and better long-term outcomes in Crohn’s disease.”

Clinical laboratories should expect these guidelines to increase demand for the processing of blood or fecal matter biomarker testing. As Crohn’s disease monitoring becomes more dependent on biomarker testing, clinical labs will play a critical role in that process.

—Ashley Croce

Related Information:

Fewer Colonoscopies? New Crohn’s Guidelines Emphasize Blood, Stool Tests as Management Tool

AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Crohn’s Disease

Biomarker- vs Endoscopy-Based Monitoring Strategy in Crohn’s Disease

First Comprehensive Guideline on Using Biomarkers for Monitoring Crohn’s Disease

National Library of Medicine: Crohn’s Disease

Crohn’s Disease Is on the Rise

UW Medicine Researchers Identify Blood Cell Genetic Mutations That Can Disrupt Liquid Biopsy Results

The discovery is yet another factor that must be considered when developing a liquid biopsy test clinical laboratories can use to detect cancer

How often do disruptive elements present in Liquid biopsies result in misdiagnoses and unhelpful drug therapies for cancer? Researchers at the University of Washington School of Medicine (UW Medicine) in Seattle wanted to know. And the results of their study provide another useful insight for pathologists about the elements that circulate in human blood which must be understood so that liquid biopsy tests can be developed that are not affected by that factor.

Based on their case series study of 69 men with advanced prostate cancer, the UW Medicine researchers determined that 10% of men have a clonal hematopoiesis of indeterminate potential (CHIP) that can “interfere” with liquid biopsies and cause incorrect reports and unneeded prostate cancer treatment, according to their paper published in the journal JAMA Oncology.

The process of clonal hematopoiesis occurs when hematopoietic stem cells generate blood cells that mimic blood mutations in the same way as hematopoiesis, Labroots explained in “Potential Problems with Liquid Biopsies.” Hence, the word “clonal” in the description. 

The UW Medicine researchers advised testing for “variants in the cell-free DNA (cfDNA)” shed in blood plasma to enable appropriate treatment for people with already diagnosed prostate cancer, noted to a UW Medicine news release.

According to pathologist Colin Pritchard, MD, PhD, Associate Professor of Laboratory Medicine and Pathology at the UW Medicine, who led the research team, “clonal hematopoiesis can interfere with liquid biopsies. For example, mutations in the genes BRCA1, BRCA2, and ATM have been closely linked to cancer development.

“Unfortunately, these same genes are also commonly mutated as a result of clonal hematopoiesis,” he told Labroots. Pritchard is also Head of the Genetics Division of Laboratory Medicine at UW Medicine, Director of Clinical Diagnostics for the Brotman Baty Institute for Precision Medicine, and Co-Director of the Genetics and Solid Tumors Laboratory at the University of Washington Medical Center.

“The good news is that, by looking at the blood cellular compartment, you can tell with pretty good certainty whether something is cancer, or something is hematopoiesis,” he said in the news release.

What Does CHIP Interference Mean to a Clinical Laboratory Blood Test?

In their published study, the UW Medicine researchers stressed the “urgent need to understand cfDNA testing performance and sources of test interferences” in light of recent US Food and Drug Administration (FDA) clearance of two PARP inhibitors (PARPi) for prostate cancer:

“We found that a strikingly high proportion of DNA repair gene variants in the plasma of patients with advanced prostate cancer are attributable to CHIP,” the researchers wrote. “The CHIP variants were strongly correlated with increased age, and even higher than expected by age group.

“The high rate of CHIP may also be influenced by prior exposure to chemotherapy,” they added. “We are concerned that CHIP interference is causing false-positive cfDNA biomarker assessments that may result in patient harm from inappropriate treatment, and delays in delivering alternative effective treatment options.

“Without performing a whole-blood control, seven of 69 patients (10%) would have been misdiagnosed and incorrectly deemed eligible for PARP-inhibitor therapy based on CHIP interference in plasma. In fact, one patient in this series had a BRCA2 CHIP clone that had been previously reported by a commercial laboratory testing company with the recommendation to use a PARPi. To mitigate these risks, cfDNA results should be compared to results from whole-blood control or tumor tissue,” the researchers concluded.

To find the clinically relevant CHIP interference in prostate cancer cfDNA testing, researchers used the UW-OncoPlex assay (developed and clinically available at UW Medicine). The assay is a multiplexed next-generation sequencing panel aimed at detecting mutations in tumor tissues in more than 350 genes, according to the UW Medicine Laboratory and Pathology website. 

“To improve cfDNA assay performance, we developed an approach that simultaneously analyzes plasma and paired whole-blood control samples. Using this paired testing approach, we sought to determine to what degree CHIP interferes with the results of prostate cancer cfDNA testing,” the researchers wrote in JAMA Oncology

Men May Receive Unhelpful Prostate Cancer Drug Therapies

The research team studied test results from 69 men with advanced prostate cancer. They analyzed patients’ plasma cfDNA and whole-blood control samples.

Tumor sequencing enabled detection of germline (cells relating to preceding cells) variants from CHIP clones.

The UW Medicine study suggested CHIP variants “accounted for almost half of the somatic (non-germline) DNA repair mutations” detected by liquid biopsy, according to the news release.

Colin Pritchard, MD, PhD
>
“About half the time when the plasma is thought to contain a mutation that would guide therapy with these drugs, it actually contains CHIP variants, not prostate cancer DNA variants. That means that in about half of those tested, a patient could be told that he should be administered a drug that is not indicated to treat to his cancer,” said Colin Pritchard, MD, PhD, pathologist and Associate Professor of Laboratory Medicine and Pathology at UW Medicine in the new release. (Photo copyright: University of Washington School of Medicine.)

Other detailed findings of the UW Medicine Study:

  • CHIP variants of 2% or more were detected in cfDNA from 13 of 69 men.
  • Seven men, or 10%, having advanced prostate cancer “had CHIP variants in DNA repair genes used to determine PARPi candidacy.
  • CHIP variants rose with age: 0% in those 40 to 50; 12.5% in men 51 to 60; 6.3% in those 61 to 70; 20.8% in men 71 to 80; and 71% in men 81 to 90.
  • Whole-blood control made it possible to distinguish prostate cancer variants from CHIP interference variants.

“Men with prostate cancer are at high risk of being misdiagnosed as being eligible for PARPi therapy using current cfDNA tests; assays should use a whole-blood control sample to distinguish CHIP variants from prostate cancer,” the researchers wrote in JAMA Oncology.

Liquid Biopsies Are ‘Here to Stay’

Surgical oncologist William Cance, MD, Chief Medical and Scientific Officer, American Cancer Society (ACS) in Atlanta, recognizes the challenge of tumor biology to liquid biopsies. 

“Genetic abnormalities are only one piece of the puzzle. We need to look comprehensively at tumors for the best therapy, from their metabolic changes and protein signatures in the blood to the epigenetic modifications that may occur, as cancers take hold,” he told Oncology Times. “It’s not just shed DNA in the blood.”

The UW Medicine study demonstrates the importance of understanding how all elements in liquid biopsies interact to affect clinical laboratory test results.

“I think liquid biopsies are here to stay,” Cance told Oncology Times. “They’re all part of precision medicine, tailored to the individual.”

Donna Marie Pocius

Related Information:

Association of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-free DNA Testing Interference

Potential Problems with Liquid Biopsies

Blood Cell Mutations Confound Prostate Cancer Liquid Biopsy

Pursing and Perfecting Use of Liquid Biopsies in Cancer Early Detection

Researchers at Harvard’s Massachusetts General Hospital Develop a Non-Invasive Liquid Biopsy Blood Test to Detect and Monitor Common Brain Tumors in Adults

Using Extracellular Vesicles, Researchers Highlight Viability of Liquid Biopsies for Cancer Biomarker Detection in Clinical Laboratories

New studies in UK and at Stanford University Show Lung Cancer Cells Circulating in Blood; Findings Could Make It Possible for Pathologists to Diagnose Cancer with ‘Liquid Biopsies’

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