News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups
Hosted by Robert Michel
News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups
Hosted by Robert Michel
Johns Hopkins researchers show that measuring DNA methylation variability can improve early cancer detection accuracy and strengthen liquid biopsy performance across diverse patient populations.
Researchers at Johns Hopkins Kimmel Cancer Center are advancing a new approach to liquid biopsy that could improve early cancer detection by focusing on variability in DNA methylation patterns—rather than absolute levels—offering a potentially more reliable biomarker across diverse patient populations.
Dark Daily’s sibling publication Today’s Clinical Lab reported that the liquid biopsy market is expected to increase by approximately 20% between 2022 and 2032, noting early cancer detection as a driver of the increase.
The method introduces a novel metric called the Epigenetic Instability Index (EII), designed to measure random variation, or “stochasticity,” in DNA methylation. In a proof-of-concept study published in Clinical Cancer Research, the approach demonstrated strong performance in distinguishing patients with early-stage cancers from healthy individuals.
“This is the first study where we are trying to really implement measuring that variation, or stochasticity, into a diagnostic tool,” said lead author Hariharan Easwaran, PhD. “We immediately found that measuring DNA methylation variation performs better than just measuring DNA methylation by itself.”
Model Targets Methylation Variability to Improve Multi-Cancer Detection
Traditional methylation-based liquid biopsies typically rely on detecting fixed changes at specific genomic sites. However, those tests are often developed using narrow patient cohorts and can struggle to generalize across broader populations. By contrast, the EII approach aims to capture a more universal biological signal tied to early tumor development.
To build the model, researchers analyzed more than 2,000 publicly available DNA methylation samples and identified 269 genomic regions (CpG islands) that capture the majority of methylation variability across cancer types.
“We identified specific genomic regions that tend to be the most variable in DNA methylation marks during cancer,” said first author Sara-Jayne Thursby, a postdoctoral researcher in Easwaran’s lab. “In cell-free DNA in the blood, that variability shouldn’t be high, but if it is, it is indicative of a developing cancerous phenotype.”
Using these regions, the team trained a machine learning model that demonstrated high accuracy across multiple cancers. In lung adenocarcinoma, the test detected stage 1A disease with 81% sensitivity at 95% specificity. For early-stage breast cancer, sensitivity reached approximately 68% at the same specificity level. The tool also showed potential utility in colon, pancreatic, brain, and prostate cancers.
Researchers say the findings support the idea that epigenetic instability may be an early hallmark of cancer progression.
“We hypothesize that early-stage tumors and precancerous lesions that exhibit high degrees of methylation variation… may be more resistant to intrinsic cancer-protective mechanisms and progress more rapidly,” said co-lead author Thomas Pisanic, PhD.
Looking ahead, the team plans to further validate the EII in larger clinical studies and position it as a complementary tool alongside existing screening methods. Easwaran noted that the test could serve as a “secondary triaging measure,” helping clinicians determine whether follow-up procedures—such as biopsies—are necessary after inconclusive or false-positive screening results.
For clinical laboratories, the approach signals a growing shift toward more nuanced, data-driven biomarkers that may improve early detection while reducing unnecessary procedures.
This article was created with the assistance of Generative AI and has undergone editorial review before publishing.
—Janette Wider
Decision is part of UK effort to diagnose 75% of all cancers at stage I or stage II by 2028 and demonstrates to pathologists that the technology used in liquid biopsy tests is improving at a fast pace
Pathologists and medical laboratory scientists know that when it comes to liquid biopsy tests to detect cancer, there is plenty of both hope and hype. Nevertheless, following a successful pilot study at the Christie NHS Foundation Trust in Manchester, England, which ran from 2015-2021, the UK’s National Health Service (NHS) is pushing forward with the use of liquid biopsy tests for certain cancer patients, The Guardian reported.
NHS’ decision to roll out the widespread use of liquid biopsies—a screening tool used to search for cancer cells or pieces of DNA from tumor cells in a blood sample—across the UK is a hopeful sign that ongoing improvements in this diagnostic technology are reaching a point where it may be consistently reliable when used in clinical settings.
The national program provides personalized drug therapies based on the genetic markers found in the blood tests of cancer patients who have solid tumors and are otherwise out of treatment options. The liquid biopsy creates, in essence, a match-making service for patients and clinical trials.
Liquid Biopsy Genetic Testing for Cancer Patients
“The learnings from our original ‘Target’ study in Manchester were that genetic testing needs to be done on a large scale to identify rare genetic mutations and that broader access to medicines through clinical trials being undertaken across the country rather than just one site are required,” Matthew Krebs, PhD, Clinical Senior Lecturer in Experimental Cancer Medicine at the University of Manchester, told The Guardian.
Krebs, an honorary consultant in medical oncology at the Christie NHS Foundation Trust, led the Target National pilot study.
“This study will allow thousands of cancer patients in the UK to access genetic testing via a liquid biopsy. This will enable us to identify rare genetic mutations that in some patients could mean access to life-changing experimental medicines that can provide great treatment responses, where there are otherwise limited or no other treatment options available.”
Detecting cancers at earlier stages of disease—when treatment is more likely to result in improved survival—has become a strategic cancer planning priority in the UK, theBMJ noted.
“The NHS is committed to diagnosing 75% of all cancers at stage I or II by 2028, from around 50% currently,” the BMJ wrote. “Achieving such progress in less than a decade would be highly ambitious, even without disruption caused by the COVID-19 pandemic. In this context, considerable hope has been expressed that blood tests for circulating free DNA—sometimes known as liquid biopsy—could help achieve earlier detection of cancers.”
The Guardian noted that the UK’s initiative will use a liquid biopsy test made by Swiss-healthcare giant Roche.
Liquid Biopsies: Hope or Hype?
In 2020, the US Food and Drug Administration (FDA) expanded its clearance for two liquid biopsy tests in this country—Guardant Health’s Guardant360 CDx and Foundation Medicine’s FoundationOne Liquid CDx—for use as companion diagnostic tests and for general tumor profiling for certain non-small cell lung, prostate, breast, and ovarian cancers, according to an NIH National Cancer Institute news release.
In her article “The Promise of Liquid Biopsies for Cancer Diagnosis,” published in the American Journal of Managed Care (AJMC) Evidence-based Oncology, serial healthcare entrepreneur and faculty lecturer at Harvard Medical School Liz Kwo, MD, detailed the optimism surrounding the “revolutionary screening tool,” including its potential for:
The AJMC article estimated the liquid biopsy market will be valued at $6 billion by 2030. However, Kwo also noted that clinical adoption of liquid biopsies in the US continues to face challenges.
In a STAT editorial, titled, “Liquid Biopsy: Misplaced Faith in Early Cancer Detection?” H. Gilbert Welch, MD, a Harvard University academic physician and cancer researcher, voiced concerns about widespread use of liquid biopsies for cancer screening.
Welch compared the investor hype surrounding liquid biopsies to that of the now-defunct blood testing company Theranos, which lured high-profile investors to pour millions into its unproven diagnostic technology.
“Effective cancer screening requires more than early detection. It also requires that starting therapy earlier helps people live to older ages than they would if they started treatment later,” he wrote. “If that doesn’t happen, liquid biopsies will only lead to people living longer with the knowledge they have a potentially incurable disease without extending their lives. These people would be subjected to cancer therapies and their toxicities earlier, but at a time when they would otherwise be experiencing no cancer-related signs or symptoms.”
And so, while there’s much excitement about the possibility of a minimally invasive way to detect cancer, anatomic pathology groups and clinical laboratories will have to wait and see if the hype and hope surrounding liquid biopsies is substantiated by further research.
—Andrea Downing Peck
Related Information:
NHS Cancer Patients to Get Pioneering Genetic Test to Find Best Treatments
‘Liquid Biopsy’ for Cancer Screening
The Promise of Liquid Biopsies for Cancer Diagnosis
Cancer ‘Liquid Biopsy’ Blood Test Gets Expanded FDA Approval
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.
Other detailed findings of the UW Medicine Study:
“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:
Potential Problems with Liquid Biopsies
Blood Cell Mutations Confound Prostate Cancer Liquid Biopsy
Pursing and Perfecting Use of Liquid Biopsies in Cancer Early Detection
