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.
“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:
Potential Problems with Liquid Biopsies
Blood Cell Mutations Confound Prostate Cancer Liquid Biopsy
Pursing and Perfecting Use of Liquid Biopsies in Cancer Early Detection
