In a recent study published in Cancer Discovery, researchers developed and validated a blood-based, cell-free deoxyribonucleic acid (cfDNA) fragmentome assay for lung cancer detection, which, if the results were positive, would be followed by low-dose computed tomography (LDCT).
Introduction
Lung cancer is a major death cause, and yearly screening is crucial. However, chest LDCT has low adoption due to patient barriers like inadequate awareness, radiation concerns, and limited availability.
Other challenges include poor smoking history recording, a lack of defined practices, and specialist follow-up.
A blood-based lung malignancy screening test, like the fragmentome technique, could increase screening rates by analyzing specific chromatin configurations in peripheral blood.
About the study
In the present DELFI-L101 study, researchers developed a hematological test using machine learning to analyze DNA fragmentomes and identify individuals at risk of lung cancer. Individuals testing positive would undergo LDCT.
Beginning March 2021, the researchers enrolled 958 individuals aged 50–80 with ≥20 pack-years of smoking across 47 United States (US) facilities. Eligibility features resembled the LDCT screening criteria of the 2015 National Health Interview Survey (NHIS).
They excluded individuals with cancer therapy within one year, a history of hematologic malignancy or myelodysplasia, organ tissue transplantation, blood product transfusion within 120 days of enrollment, pregnancy, and participation in other trials.
The team divided the study participants into three groups: A (lung cancer), B (non-cancer controls), and C (cancer other than lung cancer).
The American Joint Committee on Cancer’s Cancer Staging Manual (AJCC) criteria ascertained the disease stage. Changes in cfDNA fragmentation patterns (fragmentomes) in blood revealed genomic and chromatin features of lung cancer.
The researchers trained the classifier on 576 cases and controls before validating it on another 382 cases and controls.
They used whole genome sequences from the training dataset to assess fragmentations in 504 non-overlapping-type 5.0 MB sections with strong mappability. Each region included 80,000 pieces and covered a genome size of 2.50 GB.
The team examined genome-wide alterations to Hi-C open-type (A compartment) and closed-type (B compartment) chromatin.
They created the classifier using principal component analysis (PCA) and logistic regressions, incorporating chromosomal arm-level changes, cfDNA fractions derived from the mitochondrial genome, and cfDNA fragment length distributions.
The researchers performed Monte Carlo simulations on 15 million individuals under three scenarios:
- Base Scenario: Current practices without hematological screening.
- Low Scenario: 10% uptake of hematological screening for individuals eligible for pulmonary cancer screening but not subjected to low-dose CT in the first year, increasing to 25% in five years.
- High Scenario: 20% uptake of hematological screening for the same group in the first year, increasing to 50% in five years.
Results
The researchers observed 58% test specificity, 84% sensitivity, and 99.8% negative predictive value (NPV). Applying the rest to the screening-eligible group with 0.7% lung cancer prevalence, the number needed to screen (NNS) was 143.
Study validations showed negative and positive results related to NNS with LDCT imaging to detect 414 and 76 cases, respectively, yielding a 5.5 relative risk value. The positive predictive value (PPV) was almost double that of the LDCT qualifying requirements alone.
The cfDNA fragmentomes of lung squamous cell carcinoma (LUSC) patients comprised a component resembling cfDNA profiles from non-cancer individuals and another resembling A/B-type compartments noted in LUSC tissues.
Non-cancer individuals showed cfDNA patterns approximating lymphoblastoid Hi-C findings. Within common locations, fragmentations among samples provided by individuals with cancer presence and absence were similar.
Lung cancer patients had increased cell-free DNA representations fpr 1q, 3q, 5p, 8q, and 12p, as well as lower 1p, 3p, 4q, 5q, 10q, and 17p levels. Their cfDNA fragmentations differed from controls, revealing more closely packed chromatin in cfDNA of closed LUSC spaces, while lymphoblastoid reference regions showed the reverse impact.
At the cut-off of 0.2, ten-fold cross-validation with ten repeats within the training population yielded 50% overall specificity and sensitivities of 75%, 90%, 96%, and 97% for stages I, II, III, and IV, respectively. Sensitivity was constant across ages, with younger people having higher specificity. Using the 2015 NHIS data yielded 80% sensitivity and 58% specificity.
From the ‘base’ scenario (24,489 cases), lung cancer cases identified by screening increased to 63,523 (the ‘low’ scenario) and 100,346 (the ‘high’ scenario). In contrast, stage I cases increased by 4.80% and 9.70%, while stage IV diagnoses decreased by 4.20% and 8.70%, respectively.
In total, 4,720 deaths from lung malignancies could be averted in the ‘base’ scenario, 7,652 in the ‘low’ scenario, and 14,264 deaths in the ‘high’ scenario. LDCT use in screening could reduce the number of tests required to identify lung cancers from 202 (‘base’ scenario) to 150 (‘low’ scenario) and 139 (‘high’ scenario).
Conclusion
Based on the study findings, the DNA fragmentome assay provides a novel, accurate, affordable, blood-based tool for initial lung cancer evaluation with LDCT follow-ups.
The assay could contribute to preventing lung cancer-related deaths, with moderate adoption rates possibly lowering late-stage diagnoses and fatalities.
- Peter Mazzone et al., (2024) Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection, Cancer Discov (2024), doi: https://doi.org/10.1158/2159-8290.CD-24-0519. https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-0519/745696/Clinical-validation-of-a-cell-free-DNA-fragmentome?searchresult=1
News
Nanomedicine in 2026: Experts Predict the Year Ahead
Progress in nanomedicine is almost as fast as the science is small. Over the last year, we've seen an abundance of headlines covering medical R&D at the nanoscale: polymer-coated nanoparticles targeting ovarian cancer, Albumin recruiting nanoparticles for [...]
Lipid nanoparticles could unlock access for millions of autoimmune patients
Capstan Therapeutics scientists demonstrate that lipid nanoparticles can engineer CAR T cells within the body without laboratory cell manufacturing and ex vivo expansion. The method using targeted lipid nanoparticles (tLNPs) is designed to deliver [...]
The Brain’s Strange Way of Computing Could Explain Consciousness
Consciousness may emerge not from code, but from the way living brains physically compute. Discussions about consciousness often stall between two deeply rooted viewpoints. One is computational functionalism, which holds that cognition can be [...]
First breathing ‘lung-on-chip’ developed using genetically identical cells
Researchers at the Francis Crick Institute and AlveoliX have developed the first human lung-on-chip model using stem cells taken from only one person. These chips simulate breathing motions and lung disease in an individual, [...]
Cell Membranes May Act Like Tiny Power Generators
Living cells may generate electricity through the natural motion of their membranes. These fast electrical signals could play a role in how cells communicate and sense their surroundings. Scientists have proposed a new theoretical [...]
This Viral RNA Structure Could Lead to a Universal Antiviral Drug
Researchers identify a shared RNA-protein interaction that could lead to broad-spectrum antiviral treatments for enteroviruses. A new study from the University of Maryland, Baltimore County (UMBC), published in Nature Communications, explains how enteroviruses begin reproducing [...]
New study suggests a way to rejuvenate the immune system
Stimulating the liver to produce some of the signals of the thymus can reverse age-related declines in T-cell populations and enhance response to vaccination. As people age, their immune system function declines. T cell [...]
Nerve Damage Can Disrupt Immunity Across the Entire Body
A single nerve injury can quietly reshape the immune system across the entire body. Preclinical research from McGill University suggests that nerve injuries may lead to long-lasting changes in the immune system, and these [...]
Fake Science Is Growing Faster Than Legitimate Research, New Study Warns
New research reveals organized networks linking paper mills, intermediaries, and compromised academic journals Organized scientific fraud is becoming increasingly common, ranging from fabricated research to the buying and selling of authorship and citations, according [...]
Scientists Unlock a New Way to Hear the Brain’s Hidden Language
Scientists can finally hear the brain’s quietest messages—unlocking the hidden code behind how neurons think, decide, and remember. Scientists have created a new protein that can capture the incoming chemical signals received by brain [...]
Does being infected or vaccinated first influence COVID-19 immunity?
A new study analyzing the immune response to COVID-19 in a Catalan cohort of health workers sheds light on an important question: does it matter whether a person was first infected or first vaccinated? [...]
We May Never Know if AI Is Conscious, Says Cambridge Philosopher
As claims about conscious AI grow louder, a Cambridge philosopher argues that we lack the evidence to know whether machines can truly be conscious, let alone morally significant. A philosopher at the University of [...]
AI Helped Scientists Stop a Virus With One Tiny Change
Using AI, researchers identified one tiny molecular interaction that viruses need to infect cells. Disrupting it stopped the virus before infection could begin. Washington State University scientists have uncovered a method to interfere with a key [...]
Deadly Hospital Fungus May Finally Have a Weakness
A deadly, drug-resistant hospital fungus may finally have a weakness—and scientists think they’ve found it. Researchers have identified a genetic process that could open the door to new treatments for a dangerous fungal infection [...]
Fever-Proof Bird Flu Variant Could Fuel the Next Pandemic
Bird flu viruses present a significant risk to humans because they can continue replicating at temperatures higher than a typical fever. Fever is one of the body’s main tools for slowing or stopping viral [...]
What could the future of nanoscience look like?
Society has a lot to thank for nanoscience. From improved health monitoring to reducing the size of electronics, scientists’ ability to delve deeper and better understand chemistry at the nanoscale has opened up numerous [...]
