Researchers at the Hospital for Sick Children (SickKids), the Ontario Institute for Cancer Research (OICR), and the University Health Network (UHN) have developed a liquid biopsy that an initial study has shown provides earlier detection cancer in individuals with Li-Fraumeni syndrome (LFS) than existing methods. LFS is hereditary disorder that carries with it an almost 100% lifetime risk of developing cancer.
The integrated approach for cell-free liquid biopsy analysis combines genomic, fragmentomic and epigenetic methods to analyze LFS patients’ blood samples at a molecular level. “Until now, we really didn’t have good ways of doing surveillance in children with cancer or in children with cancer predisposition, said research co-lead David Malkin, MD, staff oncologist, senior scientist, and director of the Cancer Genetics Program at the Hospital for Sick Children (SickKids) and a professor of pediatrics and medical biophysics at the University of Toronto. “Now, we can use a simple blood test to identify when, where and if a cancer is occurring. That is precision … These promising findings can be extended to all hereditary cancer syndromes to help improve the accuracy of cancer detection, especially for common tumor types, utilizing several analysis types that leverage different biological measurements.”
Malkin, together with research co-leads Trevor Pugh, PhD, and Raymond Kim, MD, PhD, at Princess Margaret Cancer Centre, UHN reported on the study in a paper in Cancer Discovery. In their paper, they concluded, “By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with Li-Fraumeni syndrome compared to current clinical surveillance methods, such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients.”
Li-Fraumeni syndrome is an inherited condition associated with a very high risk of developing cancer—often tumors affecting the breast, soft tissue, brain and other organs. It is caused by a germline pathogenic mutation in the TP53 tumor suppressor gene, which normally encodes a protein that helps to prevent tumor formation and is commonly termed the “guardian of the genome.” The authors wrote, “Individuals with germline TP53 mutations have an estimated lifetime risk of ~75% in males and ~100% in females of developing at least one cancer.” Due to this high risk of cancer development, it is recommended that all patients with pathogenic TP53 mutation (TP53m) undergo intensive surveillance, including frequent diagnostic imaging, physical examination, and blood tests. Such tests have been shown to detect cancers earlier and improve patient outcomes, but about 20% of TP53m carriers don’t comply, citing psychosocial, logistic, and cost-related barriers.
Cancerous cells and healthy cells release pieces of DNA into the blood. By analyzing these fragments of circulating tumor DNA (ctDNA) in blood, researchers are developing methods to detect whether a tumour has developed in the body. Testing blood samples for signs of cancer—liquid biopsies—is an attractive screening approach compared to imaging methods, which require specialized machines, and biopsies, which are more invasive. The researchers commented that for patients with LFS, “Cell-free DNA (cfDNA) analysis, or “liquid biopsy,” is an emerging technology that may help to alleviate logistical barriers and complement (or even replace) current screening modalities.”
For their reported study the research team applied targeted panel sequencing (TS), shallow whole genome sequencing (sWGS), and cell-free methylated dNA immunoprecipitation sequencing (cfMeDIP-seq), to analyze blood samples from 82 individuals with Li-Fraumeni syndrome collected over several years, as well as 30 blood samples from individuals without Li-Fraumeni syndrome. The techniques were first assessed individually for their performance in detecting ctDNA, and then were integrated for a multi-modal approach. The researchers found that this multimodal approach resulted in improved cancer detection, providing proof-of-principle framework that may support the detection of specific cancers earlier for individuals with Li-Fraumeni syndrome.
“Each assay (TS, sWGS, cfMeDIP-seq) enables analyses that measure independent biological signals which when evaluated together and in conjunction with other clinical screening modalities, can improve the overall sensitivity, specificity, and robustness of predictions,” the team wrote. “The increased sensitivity observed in our study through a combination of multi-modal analyses suggests that future clinical tests aimed towards early detection will likely need to utilize several analysis types that leverage different biological measurements.”
Added Kim, “Each of these methods were able to detect cancer-associated signals in the samples, but the integration of multiple analyses provides a more holistic view of tumor DNA events. This more robust approach is paramount in early cancer detection where the stakes are high. To improve the accuracy of early stage cancer diagnoses, such genetic tests can be used to complement other clinical screening methods, and they can be performed at a higher frequency.”
Pugh said, “The key to these long, multi-year studies is keeping up the momentum and building infrastructure to enable comparisons of multiple types of data over time. Here, we were able to detect multiple different types of DNA changes in blood that were a telltale sign that cancer was developing somewhere in the body months before cancer would show up in imaging.”
The team will conduct a clinical trial to further test this approach and screen patients in the hope of finding their cancer earlier. The aim is to include patients with different types of high-risk cancer predisposition syndromes, including Li-Fraumeni syndrome, Lynch syndrome, and hereditary breast and ovarian cancer; all of which are brought under a nation-wide research consortium that Pugh and Kim founded in 2017.
As the authors also pointed out, “Many ctDNA studies are currently focused on singular or bimodal approaches to ctDNA detection in sporadic cancer. However, our study suggests that multi-omic, multi-modal analyses should be adopted and explored further to assess the relative benefits of including additional assays, analyses, and biological information … Given the relative lower invasiveness and increased accessibility of liquid biopsy, compared to current surveillance methods, future studies should assess the effects of liquid biopsy on the psychosocial impact of current surveillance programs.”
