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Multimodal Cell-Free DNA Test May Help Detect Cancer Early in Li-Fraumeni Syndrome Patients

NEW YORK – Findings from a proof-of-principle study suggest a cell-free DNA blood test that analyzes the genome, fragmentome, and methylome can help detect cancer early in individuals affected by a hereditary cancer predisposition syndrome. The condition, called Li-Fraumeni syndrome, is marked by the presence of risky germline TP53 mutations.

As they reported in Cancer Discovery on Tuesday, the researchers from the Hospital for Sick Children (SickKids), Ontario Institute for Cancer Research, the Princess Margaret Cancer Centre, and elsewhere retrospectively analyzed cell-free DNA (cfDNA) in 193 blood plasma samples collected from 89 adults or children with germline TP53 mutations that increase the risk of brain tumors, breast cancer, adrenocortical carcinoma, soft tissue sarcoma, or osteosarcoma.

A subset of 42 Li-Fraumeni-affected participants were tested over time, providing between two and 11 samples each, while the other individuals provided single samples. The 89 participants included 26 with active cancer, while 18 began as cancer-negative and went on to develop one or more cancers.

Using targeted gene panel sequencing, shallow whole-genome sequencing, and cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq), the team searched for tumor mutations, copy number changes, cancer-related ctDNA fragmentation patterns, and methylation markers found in cfDNA from blood plasma samples of individuals with active cancer or a subsequent cancer diagnosis.

The approach made it possible 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," Trevor Pugh, an OICR director, Princess Margaret Cancer Centre senior scientist, and University of Toronto researcher, and a co-senior and co-corresponding author on the study, said in a statement.

With the help of machine learning, the team narrowed in on blood plasma markers that corresponded to early-stage cancer with an overall positive predictive value of 67.6 percent and a negative predictive value approaching 97 percent. In individuals classified as clinically cancer-free, they saw a positive predictive value of just over 54 percent and a negative predictive value of more than 95 percent.

Along with cfDNA alterations that coincided with cancer in general, the team's analyses offered clues to the primary site involved when cancers were present. In particular, differentially methylated regions found in individuals with active breast cancer tended to be hypermethylated in relation to samples from individuals who were cancer-free or had other cancer types.

"Until now, we really didn't have good ways of doing surveillance in children with cancer or in children with cancer predisposition," co-senior and co-corresponding author David Malkin, an oncologist, director of SickKids' cancer genetic program, and researcher at the University of Toronto, said in a statement. "Now, we can use a simple blood test to identify when, where, and if a cancer is occurring."

The researchers were able to boost the cancer surveillance sensitivity of the cfDNA approach by combining the available data types, coming up with an integrated signature that made it possible to accurately find cancer clues in about half of samples from participants with early-stage cancers, rising to nearly 92 percent in samples from a handful of late-stage cancer cases.

"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," co-senior and co-corresponding author Raymond Kim, medical director of the Princess Margaret Cancer Centre Bhalwani Familial Cancer Clinic's cancer early detection program, said in a statement.

"This more robust approach is paramount in early cancer detection where the stakes are high," explained Kim, who is also affiliated with SickKids and the OICR Ontario Hereditary Cancer Research Network.

Based on their findings, the authors suggested that the work "provides a framework for individuals with Li-Fraumeni syndrome," though they cautioned that "adoption of liquid biopsy into current surveillance will require further clinical validation."

"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," they wrote, noting that "[l]iquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients."