NEW YORK – A new study underscores how molecular analyses of patient blood samples can help find early forms of cancer in at-risk individuals.
In the study, published in PLOS Medicine on Tuesday, a team led by investigators at Washington University School of Medicine and The National Cancer Institute identified circulating tumor DNA features for differentiating between a soft tissue sarcoma known as malignant peripheral nerve sheath tumors (MPNST) and a benign precursor condition called plexiform neurofibroma (PN) in individuals with neurofibromatosis type 1 (NF1) — an inherited cancer predisposition syndrome due to inactivating mutations that affect one copy of the NF1 tumor suppressor gene.
"Using ultra-low-pass whole genome sequencing coupled with cell-free DNA fragment size selection, we were able to sensitively and specifically distinguish patients with MPNST from those harboring the benign precursor lesion, showing for the first time to our knowledge proof of concept that we can delineate malignancy from pre-malignancy in a hereditary cancer predisposition syndrome via liquid biopsy cell-free DNA analysis," co-senior and co-corresponding author Aadel Chaudhuri, a cancer biology researcher and ctDNA Working Group leader at the Washington University Siteman Center, explained in an email.
With this approach, members of the team assessed cell-free DNA (cfDNA) in blood plasma samples from 16 unaffected volunteer individuals and 37 individuals with NF1 — including samples from 23 PN patients and 46 samples from 14 individuals with MPNST. Similar to features found in MPNST tumors, the cfDNA from individuals with MPNST contained characteristic chromosomal gains and losses.
Based on cfDNA fragment sizes, copy number profiles, and genomic instability patterns, the researchers developed a classifier that could discriminate between individuals with or without the tumor conditions while distinguishing the malignant and benign forms of disease with 86 accuracy (75 percent sensitivity and 91 percent specificity) in untreated individuals.
"Plasma cfDNA from MPNST and PN patients harbored focal copy number loss of NF1 not found in healthy donors," the authors reported, noting that "MPNST patient cfDNA also had significantly greater tumor genomic instability compared to PN, with [copy number alterations] in key genomic loci previously observed in MPNST tissue … which enabled sensitive and specific liquid biopsy discrimination of MPNST from PN."
In samples collected over time, the team reported, the cfDNA-based tool correctly classified 89 percent of the MPNST and PN cases, with 83 percent sensitivity and a specificity of around 91 percent. Moreover, Chaudhuri noted that when the investigators quantified ctDNA in serial MPNST samples for their proof-of-concept analyses, they found that the approach may help in tracking treatment response and detecting relapse-related minimal residual disease after treatment at time points where MRD did not show up by radiographic imaging.
"In the future," the authors reported, "our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations."