https://orcid.org/0000-0001-9283-9978
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Sasha Witts, Nicholas J Clemons, David S Liu, Commentary on Liquid Biopsy Detection of a TP53 Variant in a “Disease-Free” Pediatric Patient with a History of TP53-mutant Adrenocortical Carcinoma, Clinical Chemistry, Volume 71, Issue 1, January 2025, Page 30, https://doi.org/10.1093/clinchem/hvae132
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Plasma cell-free DNA (cfDNA) may assist in cancer diagnosis, prognosis, surveillance, and assessing treatment response. In the analysis of cfDNA, matched tumor and normal tissue/cells are commonly used to differentiate germline variants vs tumor-derived somatic variants in the cfDNA. Without access to tumor tissue for comparison, variant allele frequency (VAF) may be used to infer whether a variant in cfDNA is hereditary. While a VAF of approximately 50% may indicate a germline mutation, preferential amplification or normal homologue capture may result in <50% VAF for certain germline variants. However, as described in a recent case report by Blackburn et al. (1), post-zygotic genetic mosaicism can complicate the analysis and interpretation of cfDNA, particularly in the context of monitoring for minimal residual disease (MRD).
Blackburn et al. (1) describe plasma cfDNA analysis in a patient with metastatic adrenocortical carcinoma and mosaic Li–Fraumeni syndrome (LFS). The incidence of post-zygotic TP53 mutational mosaicism in patients with LFS-associated cancers can be as high as 11% (2). This decreases the specificity of cfDNA for MRD, particularly if the TP53 variant is the only abnormality detected, as this cfDNA may be derived from non-tumor origins. The VAF for a post-zygotic mosaic mutation will thus vary depending on the extent of mosaicism and is uninformative for monitoring MRD if there is truly a tumor-free reference point or “baseline”. Therefore, sequencing and comparing several non-tumor tissues (e.g., blood, skin, and buccal mucosa) with the tumor should be undertaken early, especially when (a) there are no other variants detected in plasma, (b) the TP53 variant is non-oncogenic, (c) the VAF is low, and (d) there is a family history of LFS-associated cancers.
