Commentary on Liquid Biopsy Detection of a TP53 Variant in a “Disease-Free” Pediatric Patient with a History of TP53-Mutant Adrenocortical Carcinoma
Christina M. Lockwood iDa,*
In oncology, the intersection between germline and somatic sequencing is pivotal: germline testing can reveal hereditary cancer risk, while somatic testing can direct cancer therapy, guide diagnosis, and aid disease moni- toring. Somatic tumor molecular profiling uses sensitive, high-throughput technologies like next-generation se- quencing to simultaneously interrogate many genes and identify tumor-specific alterations. Most somatic profiling tests are performed on tumor tissue only, which is a limitation because variants cannot be unambiguous- ly assigned as inherited or somatic.
The introduction of plasma cell-free DNA (cfDNA) tests can potentially transform clinical care across the can- cer evolution spectrum. A challenge in detecting variants in peripheral blood cfDNA is that they are derived from multiple sources. For example, cfDNA variants that are not tumor-acquired can reflect blood cell expansion in clonal hematopoiesis of indeterminate potential as well as leukocyte and healthy tissue-derived alterations either present in all cells (germline variant) or only some cells (mosaic variant).
This case was challenging due to the persistent detec- tion of a low-level TP53 variant in plasma cfDNA despite the complete tumor resection. Detecting a low-level vari- ant relies on highly sensitive molecular methods such as deep next-generation sequencing, which has not historic- ally been used for germline testing. A plasma cfDNA vari- ant at 2.5% variant allele frequency could theoretically originate from (a) a tumor, (b) clonal hematopoiesis of in-
determinate potential, or (c) a post-zygotic mosaic variant. This case illustrates the complexity encountered in cfDNA testing, where interpretation relies on integrating patient history, family history, and patient therapy, and requires close communication between care teams and the laboratory.
As sensitive plasma cfDNA tests become more com- mon in clinical care, it is crucial to implement consensus guidance such as performing paired germline analyses to distinguish clonal hematopoiesis of indeterminate po- tential from potential somatic mosaicism and disclosing limitations on test reports.
Author Contributions: The corresponding author takes full responsibil- ity that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) fi- nal approval of the published article; and (d) agreement to be account- able for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately inves- tigated and resolved. Nobody who qualifies for authorship has been omit- ted from the list.
Authors’ Disclosures or Potential Conflicts of Interest: Upon manu- script submission, all authors completed the author disclosure form.
Research Funding: None declared.
Disclosures: C.M. Lockwood is an associate editor for Clinical Chemistry, ADLM.
ªDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
*Address correspondence to this author at: Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St, NW120, Box 357110, Seattle, WA 98195, United States. Tel 206-598- 2142; e-mail tinalock@uw.edu. Received July 24, 2024; accepted September 9, 2024.
https://doi.org/10.1093/clinchem/hvae171
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