Abstract
Objectives
We analysed whether temporal heterogeneity of ctDNA encodes evolutionary patterns in ovarian cancer.
Methods
Targeted sequencing of 275 cancer-associated genes was performed in a primary tumor biopsy and in ctDNA of six longitudinal plasma samples from 15 patients, using the Illumina platform.
Results
While there was low overall concordance between the mutational spectrum of the primary tumor biopsies vs. ctDNA, TP53 variants were the most commonly shared somatic alterations. Up to three variant clusters were detected in each tumor biopsy, likely representing predominant clones of the primary tumor, most of them harbouring a TP53 variant. By tracing these clusters in ctDNA, we propose that liquid biopsy may allow to assess the contribution of ancestral clones of the tumor to relapsed abdominal masses, revealing two evolutionary patterns. In pattern#1, clusters detected in the primary tumor biopsy were likely relapse seeding clones, as they contributed a major share to ctDNA at relapse. In pattern#2, similar clusters were present in tumors and ctDNA; however, they were entirely cleared from liquid biopsy after chemotherapy and were undetectable at relapse. ctDNA private variants were present among both patterns, with some of them mirroring subclonal expansions after chemotherapy.
Conclusions
We demonstrate that tracing the temporal heterogeneity of ctDNA, even below exome scale resolution, deciphers evolutionary trajectories in ovarian cancer. Furthermore, we describe two evolutionary patterns that may help to identify relapse seeding clones for targeted therapy.
Funding source: Deutsche Krebshilfe
Award Identifier / Grant number: 70113616, 70113636
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Research ethics: The study was approved by the Local Research Ethics Committee in Dresden, Germany (EK74032013, EK23602012) and was performed in accordance with good clinical practice guidelines, national laws, and the Declaration of Helsinki.
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Informed consent: Written informed consent was obtained from all patients.
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Author contributions: JDK, OK and SD and DA made substantial contributions to the conception and design of the study. OK, JDK, AK, SO contributed to the experimental work. OK, AK, JDK, DA, SD contributed to the acquisition of data. JDK, OK, DW, SD analyzed and interpreted the results. JDK, OK, TL, PW, GB, ES were involved in drafting the manuscript, creating figures or revising the manuscript. All authors read and approved the manuscript in its final version.
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Competing interests: The authors state no conflict of interest.
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Research funding: The study was supported by Deutsche Krebshilfe (reference numbers: 70113616, 70113636).
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Data availability: The sequence raw data of this study have been deposited in the SRA (Sequence Read Archive) with the submission number SUB13842319.
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Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/cclm-2023-1266).
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