Abstract
Multiple dominant somatic populations are present in ctDNA, with AR alterations driving treatment resistance.
Major Finding: Multiple dominant somatic populations are present in ctDNA, with AR alterations driving treatment resistance.
Approach: Deep whole-genome sequencing was performed on ctDNA and matched metastatic prostate cancer tissue.
Impact: This work advances ctDNA profiling to include clinical insight into progressing metastatic cancers.
Obtaining circulating tumor DNA (ctDNA) from the blood is a minimally invasive way of receiving information regarding cancer diagnosis, treatment selection, and potential relapse. However, there is a lack of understanding regarding the populations that comprise ctDNA as well as their relationship with metastatic disease and dynamics during treatment. Using deep whole-genome sequencing of 61 plasma and 15 synchronous metastases from 33 patients with metastatic castration-resistant prostate cancer, Herberts, Annala, Sipola, and colleagues sought to identify dominant somatic populations in collected ctDNA samples and detected 2.9 subclonal populations per patient with distinct copy-number landscapes, which implies varying patterns of evolution. Whole-genome duplication (WGD), which can be associated with poor prognosis, was detected in 55% of patients, and samples with chromosomal instability and whole-genome copy-number alterations were increased in WGD samples. Additionally, ctDNA was found to be derived from multiple metastases with a minor portion of ctDNA being provided by each, and comparison of mutation and copy-number landscape between same-patient samples revealed that 96.9% of mutations detected in tissue were redetected in ctDNA, suggesting the ability of ctDNA to recapitulate the clonally expanded driver mutation landscape. Specific investigation into androgen receptor (AR) alterations, which drive castration resistance, showed that most recurrent changes to copy number, mutations, or structural rearrangements occurred at the AR locus, suggesting AR drives differential clonal fitness and population shifts. Moreover, an alteration to AR was observed in 95% of ctDNA samples, with copy-number gain being variable between samples indicating multiple subclones with different AR genotypes. Finally, nucleosome footprinting, which reveals distinct ctDNA fragmentation patterns, demonstrated depletion of nucleosomes at sites of highly expressed genes like AR in ctDNA and was also able to identify loss of AR signaling. Overall, this study determines that ctDNA can show metastatic evolution histories as well as genomic and transcriptomic mechanisms of treatment resistance, suggesting the use of liquid biopsy as a future tool for multiomic discovery.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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