Orlando, Francesco; Romanel, Alessandro; Trujillo, Blanca; Sigouros, Michael; Wetterskog, Daniel; Quaini, Orsetta; Leone, Gianmarco; Xiang, Jenny Z; Wingate, Anna; Tagawa, Scott; Jayaram, Anuradha; Linch, Mark; Jamal-Hanjani, Mariam; Swanton, Charles; Rubin, Mark A; Wyatt, Alexander W; Beltran, Himisha; Attard, Gerhardt; Demichelis, Francesca (2022). Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay. NAR cancer, 4(2), zcac016. Oxford University Press 10.1093/narcan/zcac016
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Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Rubin, Mark Andrew |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2632-8674 |
Publisher: |
Oxford University Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
08 Jun 2022 11:30 |
Last Modified: |
05 Dec 2022 16:20 |
Publisher DOI: |
10.1093/narcan/zcac016 |
PubMed ID: |
35664542 |
BORIS DOI: |
10.48350/170464 |
URI: |
https://boris.unibe.ch/id/eprint/170464 |
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