Copy number analysis is an important aspect of cancer genomics that enables identification of activated oncogenes, inactivated tumor suppressor genes and genome-wide signatures such as homologous recombination deficiency and the tandem duplication phenotype. Despite continuous development of copy number algorithms, the current sensitivity to detect clinically relevant focal alterations is poor if the cancer DNA fraction is low. This is particularly challenging for analysis of circulating tumor DNA (ctDNA) as it is not possible to know the cancer DNA fraction in advance or, as for tissue, macrodissect to increase the cancer DNA fraction. Here, we combine a novel algorithm (Jumble) with a tailored gene panel design and selected reference samples that achieve sensitive and highly specific detection of clinically relevant copy number alterations with limits of detection at 1-2% ctDNA fraction for amplifications and 4-8% for homozygous deletions. Jumble lowers the ctDNA fraction required for detection of homozygous deletions 3-6 times compared to commercial alternatives. Jumble is freely available as an R script and container, ready for integration into bioinformatic pipelines.

The authors have declared no competing interest.

Swedish Cancer Society, Swedish Research Council, Swedish prostate cancer foundation, Radiumhemmets reserach foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Swedish Ethical Review Authority (Sweden) gave ethical approval for this work. The National Committee on Health Research Ethics (Denmark) gave ethical approval for this work.

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All data relevant for the interpretation of our findings is provided in the main manuscript or the supplemental information. Dataset 1: Panel sequencing data, cfDNA and matched gDNA, from the ProBio trial (ClinicalTrials.gov identifier: NCT03903835, www.probiotrial.org). Any data providing information on individual outcomes or genotypes is considered to be a personal registry by the Swedish law (Personal Data Act), thereby prohibiting the submission of the sequencing files to a public repository. Access to the sequencing data data requires approval from the Swedish Ethical Review Authority and an agreement with the data protection- and legal unit at Karolinska Institutet. Dataset 2: Panel sequencing data of cfDNA from the MAGNITUDE trial (ClinicalTrials.gov identifier: NCT03748641). The data sharing policy is described in the publication, "Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer", pmid 36952634. Dataset 3: Panel sequencing data and low-pass whole genome sequencing from a Danish retrospective cohort. See publication "Prognostic Value of Low-Pass Whole Genome Sequencing of Circulating Tumor DNA in Metastatic Castration-Resistant Prostate Cancer", pmid 36762756, for data access information.