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What is the Cancer Predisposition Sequencing Reporter (CPSR)?

The Cancer Predisposition Sequencing Reporter (CPSR) is a computational workflow that interprets germline variants identified from next-generation sequencing in the context of cancer predisposition. The workflow is integrated with the framework that underlies the Personal Cancer Genome Reporter (PCGR), utilizing the Docker environment for encapsulation of code and software dependencies. While PCGR is intended for reporting and analysis of somatic variants detected in a tumor, CPSR is intended for reporting and ranking of germline variants in protein-coding genes that are implicated in cancer predisposition and inherited cancer syndromes.

CPSR accepts a query file with raw germline variant calls encoded in the VCF format (i.e. analyzing SNVs/InDels). Furthermore, through the use several different virtual cancer predisposition gene panels harvested from the Genomics England PanelApp, the user can flexibly put a restriction on which genes and findings are displayed in the cancer predisposition report.

Snapshots of sections in the cancer predisposition genome report:

CPSR views

CPSR views

The software performs extensive variant annotation on the selected geneset and produces an interactive HTML report, in which the user can investigate:

  • ClinVar variants - pre-classified variants according to a five-level tier scheme in ClinVar (Pathogenic to Benign)
  • Non-ClinVar variants - classified by CPSR through ACMG criteria (variant frequency levels and functional effects) into to a five-level tier scheme (Pathogenic to Benign)
  • Biomarkers - cancer predisposition variants with reported implications for prognosis, diagnosis or therapeutic regimens
  • Secondary findings (optional) - pathogenic ClinVar variants in the ACMG recommended list for reporting of secondary findings
  • GWAS hits (optional) - variants overlapping with previously identified hits in genome-wide association studies (GWAS) of cancer phenotypes (i.e. low to moderate risk conferring alleles), using NHGRI-EBI Catalog of published genome-wide association studies as the underlying source.

The variant sets can be interactively explored and filtered further through different types of filters (phenotypes, genes, variant consequences, population MAF etc.). Importantly, the unclassified non-ClinVar variants are assigned a pathogenicity level based on the aggregation of scores according to previously established ACMG criteria. The ACMG criteria includes cancer-specific criteria, as outlined and specified in several previous studies (Huang et al., Cell, 2018; Nykamp et al., Genet Med., 2017; Maxwell et al., Am J Hum Genet., 2016; Amendola et al., Am J Hum Genet., 2016). See also Related work

Virtual cancer predisposition panels - targets for reporting

The cancer predisposition report can show variants found in a number of well-known cancer predisposition genes, and the specific set of genes can be customized by the user by choosing any of the following virtual gene panels (0 - 42):

Citation

IMPORTANT: If you use CPSR, please cite the following bioRxiv preprint:

Sigve Nakken, Vladislav Saveliev, Oliver Hofmann, Pål Møller, Ola Myklebost, and Eivind Hovig. Cancer Predisposition Sequencing Reporter: a flexible variant report engine for high-throughput germline screening in cancer (2020). bioRxiv. doi:10.1101/846089

Docker-based technology

The CPSR workflow is developed using the Docker technology. The software is thus packaged into an isolated container, in which the installation of all software libraries/tools and required dependencies have been taken care of. In addition to the bundled software, in the form of a Docker image, the workflow needs to be attached with an annotation data bundle.

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