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Identification of community-consensus clinically relevant variants and development of single molecule molecular inversion probes using the CIViC database

View ORCID ProfileErica K. Barnell, View ORCID ProfileAdam Waalkes, View ORCID ProfileKelsi Penewit, View ORCID ProfileKatie M. Campbell, View ORCID ProfileZachary L. Skidmore, Colin C. Pritchard, View ORCID ProfileTodd A. Fehniger, Ravindra Uppaluri, Ramaswamy Govindan, View ORCID ProfileMalachi Griffith, View ORCID ProfileStephen J. Salipante, View ORCID ProfileObi L. Griffith
doi: https://doi.org/10.1101/479394
Erica K. Barnell
1McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
2Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;
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Adam Waalkes
3Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
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Kelsi Penewit
3Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
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Katie M. Campbell
1McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
4Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, CA, USA.
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Zachary L. Skidmore
1McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
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Colin C. Pritchard
3Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
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Todd A. Fehniger
5Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
6Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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Ravindra Uppaluri
7Department of Surgery/Otolaryngology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA, USA.
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Ramaswamy Govindan
2Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;
5Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
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Malachi Griffith
1McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
2Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;
5Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
6Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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Stephen J. Salipante
3Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
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Obi L. Griffith
1McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
2Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;
5Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
6Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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Abstract

Clinical targeted sequencing panels are important for identifying actionable variants for cancer patients, however, there are currently no strategies to create impartial and rationally-designed panels to accommodate rapidly growing knowledge within the field. Here we use the Clinical Interpretations of Variants in Cancer database (CIViC) in conjunction with single-molecule molecular inversion probe (smMIP) capture to identify and design probes targeting clinically relevant variants in cancer. In total, 2,027 smMIPs were designed to target 111 eligible CIViC variants. The total genomic region covered by the CIViC smMIPs reagent was 61.5 kb. When compared to existing genome or exome sequencing results (n = 27 cancer samples from 5 tumor types), CIViC smMIP sequencing demonstrated a 95% sensitivity for variant detection (n = 61/64 variants). Variant allele frequency for variants identified on both sequencing platforms were highly concordant (Pearson correlation = 0.885; n = 61 variants). Moreover, for individuals with paired tumor/normal samples (n = 12), 182 clinically relevant variants missed by original sequencing were discovered by CIViC smMIPs sequencing. This design paradigm demonstrates the utility of an open-sourced database built on attendant community contributions for each variant with peer-reviewed interpretations. Use of a public repository for variant identification, probe development, and variant annotation could provide a transparent approach to build a dynamic next-generation sequencing–based oncology panel.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 06, 2018.
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Identification of community-consensus clinically relevant variants and development of single molecule molecular inversion probes using the CIViC database
Erica K. Barnell, Adam Waalkes, Kelsi Penewit, Katie M. Campbell, Zachary L. Skidmore, Colin C. Pritchard, Todd A. Fehniger, Ravindra Uppaluri, Ramaswamy Govindan, Malachi Griffith, Stephen J. Salipante, Obi L. Griffith
bioRxiv 479394; doi: https://doi.org/10.1101/479394
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Identification of community-consensus clinically relevant variants and development of single molecule molecular inversion probes using the CIViC database
Erica K. Barnell, Adam Waalkes, Kelsi Penewit, Katie M. Campbell, Zachary L. Skidmore, Colin C. Pritchard, Todd A. Fehniger, Ravindra Uppaluri, Ramaswamy Govindan, Malachi Griffith, Stephen J. Salipante, Obi L. Griffith
bioRxiv 479394; doi: https://doi.org/10.1101/479394

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