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Germline whole genome sequencing in adults with multiple primary tumors

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Abstract

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was conducted with support from the Cancer Genomics Program at Princess Margaret Hospital. RHK is supported by the Bhalwani Family Charitable Foundation, Karen Green and George Fischer Genomics and Genetics Fund, Lindy Green Family Foundation, the FDC Foundation, the Shar Foundation, and the Princess Margaret Cancer Foundation.

Funding

This work was supported by the University of Toronto Division of Medical Oncology Strategic Innovation Fund, the Soper Kidney Cancer Foundation, and the Princess Margaret Cancer Foundation.

Author information

Author notes

  1. Kalene van Engelen

    Present address: Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada

  2. Kalene van Engelen

    Present address: Department of Pediatrics, Western University, London, ON, Canada

Authors and Affiliations

  1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Yiming Wang, Stephenie Prokopec, Kirsten M. Farncombe, Jeffrey Bruce, Jeanna McCuaig, Marta Szybowska, Kalene van Engelen, Trevor J. Pugh & Raymond H. Kim

  2. Ontario Institute for Cancer Research, Toronto, ON, Canada

    Yiming Wang, Stephenie Prokopec, Kirsten M. Farncombe, Jeffrey Bruce, Trevor J. Pugh & Raymond H. Kim

  3. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

    Yiming Wang, Qiliang Ding & Raymond H. Kim

  4. Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada

    Selina Casalino, Jordan Lerner-Ellis & Raymond H. Kim

  5. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada

    Selina Casalino & Jordan Lerner-Ellis

  6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Jeanna McCuaig, Marta Szybowska & Kalene van Engelen

  7. London Health Science Centre, London, Canada

    Kalene van Engelen

  8. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Jordan Lerner-Ellis

  9. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Raymond H. Kim

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  1. Yiming Wang
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Contributions

RHK: supervises this work, and all authors contributed to the study’s conception and design. YW, QD, SP, KMF, JB and TJP: performed material preparation, data collection, and analysis. JMC, MS and KE: conducted patient recruitment and informed consent. SC and JL-E: compiled the custom list of 735 cancer-associated genes. YW and RHK: wrote the first draft of the manuscript, and all authors read and approved the final manuscript.

Corresponding author

Correspondence to Raymond H. Kim.

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The authors declare no conflict of interest.

Ethical approval

The study was approved by the Research Ethics Board at the University Health Network (#16–5831) and is registered at clinicaltrials.gov (clinical trials registration number: NCT03857594).

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Written informed consent was obtained from the patients to publish this report in accordance with the journal's patient consent policy.

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Wang, Y., Ding, Q., Prokopec, S. et al. Germline whole genome sequencing in adults with multiple primary tumors. Familial Cancer 22, 513–520 (2023). https://doi.org/10.1007/s10689-023-00343-2

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