Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach

Pratibha Bhai; Michael A Levy; Kathleen Rooney; Deanna Alexis Carere; Jack Reilly; Jennifer Kerkhof; Michael Volodarsky; Alan Stuart; Mike Kadour; Karen Panabaker; Laila C Schenkel; Hanxin Lin; Peter Ainsworth; Bekim Sadikovic

doi:10.3389/fgene.2021.698595

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach

Front Genet. 2021 Jul 13:12:698595. doi: 10.3389/fgene.2021.698595. eCollection 2021.

Authors

Pratibha Bhai¹, Michael A Levy¹, Kathleen Rooney¹, Deanna Alexis Carere¹, Jack Reilly², Jennifer Kerkhof¹, Michael Volodarsky¹, Alan Stuart¹, Mike Kadour^{2

3}, Karen Panabaker⁴, Laila C Schenkel^{1

2}, Hanxin Lin^{1

2}, Peter Ainsworth^{1

2

3}, Bekim Sadikovic^{1

2}

Affiliations

¹ Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
² Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
³ Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada.
⁴ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.

Abstract

Background: Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient's personal and/or family history of cancer.

Methods: A 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).

Results: A 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.

Conclusion: This study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.

Keywords: breast cancer; colorectal cancer; copy number variants; familial cancer syndromes; next generation sequencing.