Abstract
BackgroundHereditary 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.MethodsA 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).ResultsA 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.ConclusionThis 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.
Highlights
Hereditary cancer predisposition syndromes account for up to 10% of all diagnosed cancer cases
copy number variants (CNVs) identified by next generation sequencing (NGS) based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy
It is established that additional hereditary cancer predisposition syndromes are linked to an ever increasing number of genes, including but not limited to TP53, CDH1, SKT11, PTEN, PALB2, MLH1, MSH2, PMS1, PMS2, and MSH6, which have been associated with increased risk of breast, ovarian, and other cancers, often as part of more complex family histories including colon, endometrial, gastric, brain, and/or other cancers (Rahman et al, 2007; Roberts et al, 2018; Schon and Tischkowitz, 2018)
Summary
Hereditary cancer predisposition syndromes account for up to 10% of all diagnosed cancer cases. Ease of testing of multiple genes simultaneously, along with reduced cost and rapid turnaround times has enabled implementation of this technique as a frontline clinical test for individuals suspected to have a familial cancer syndrome (Okur and Chung, 2017). CNVs in cancer susceptibility genes constitute for a significant number of pathogenic variants (PVs) (approximately 7%) and can be identified using NGS based algorithms with significant reduction in turnaround times and cost (Mancini-DiNardo et al, 2019). Generation sequencing (NGS) based multi-gene targeted panels is a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. 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
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