A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients

Abstract

Gene panels for hereditary breast and ovarian cancer risk assessment are gaining acceptance, even though the clinical utility of these panels is not yet fully defined. Technical questions remain, however, about the performance and clinical interpretation of gene panels in comparison with traditional tests. We tested 1105 individuals using a 29-gene next-generation sequencing panel and observed 100% analytical concordance with traditional and reference data on >750 comparable variants. These 750 variants included technically challenging classes of sequence and copy number variation that together represent a significant fraction (13.4%) of the pathogenic variants observed. For BRCA1 and BRCA2, we also compared variant interpretations in traditional reports to those produced using only non-proprietary resources and following criteria based on recent (2015) guidelines. We observed 99.8% net report concordance, albeit with a slightly higher variant of uncertain significance rate. In 4.5% of BRCA-negative cases, we uncovered pathogenic variants in other genes, which appear clinically relevant. Previously unseen variants requiring interpretation accumulated rapidly, even after 1000 individuals had been tested. We conclude that next-generation sequencing panel testing can provide results highly comparable to traditional testing and can uncover potentially actionable findings that may be otherwise missed. Challenges remain for the broad adoption of panel tests, some of which will be addressed by the accumulation of large public databases of annotated clinical variants.

The use of panel testing in familial breast and ovarian cancer

“…The analytical validity of panel testing was comparable to traditional sequencing methods (separate Sanger sequencing and deletion/duplication analyses of each gene). 11,12 Overall, 'high-risk' breast cancer susceptibility genes are thought to account for 20-25% of familial breast cancer, with 'intermediate' risk genes explaining a further 5% and 'low risk' gene variants cumulatively covering an additional 14% of the familial risk. 12 In a recent study by Desmond et al , 13 panel testing in 1046 BRCA1/2 -negative cases referred for hereditary breast-ovarian cancer predisposition led to identification of deleterious mutations in other hereditary cancer predisposition genes in 3.8% of individuals, which was consistent with previous similar studies.…”

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape

“…This activity encompasses all types of hereditary cancer (HC) syndromes, although we work mainly with hereditary colorectal cancer (Familial Adenomatous Polyposis, FAP, and Hereditary Non-Polyposis Colorectal Cancer, HNPCC), hereditary breast and ovarian cancer (HBOC) and neurofibromatoses Type 1 and Type 2 (NF1, NF2) and related disorders such as RASopathies and Phakomatoses. Due to genetic heterogeneity, clinical heterogeneity and overlapping clinical manifestations, diagnostic activity in the field of hereditary cancer requires multiple gene testing122526.…”

Molecular Diagnostics in Clinical Oncology

“…There is a number of NGS panels, which provide information on mutation status of dozens of cancer-causing genes. They are characterized by excellent technical performance, demonstrating virtually null rate of false results (Lincoln et al, 2015). However, most of available diagnostic panels mix together genes with well-established medical significance and gene-candidates with poorly proven disease-predisposing role (Easton et al, 2015; Sokolenko and Imyanitov, 2017).…”