Abstract
BackgroundHereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory.MethodsIn total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA).ResultsA pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR.ConclusionsIn our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.
Highlights
Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases
BRCA1 and BRCA2 pathogenic variants were identified in 12.6% (97/768) of breast cancer patients, whereas, 2.5% (19/768) of the individuals carried a variant in another high risk gene and 9.7% (74/768) in a moderate/low penetrance gene (Fig. 6)
The advent of Next Generation Sequencing (NGS) technology has enabled the wide use of multi-gene testing in clinical practice
Summary
Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. The application of Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The advent of Generation Sequencing (NGS) has allowed for multi-gene panel analysis, an approach widely used in clinical practice for the identification of individuals with an inherited predisposition to cancer [3, 4]. These multi-gene panels usually include high and moderate penetrance genes and in many cases some low or of yet unknown risk genes. The aim of this analysis was the identification of cancer-susceptibility significant variants and the assessment of the applicability and utility of such an analysis for these individuals
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