Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations

Abstract

Background Hereditary 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. Methods In 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). Results A 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. Conclusions In 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5756-4) contains supplementary material, which is available to authorized users.

Complex Characterization of Germline Large Genomic Rearrangements of the BRCA1 and BRCA2 Genes in High-Risk Breast Cancer Patients—Novel Variants from a Large National Center

“…LGRs constitute 0-6% of all BRCA mutations [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]). The difference is at least partly explained by the larger number of Alus and other repetitive sequences as well as the pseudogene counterpart in BRCA1 [32].…”

Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls

“…10 The pathogenic variant spectrum in BC and CRC patients in Turkish population has not been fully explored, as previous studies were limited in sample size and/or confined to one or few genes. [11][12][13] Here, we aimed to determine the pathogenic variant frequency in 25 cancer susceptibility genes in a large cohort of Turkish BC and CRC patients using comprehensive cancer panels and multiplex ligation-dependent probe amplification (MLPA) tests. We examined correlations between pathogenic variants and clinical characteristics and compared variant frequencies between high-risk or all cancer patients and elderly controls.…”

“…Prevalence of pathogenic variants and risk estimates might vary across populations 10 . The pathogenic variant spectrum in BC and CRC patients in Turkish population has not been fully explored, as previous studies were limited in sample size and/or confined to one or few genes 11‐13 . Here, we aimed to determine the pathogenic variant frequency in 25 cancer susceptibility genes in a large cohort of Turkish BC and CRC patients using comprehensive cancer panels and multiplex ligation‐dependent probe amplification (MLPA) tests.…”

Yeast-based assays for the functional characterization of cancer-associated variants of human DNA repair genes

“…Genetic methods are often not informative due to the low frequency of the variant, which is, consequently, listed as "variant of unknown significance" (VUS). In hereditary cancer syndromes, the classification of the missense variants is urgently needed for risk assessment and to set up more precise therapies [36,37]. One strategy to improve our knowledge on the functional impact of VUS is the use of functional assays.…”