Journal Article

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

Ozmen, Vahit, Floros, Theofanis, Markopoulos, Christos, Ungureanu, Andrei, Xanthakis, Ioannis, Stanculeanu, Dana Lucia, Koumarianou, Anna, Negru, Serban, Katopodi, Ourania, Venizelos, Vasileios, Nasioulas, George, Tansan, Sualp, Yalcin, Suayib, Iosifidou, Rodoniki, Diamantopoulos, Nikolaos, Agiannitopoulos, Konstantinos, Papazisis, Konstantinos, Banu, Eugeniu, Eniu, Dan Tudor, Kampouri, Stavroula, Papadopoulou, Eirini, Tekinel, Mehmet, Apessos, Angela, Pepe, Georgia, Xepapadakis, Grigorios, Tsaousis, Georgios N.

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Adult / Aged / Aged, 80 and over / Biomedical and Life Sciences / Biomedicine / BRCA1 & BRCA2 / BRCA1 protein / Breast cancer / Breast Neoplasms - genetics / Cancer / Cancer genetics / Cancer Research / Cancer susceptibility genes / Child / Child, Preschool / Cohort Studies / Colorectal Neoplasms - genetics / Computer applications / DNA sequencing / Family medical history / Female / Genes / Genes, BRCA1 / Genes, BRCA2 / Genetic aspects / Genetic Predisposition to Disease / Genetic research / Genetic screening / Genetic testing / Genetic Testing - methods / Genetic Variation / Genetics / genomics and epigenetics / Greece / Health Promotion and Disease Prevention / Health risk assessment / Hereditary cancer / Heritability / High-Throughput Nucleotide Sequencing / Humans / Infant / Male / Medical research / Medicine/Public Health / Middle Aged / Multigene panels / Mutation / Neoplastic Syndromes, Hereditary - genetics / Next generation sequencing / Oncology / Ovarian cancer / Ovarian Neoplasms - genetics / Panel analysis / Patient outcomes / Pedigree / Research Article / Romania / Surgical Oncology / Technology / Turkey / Young Adult