Application of Multigene Panels Testing for Hereditary Cancer Syndromes

Simple Summary Hereditary cancer predisposition syndromes (HCPS) are caused by mutations of a single gene and constitute 5-10% of all cancer cases. HCPS are characterized by early manifestation and the presence of cancer cases in family history. Early identification of genetic predisposition to cancer is crucial for both the patients and their relatives at risk, as it can guide the choice of a treatment strategy for the patients and design personalized surveillance and prevention strategies for family members at risk. The wide use of next-generation sequencing (NGS)-based approaches has facilitated ubiquitous integration of targeted sequencing into clinical practice. Multigene panel testing of cancer predisposition genes is now considered to be a major approach for identification of clinically significant variants in individuals of high risk. This study aims to evaluate the landscape of HCPS-associated genetic variants in Russian individuals with personal and/or family history of cancer using NGS-based multigene panel testing. Background: Approximately 5-10% of all cancers are associated with hereditary cancer predisposition syndromes (HCPS). Early identification of HCPS is facilitated by widespread use of next-generation sequencing (NGS) and brings significant benefits to both the patient and their relatives. This study aims to evaluate the landscape of genetic variants in patients with personal and/or family history of cancer using NGS-based multigene panel testing. Materials and Methods: The study cohort included 1117 probands from Russia: 1060 (94.9%) patients with clinical signs of HCPS and 57 (5.1%) healthy individuals with family history of cancer. NGS analysis of 76 HCPS genes was performed using a custom Roche NimbleGen enrichment panel. Results: Pathogenic/likely pathogenic variants were identified in 378 of 1117 individuals (33.8%). The predominant number (59.8%) of genetic variants was identified in BRCA1/BRCA2 genes. CHEK2 was the second most commonly altered gene with a total of 28 (7.4%) variants, and 124 (32.8%) genetic variants were found in other 35 cancer-associated genes with variable penetrance. Conclusions: Multigene panel testing allows for a differential diagnosis and identification of high-risk group for oncological diseases. Our results demonstrate that inclusion of non-coding gene regions into HCPS gene panels is highly important for the identification of rare spliceogenic variants with high penetrance.