Application of Multigene Panels Testing for Hereditary Cancer Syndromes

Abstract

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.

CDKN2A Gene Mutations: Implications for Hereditary Cancer Syndromes

“…A search for mutations in the CDKN2A gene was performed using either the targeted NGS panel or WGS. Targeted NGS testing of 111 cancer-associated genes was performed in the Laboratory of Oncogenetics and Hereditary Diseases in the Loginov Moscow Clinical Scientific Center, as previously described [25]. WGS was performed in a large-scale scientific research project that was implemented in Moscow (Russia) between 2021 and 2023 with the aim of identifying hereditary cancer syndromes (HCS) using WGS in the patients with colorectal, breast, pancreatic, ovarian, gastric, and endometrial cancer, as well as neuroendocrine tumors in the LLC Evogen, as previously described [26].…”

Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis

“…The study cohort included 657 patients from Russia divided into two groups: 632 (96.2%) cancer patients with clinical signs of cancer and 25 (3.8%) patients with benign tumors. These individuals were selected based on criteria established in a prior study and underwent consultations with geneticists [ 16 ]. Participation in the study involved molecular genetic testing, for which all participants provided detailed information regarding their personal and familial cancer histories.…”

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach

“…Gene panels are currently utilized globally to identify cancer predisposition alterations for hereditary cancers. These panels are available to adults who have a history of specific cancers, including breast cancer, ovarian cancer, skin cancer, and bowel cancer [ 149 ]. The gene panel used for hereditary cancers includes 20 genes that have been identified as having a predisposition for the development of cancers in early adulthood.…”

“…The gene panel used for hereditary cancers includes 20 genes that have been identified as having a predisposition for the development of cancers in early adulthood. These genes are APC , BMPR1A , BRCA1 , BRCA2 , CDH1 , CDK4 , CDKN2A , HOXB13 , MLH1 , MSH2 , MSH6 , MUTYH , PALB2 , PMS2 , POLD1 , POLE , PTEN , SMAD4 , STK11 , and TP53 [ 149 ].…”