Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer

Abstract

As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS. Patient clinical features of BC and OC and cancer family history were collected and compared to the patient genetic profile.A total of 255 women were analyzed, 57 of whom had a pathogenic mutation in BRCA1/2 genes, and 17 carried pathogenic mutations in other genes, such as PALB2, ATM, BRIP1, RAD51D, MSH6, PPM1D, RECQL4, ERCC3, TSC2, SLX4 and other Fanconi anemia genes.Patients with a pathogenic mutation in genes other than BRCA1 and BRCA2 showed no significant difference from the BRCA1/2-mutated carriers with respect to age at diagnosis and clinical features, suggesting that mutations in other genes could pose a high risk of cancer development.These patients had a much higher percentage of bilateral breast cancer (BBC) and a lower rate of OC than BRCA-mutated patients and patients with no pathogenic mutations: as a consequence, the surveillance protocol should be customized to the patient genetic characteristics.

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

“…High throughput NGS‐based multiple gene panel analyses are routinely used for genetic risk assessment in HBOC. Several studies have confirmed the suitability of the commercially available TSCP for HBOC diagnostics . In our study, we performed a systematic screen for PVs in 94 cancer predisposing genes via NGS and CGH.…”

“…Twenty‐five PVs were detected by NGS in BRCA1/2 negative, high risk HBOC patients, leading to a detection rate of 10.6% (25/235). This is higher compared to a former study by Tedaldi et al ., 2017, who discovered PVs in 8.6% of 198 patients with the same NGS‐based panel screening . This discrepancy could be explained by our stringent inclusion criteria for patients in our cohort; a heterozygosity risk ≥20%.…”

“…Moreover, NGS is a common technique used in clinical diagnostics for HBOC for rapid pathogenic variant (PV) detection at a low cost. NGS‐based multiple gene panels and high resolution comparative genomic hybridization (CGH)‐arrays have been used in multiple studies to identify PVs predisposing for HBOC …”

“…NGS-based multiple gene panels and high resolution comparative genomic hybridization (CGH)-arrays have been used in multiple studies to identify PVs predisposing for HBOC. 4,[7][8][9] In our study we screened 237 breast and ovarian cancer patients negative for known BRCA1 and BRCA2 PVs, but holding a high risk of genetic disease for PVs, in 94 cancer predisposition genes. This genetic risk is based on family history and age of onset of disease within the family.…”

Current review ofTP53pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome

“…While most of the published multigene panel studies tested patients of (mostly) European ancestry, a limited number of studies have analyzed other populations. We therefore compared the frequency of TP53 carriers among cohorts of patients with different ancestries and without previous BRCA1/2 testing (BRCA unknown) for Europeans (Bunnell et al., ; Buys et al., ; Castera et al., ; Couch et al., ; Couch et al., ; Doherty, Bonadies, & Matloff, ; Eliade et al., ; Kapoor et al., ; Kraus et al., ; Moran et al., ; Pinto et al., ; Rummel, Lovejoy, Shriver, & Ellsworth, ; Schroeder et al., ; Shirts et al., ; Susswein et al., ; Tedaldi et al., ; Tung et al., ; Tung et al., ) Asians (Kwong et al., ; Lin et al., ; Ng et al., ; Rajkumar, Meenakumari, Mani, Sridevi, & Sundersingh, ; Wong et al., ; Yang et al., ), and Middle Easterns (Jalkh et al., ; Lolas Hamameh et al., ).…”