Abstract
(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.
Highlights
Breast cancer (BC) is the most frequent cancer type in women and one of the main causes of female mortality
Advances in sequencing methods have revealed a marked heterogeneity in the loci related to hereditary breast and ovarian cancer (HBOC), with more than 25 genes emerging, most of which are involved in maintenance and repair genome pathways connected with BRCA1/2 [4]
All the pathogenic variants (PVs) detected in our series have been previously described as disease-causing agents (BC families, Li-Fraumeni syndrome, Lynch syndrome, or ataxia-telangiectasia) [11,14,15,16,17,18,19,20,21,22,23,24], except for the BRIP1 NM_032043.2:c.508-2A > T and CASP8 NM_01228.4: c.331delG
Summary
Breast cancer (BC) is the most frequent cancer type in women and one of the main causes of female mortality. Advances in sequencing methods have revealed a marked heterogeneity in the loci related to hereditary breast and ovarian cancer (HBOC), with more than 25 genes emerging, most of which are involved in maintenance and repair genome pathways connected with BRCA1/2 [4]. These moderate-risk genes confer a two to five-fold higher risk of BC, have a variable penetrance, and their expression can be modified by many factors such as other genes, family history, and environmental influences [5]. Recent studies have reported that in families with suspected HBOC, almost 50% of the PVs detected were identified in genes other than
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
