Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Hereditary breast and ovarian cancer (HBOC) is primarily linked to BRCA1/2 mutations.
• Emerging evidence implicates other genes in HBOC and associated malignancies.
• Advancements in multigene panels reveal broader genetic contributions to cancer risk.

Purpose of the Study:

• To evaluate the diagnostic yield of multigene panel testing in patients with suspected HBOC.
• To identify pathogenic variants in genes beyond BRCA1/2.
• To correlate genetic findings with clinical phenotypes in HBOC families.

Main Methods:

• Utilized a multigene panel for genetic testing in 280 patients with suspected HBOC.
• Included BRCA1, BRCA2, and other homologous recombination/DNA repair genes.
• Classified variants (PVs, VUS, novel) and used in silico tools for VUS/novel variant assessment.

Main Results:

• Pathogenic variants (PVs) were found in 19.3% of patients: 8.9% in BRCA1/2 and 10.4% in other genes (CHEK2, ATM, PALB2, BRIP1).
• An additional 1.8% had likely pathogenic VUS or novel variants.
• Breast and ovarian cancers were the most common malignancies observed.

Conclusions:

• Broad genetic testing beyond BRCA improves HBOC diagnostics.
• Identifies additional at-risk families for targeted surveillance.
• Enables more personalized cancer treatment strategies.