Using next-generation sequencing to redefine BRCAness in triple-negative breast cancer

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• BRCAness is a predictive biomarker for platinum and poly(ADP-ribose) polymerase (PARP) inhibitors, but its utility is limited in triple-negative breast cancer (TNBC) treated with platinum.
• Tumors with mutations in DNA damage response (DDR) genes, including homologous recombination (HR) genes, may respond to platinum and PARP inhibitors.

Purpose of the Study:

• To investigate the relationship between DDR gene mutation status and BRCAness in TNBC.
• To explore how different DDR gene mutations influence BRCAness features and predict treatment response.

Main Methods:

• Sequencing of 56 DDR genes in 120 TNBC patients.
• Identification of BRCAness using array comparative genomic hybridization (aCGH).
• Analysis of large-scale structural aberrations (LSAs) in relation to gene mutation status.

Main Results:

• Identified mutations in BRCA (13 patients), non-BRCA HR genes (14 patients), and non-HR DDR genes (14 patients).
• BRCA-mutated and HR gene-mutated TNBC exhibited similar BRCAness features, characterized by higher LSA counts and lengths.
• Mutations in non-HR DDR genes (PTEN, MSH6) showed distinct LSA patterns, potentially explaining differential sensitivity to PARP inhibitors.

Conclusions:

• Non-BRCA HR gene-mutated TNBC shares BRCAness characteristics with BRCA-mutated TNBC, suggesting sensitivity to platinum and PARP inhibitors.
• Heterogeneity in BRCAness genomic backgrounds indicates varying responsiveness to platinum and PARP inhibitors.
• Direct sequencing of DDR genes in TNBC is recommended for predicting sensitivity to platinum and PARP inhibitors.