Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• Germline BRCA1/BRCA2 mutations in breast cancer (BC) predict response to DNA damage response (DDR) therapies.
• These mutations account for only 5-7% of BC cases, necessitating identification of other homologous recombination deficiency (HRD) tumors.

Purpose of the Study:

• To characterize HRD tumors in BC.
• To analyze correlations between BRCA1/BRCA2 mutations and BC subtypes.
• To identify BC tumors with HRD independent of BRCA mutations.

Main Methods:

• Analysis of 981 BC tumors from The Cancer Genome Atlas (TCGA) database.
• Utilized signature analyzer to assess HRD and BRCA signatures.
• Correlated genetic mutations with gene expression and BC subtypes.

Main Results:

• BRCA signature strongly associated with top 10% HRD scores (≥57).
• HRD tumors exhibited high mutation rates in DDR genes, including BRCA1/2.
• BRCA1/2 mutations were prevalent in basal and luminal BC subtypes, respectively.
• BRCA1 mutations showed a stronger influence on HRD features than BRCA2 mutations.
• High expression of BARD1 and BRIP1 associated with HRD tumors.

Conclusions:

• HRD features are strongly linked to BRCA1/2 mutations and DDR gene mutations.
• BRCA1 mutations have a more pronounced impact on HRD than BRCA2.
• Findings provide a basis for identifying HRD and BRCA-associated BCs for targeted therapies.