Compromised BRCA1-PALB2 interaction is associated with breast cancer risk

Area of Science:

• Genetics and Genomics
• Cancer Biology
• Molecular Biology

Background:

• BRCA1 and BRCA2 are key breast cancer suppressor proteins involved in DNA repair.
• PALB2 links BRCA1 and BRCA2 in the homologous recombination (HR) pathway.
• Interpreting missense variants in these genes is challenging for pathogenicity assessment.

Purpose of the Study:

• To identify and characterize pathogenic missense variants in PALB2.
• To investigate the role of the PALB2-BRCA1 interaction in breast cancer suppression.
• To establish the pathogenicity of a novel PALB2 variant, c.104T>C (p.L35P).

Main Methods:

• Segregation analysis in a family with breast cancer history.
• Functional assays to assess HR promotion and drug resistance.
• Whole-exome sequencing to identify somatic mutations.
• Analysis of germline variants in the PALB2 N-terminal BRCA1-binding domain.

Main Results:

• The novel PALB2 variant L35P abrogates the PALB2-BRCA1 interaction.
• L35P completely disables HR promotion and resistance to platinum salts and PARP inhibitors.
• A tumor from a carrier showed a second somatic truncating PALB2 mutation and HR-defective genomic features.
• Other germline variants in the PALB2 BRCA1-binding domain variably affect HR function.

Conclusions:

• L35P is the first pathogenic missense mutation identified in PALB2.
• The PALB2-BRCA1 interaction is essential for breast cancer suppression.
• Germline variants in the PALB2 BRCA1-binding domain may contribute to cancer development.