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Two pathogenic germline truncating variants of BRCA2 confer different haploinsufficiency phenotypes

GSE272335 Homo sapiens Expression profiling by high throughput sequencing 9 samples Submitted 2024/11/21 Platform GPL16791Platform GPL24676
Summary
Inactivating germline monoallelic mutations in the tumor suppressor BRCA2 predispose to breast and ovarian cancer. BRCA2 is essential in DNA repair via homologous recombination (HR). Tumorigenesis in this setting is thought to require the inactivation of the second allele; however, this event is not always observed suggesting haploinsufficiency. We investigated this question recreating two BRCA2 pathogenic truncating variants in heterozygosis in breast epithelial cells. One prompted sensitivity to PARP inhibitors (PARPi) and reduced HR capacity unlike the other. The other resulted in transcriptomic and epigenetic changes including histone H4 acetylation levels and NF-kB activation that we link to PCAF acetyl transferase. These changes impacted on cell migration and proliferation in 2D and 3D, processes that were also deregulated in tumors. Our work demonstrates that distinct truncating variants of BRCA2 are not phenotypically equivalent. It also identifies PCAF as shaping BRCA2-related gene expression. These findings may have implications in cancer prevention.
Published in
A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription
Minello A, Gomez-Escudero J, Sridhara SC et al. · Nature communications 2025 · PMID 41372141 · doi:10.1038/s41467-025-67209-2
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Also filed as BioProject PRJNA1136477 and SRA study SRP520263. Searching any of these in the dataset finder brings you back here.

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