Abstract IA022: BRCA mutations and protein products in cancer

BRCA1, BRCA2, and PALB2 mutations frequently involve shifting of the gene reading frame, resulting in the production of premature stop codons and truncated proteins. Frequently, the latter are subject to misfolding and proteasomal degradation. We have found that in response to prolonged PARP inhibitor (PARPi) treatment, multiple common pathogenic BRCA1 mutations use post-transcriptional mechanisms to produce truncated and hypomorphic protein isoforms. BRCA1 protein isoforms could induce PARPi resistance when expressed at sufficiently high levels. Moreover, we discovered several BRCA1 genetic alterations, such as secondary splice site mutations, and Alu-mediated gene rearrangements, which result in the production of protein isoforms that avoid misfolding and promote PARPi resistance. Finally, we are currently assessing the impact of PALB2 hypomorphic proteins on cancer initiation and will discuss recent results. Citation Format: Neil Johnson. BRCA mutations and protein products in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA022.