Abstract Germline pathogenic mutations in the BRCA1 and BRCA2 genes (BRCA1/2mut) are the strongest genetic risk factors for high-grade serous ovarian cancer, and estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC). Pathogenic variants in these genes are implicated in about 15% of women with heritable risks of these cancers. Moreover, BRCA2mut are associated with increased risk of ER+ breast cancer and aggressive prostate cancer in men. Precise risk estimates for BRCA1/2mut that affect different cancer types are crucial to evaluate treatments and enhance drug sensitivity. Patient-specific induced pluripotent stem cell (iPSC) methods create opportunities to model human diseases in vitro. iPSCs derived from patients with known genetic mutations carry the patient's unique genetic background, to provide platforms for studying the functional effects of specific genes. Several inherited disease models created from iPSCs have successfully replicated high-risk cancers. This study aimed to utilize iPSC-based modeling to investigate the functional impact of pathogenic BRCA1/2mut on early-stage phenotypes and genomic alterations that contribute to cancer progression. Methods: We generated iPSC from both BRCA1/2mut carriers’ women and BRCA2mut carrier male. From female BRCA1/2mut, we have established iPSC-derived organoid models of ovarian cancer -OC-(fallopian tube epithelium, FTE) and breast cancer -BC-(mammary gland epithelium, MGE) and from male BRCA2mut prostate cancer-PC. Results: Following differentiation into FT organoids, both heterozygous BRCA1/2mut models show specific cellular abnormalities - neoplastic transformation, expression of cancer-specific biomarkers - compared to BRCAWT controls. ER+ BC and TNBC models revealed that following differentiation into MG organoids: models from heterozygous BRCA1/2mut carriers conferred a neoplastic phenotype reminiscent of a ductal carcinoma in situ (DCIS) compared to BRCAWT controls. Notably, the development of DCIS in BRCA2mut carriers was dependent on estrogen (E2) exposure, while in BRCA1mut carriers, it was independent of hormonal influences; this may suggest that BRCA haploinsufficiency contributes to the observed phenotype. PC models from BRCA2mut subjects exhibit abnormalities reminiscent of early-stage neoplastic development. Importantly, prostate organoids with combinations of BRCA2mut and PTEN alterations exhibited more aggressive PC phenotypes compared to BRCA2mut and BRCAWT organoids alone, and shared genomic signatures with primary aggressive PC. Conclusion and Impact. iPSC-derived multi-tissue organoid platform can accurately replicate BRCA1/2mut and BRCAWT precursor tissues. This allows cancer to evolve in a dish, making it an ideal model for mechanistic studies and screening approaches to identify novel drug targets. Citation Format: Nur Yucer, Alyssa Okimoto, Subash Dhungana, Dean Bacich, Rebecca Webster, Beatriz German Falcon, Michelle Jones, Sarah Parker, Bobbie Jo Rimel, Beth Y. Karlan, Leigh Ellis, Matthew Freedman, Robin J. Leach, Xiaojiang Cui, Kate Lawrenson, Simon Gayther. Multi-tissue modeling of BRCA cancers using iPSC-derived organoids platform abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 840.
Yucer et al. (Fri,) studied this question.