Abstract 840: Multi-tissue modeling of BRCA cancers using iPSC-derived organoids platform.

作者：Nur Yucer, Alyssa Okimoto, Subash Dhungana, Dean J. Bacich, Rebecca Webster, Beatriz German Falcon, Michelle Jones, Sarah J. Parker, Bobbie Jo Rimel, B. Y. Karlan, Leigh Ellis, Matthew Freedman, Robin J. Leach, Xiaojiang Cui, Kate Lawrenson, Simon A. Gayther · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-840 · 研究领域：PARP inhibition in cancer therapy、Cancer Cells and Metastasis、Cancer Genomics and Diagnostics

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...