Abstract
SUMMARYGermline pathogenic mutations in BReast CAncer (BRCA1) genes are thought to drive normal fallopian tube epithelial (FTE) cell transformation to high-grade serous ovarian cancer. No human models capture the sequence of events for disease initiation and progression. Here, we generate induced pluripotent stem cells (iPSCs) from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut). Following differentiation into FTE organoids, BRCA1mut lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset. These human FTE organoids from BRCA1mut carriers provide a faithful physiological in vitro model of FTE lesion generation and early carcinogenesis. This platform can be used for personalized mechanistic and drug screening studies.
Highlights
Ovarian cancer is the leading cause of gynecologic cancer death worldwide, with only slight improvements in overall survival rates over the last 40 years
IPSCs were generated from three patients diagnosed with epithelial ovarian cancer, and all carried germline pathogenic mutations in the BRCA1 gene and three unaffected, nonBRCA1 mutation controls (Barrett et al, 2014)
Sequencing confirmed the presence of BRCA1 heterozygous mutations in induced pluripotent stem cells (iPSCs) lines (Figure 1A), with each patient having a different heterozygous mutation—79i-BRCA (IVGS5+1G > A, located at the junction between exon 5 and intron 6), 70i-BRCA (1048delA), and 08i-BRCA (3875del4, located in exon 11)—with all mutations predicted to be protein truncating and highly penetrant. qRTPCR demonstrated that the BRCA1mut does not discernably alter BRCA1 transcript expression in iPSC lines from carriers versus non-carriers (Figure 1B)
Summary
Ovarian cancer is the leading cause of gynecologic cancer death worldwide, with only slight improvements in overall survival rates over the last 40 years. Epithelial ovarian cancer represents a heterogeneous group of diseases with different cells of origin, histology, risk factors, and biologic behaviors. High-grade serous cancer (HGSC) is the most common and lethal subtype of ovarian cancer, with approximately 70% of newly diagnosed ovarian cancer cases classified as HGSC (Koshiyama et al, 2014, 2017; Kurman, 2013). Patients are typically diagnosed with late-stage (III/IV) clinical disease and present with widespread peritoneal metastases. The strongest genetic risk factor for developing HGSC is carrying a germline mutation in the BReast Cancer (BRCA1) gene (BRCA1mut). The risk of ovarian cancer in the general population is approximately 1.37% (Pearce et al, 2015), which jumps over 30-fold to 40%–59% among individuals that carry BRCA1mut (Kuchenbaecker et al, 2017)
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