Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Details
Publication Year 2024-08-15,Volume 30,Issue #16,Page 3481-3498
Journal Title
Clinical Cancer Research
Publication Type
Research article
Abstract
PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
Publisher
American Association for Cancer Research
Keywords
Humans; Female; *Ovarian Neoplasms/genetics/mortality/immunology/pathology; *BRCA2 Protein/genetics/deficiency; *BRCA1 Protein/genetics/deficiency; *Cystadenocarcinoma, Serous/genetics/pathology/mortality/immunology; *Retinoblastoma Binding Proteins/genetics; Prognosis; Ubiquitin-Protein Ligases/genetics; Neoplasm Grading; Lymphocytes, Tumor-Infiltrating/immunology/metabolism; Middle Aged; Germ-Line Mutation; Gene Expression Regulation, Neoplastic; Aged; Biomarkers, Tumor/genetics; CD8-Positive T-Lymphocytes/immunology/metabolism
Department(s)
Laboratory Research
Open Access at Publisher's Site
https://doi.org/10.1158/1078-0432.Ccr-23-3552
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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