{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Saner FAM"],"funding":["Cancer Research UK","NCATS NIH HHS","Medical Research Council","NCI NIH HHS"],"pubmed_abstract":["Background
Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.Patients and methods
RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss.Results
RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.Conclusions
Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation."],"journal":["medRxiv : the preprint server for health sciences"],"pagination":["2023.11.09.23298321"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10659507"],"repository":["biostudies-literature"],"pubmed_title":["Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma."],"pmcid":["PMC10659507"],"funding_grant_id":["R01 CA172404","R01 CA248288","P50 CA136393","UL1 TR000124","P30 CA015083","22905","15601","MC_UU_00004/01","P30 CA071789"],"pubmed_authors":["Shah M","Sherman ME","Kobel M","Harnett PR","Rinda Soong T","Boros J","Lubinski J","Garsed DW","Gronwald J","Alsop J","Gentry-Maharaj A","Alsop K","El-Bahrawy MA","Shvetsov YB","Jones ME","Courtney-Brooks M","Kelemen LE","Zwimpfer TA","Orsulic S","Lester J","Bolithon A","Modugno F","Koziak JM","Jimenez-Linan M","Hein A","Fortner RT","Karlan BY","Gayther SA","Meagher NS","Vierkant RA","Talhouk A","Bowtell DDL","Sundfeldt K","Steed H","Hendley J","Huntsman DG","Schildkraut JM","Cushing-Haugen KL","Coulson P","Riggan MJ","Goodman MT","Wilkens LR","Hoang T","Lee CH","Taylor SE","Cybulski C","Erber R","Traficante N","Blake Gilks C","Kennedy CJ","Wang C","Pharoah PDP","Winham SJ","Swerdlow AJ","Singh N","Kaufmann SH","Twomey L","Saner FAM","Schoemaker MJ","Sharma R","Fereday S","Fasching PA","Pishas KI","Nelson GS","Widschwendter M","Christie EL","Carney ME","Hernandez BY","Brooks-Wilson A","Kluz T","Kristjansdottir B","Berchuck A","Le ND","Cook LS","Doherty JA","Budden T","AOCS Group","Ghatage P","Menon U","Sukumvanich P","Brand AH","Mateoiu C","Beckmann MW","Ramus SJ","Harris HR","Pandey A","Takahashi K","Ariyaratne D","DeFazio A","Hartmann A","Ruebner M","Brenton JD","Elishaev E","Campbell I","Kang EY","Anglesio MS","Jakubowska A","Lener M","Goode EL"],"additional_accession":[]},"is_claimable":false,"name":"Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.","description":"Background
Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.Patients and methods
RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss.Results
RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.Conclusions
Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Nov","modification":"2026-06-23T03:22:31.57Z","creation":"2026-06-23T03:10:02.063Z"},"accession":"S-EPMC10659507","cross_references":{"pubmed":["37986741"],"doi":["10.1101/2023.11.09.23298321"]}}