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Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.

Publication ,  Journal Article
Saner, FAM; Takahashi, K; Budden, T; Pandey, A; Ariyaratne, D; Zwimpfer, TA; Meagher, NS; Fereday, S; Twomey, L; Pishas, KI; Hoang, T; Hein, A ...
Published in: Clin Cancer Res
August 15, 2024

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 15, 2024

Volume

30

Issue

16

Start / End Page

3481 / 3498

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Retinoblastoma Binding Proteins
  • Prognosis
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Grading
  • Middle Aged
  • Lymphocytes, Tumor-Infiltrating
  • Humans
  • Germ-Line Mutation
 

Citation

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Chicago
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MLA
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Saner, F. A. M., Takahashi, K., Budden, T., Pandey, A., Ariyaratne, D., Zwimpfer, T. A., … Garsed, D. W. (2024). Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma. Clin Cancer Res, 30(16), 3481–3498. https://doi.org/10.1158/1078-0432.CCR-23-3552
Saner, Flurina A. M., Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A. Zwimpfer, Nicola S. Meagher, et al. “Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.Clin Cancer Res 30, no. 16 (August 15, 2024): 3481–98. https://doi.org/10.1158/1078-0432.CCR-23-3552.
Saner FAM, Takahashi K, Budden T, Pandey A, Ariyaratne D, Zwimpfer TA, et al. Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma. Clin Cancer Res. 2024 Aug 15;30(16):3481–98.
Saner, Flurina A. M., et al. “Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.Clin Cancer Res, vol. 30, no. 16, Aug. 2024, pp. 3481–98. Pubmed, doi:10.1158/1078-0432.CCR-23-3552.
Saner FAM, Takahashi K, Budden T, Pandey A, Ariyaratne D, Zwimpfer TA, Meagher NS, Fereday S, Twomey L, Pishas KI, Hoang T, Bolithon A, Traficante N, Australian Ovarian Cancer Study Group, Alsop K, Christie EL, Kang E-Y, Nelson GS, Ghatage P, Lee C-H, Riggan MJ, Alsop J, Beckmann MW, Boros J, Brand AH, Brooks-Wilson A, Carney ME, Coulson P, Courtney-Brooks M, Cushing-Haugen KL, Cybulski C, El-Bahrawy MA, Elishaev E, Erber R, Gayther SA, Gentry-Maharaj A, Gilks CB, Harnett PR, Harris HR, Hartmann A, Hein A, Hendley J, Hernandez BY, Jakubowska A, Jimenez-Linan M, Jones ME, Kaufmann SH, Kennedy CJ, Kluz T, Koziak JM, Kristjansdottir B, Le ND, Lener M, Lester J, Lubiński J, Mateoiu C, Orsulic S, Ruebner M, Schoemaker MJ, Shah M, Sharma R, Sherman ME, Shvetsov YB, Soong TR, Steed H, Sukumvanich P, Talhouk A, Taylor SE, Vierkant RA, Wang C, Widschwendter M, Wilkens LR, Winham SJ, Anglesio MS, Berchuck A, Brenton JD, Campbell I, Cook LS, Doherty JA, Fasching PA, Fortner RT, Goodman MT, Gronwald J, Huntsman DG, Karlan BY, Kelemen LE, Menon U, Modugno F, Pharoah PDP, Schildkraut JM, Sundfeldt K, Swerdlow AJ, Goode EL, DeFazio A, Köbel M, Ramus SJ, Bowtell DDL, Garsed DW. Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma. Clin Cancer Res. 2024 Aug 15;30(16):3481–3498.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 15, 2024

Volume

30

Issue

16

Start / End Page

3481 / 3498

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Retinoblastoma Binding Proteins
  • Prognosis
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Grading
  • Middle Aged
  • Lymphocytes, Tumor-Infiltrating
  • Humans
  • Germ-Line Mutation