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

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ccr-23-3552.pdf (4.07 MB)

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ICR Authors

Jones, Michael
 Schoemaker, Minouk

Authors

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

Document Type

Journal Article

Date

2024-08-15

Date Accepted

2024-05-31

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.

Citation

Clinical Cancer Research, 2024, 30 (16), pp. 3481 - 3498

DOI

10.1158/1078-0432.CCR-23-3552
10.1158/1078-0432.CCR-23-3552

URI

https://repository.icr.ac.uk/handle/internal/6376

Rights

https://creativecommons.org/licenses/by-nc-nd/4.0/

Source Title

Clinical Cancer Research

Publisher

AMER ASSOC CANCER RESEARCH

ISSN

1078-0432

eISSN

1557-3265
1557-3265

Collections

Breast Cancer Research

Research Team

Integrative Cancer Epidem
Aetiological Epidemiology

Notes