1. Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.
- Author
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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, 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, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, 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, Singh, N, Rinda Soong, T, 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, 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, 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, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, 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, Singh, N, Rinda Soong, T, 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, and Garsed, DW
- 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-carr
- Published
- 2023