Dataset Information

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

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.

SUBMITTER: Saner FAM

PROVIDER: S-EPMC10659507 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Saner Flurina A M FAM Takahashi Kazuaki K Budden Timothy T Pandey Ahwan A Ariyaratne Dinuka D Zwimpfer Tibor A TA Meagher Nicola S NS Fereday Sian S Twomey Laura L Pishas Kathleen I KI Hoang Therese T Bolithon Adelyn A Traficante Nadia N Alsop Kathryn K Christie Elizabeth L EL Kang Eun-Young EY Nelson Gregg S GS Ghatage Prafull P Lee Cheng-Han CH Riggan Marjorie J MJ Alsop Jennifer J Beckmann Matthias W MW Boros Jessica J Brand Alison H AH Brooks-Wilson Angela A Carney Michael E ME Coulson Penny P Courtney-Brooks Madeleine M Cushing-Haugen Kara L KL Cybulski Cezary C El-Bahrawy Mona A MA Elishaev Esther E Erber Ramona R Gayther Simon A SA Gentry-Maharaj Aleksandra A Blake Gilks C C Harnett Paul R PR Harris Holly R HR Hartmann Arndt A Hein Alexander A Hendley Joy J Hernandez Brenda Y BY Jakubowska Anna A Jimenez-Linan Mercedes M Jones Michael E ME Kaufmann Scott H SH Kennedy Catherine J CJ Kluz Tomasz T Koziak Jennifer M JM Kristjansdottir Björg B Le Nhu D ND Lener Marcin M Lester Jenny J Lubiński Jan J Mateoiu Constantina C Orsulic Sandra S Ruebner Matthias M Schoemaker Minouk J MJ Shah Mitul M Sharma Raghwa R Sherman Mark E ME Shvetsov Yurii B YB Singh Naveena N Rinda Soong T T Steed Helen H Sukumvanich Paniti P Talhouk Aline A Taylor Sarah E SE Vierkant Robert A RA Wang Chen C Widschwendter Martin M Wilkens Lynne R LR Winham Stacey J SJ Anglesio Michael S MS Berchuck Andrew A Brenton James D JD Campbell Ian I Cook Linda S LS Doherty Jennifer A JA Fasching Peter A PA Fortner Renée T RT Goodman Marc T MT Gronwald Jacek J Huntsman David G DG Karlan Beth Y BY Kelemen Linda E LE Menon Usha U Modugno Francesmary F Pharoah Paul D P PDP Schildkraut Joellen M JM Sundfeldt Karin K Swerdlow Anthony J AJ Goode Ellen L EL DeFazio Anna A Köbel Martin M Ramus Susan J SJ Bowtell David D L DDL Garsed Dale W DW

medRxiv : the preprint server for health sciences 20231110

<h4>Background</h4>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-occurren ...[more]

PMID: 37986741

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Project description:Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

Dataset Information

Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background

Patients and methods

Results

Conclusions

Publications

Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background

Patients and methods

Results

Conclusions

Publications

Concurrent RB1 loss and &lt;i&gt;BRCA&lt;/i&gt;-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Concurrent RB1 loss and <i>BRCA</i>-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.