Saner Flurina A M, Takahashi Kazuaki, Budden Timothy, Pandey Ahwan, Ariyaratne Dinuka, Zwimpfer Tibor A, Meagher Nicola S, Fereday Sian, Twomey Laura, Pishas Kathleen I, Hoang Therese, Bolithon Adelyn, Traficante Nadia, Alsop Kathryn, Christie Elizabeth L, Kang Eun-Young, Nelson Gregg S, Ghatage Prafull, Lee Cheng-Han, Riggan Marjorie J, Alsop Jennifer, Beckmann Matthias W, Boros Jessica, Brand Alison H, Brooks-Wilson Angela, Carney Michael E, Coulson Penny, Courtney-Brooks Madeleine, Cushing-Haugen Kara L, Cybulski Cezary, El-Bahrawy Mona A, Elishaev Esther, Erber Ramona, Gayther Simon A, Gentry-Maharaj Aleksandra, Blake Gilks C, Harnett Paul R, Harris Holly R, Hartmann Arndt, Hein Alexander, Hendley Joy, Hernandez Brenda Y, Jakubowska Anna, Jimenez-Linan Mercedes, Jones Michael E, Kaufmann Scott H, Kennedy Catherine J, Kluz Tomasz, Koziak Jennifer M, Kristjansdottir Björg, Le Nhu D, Lener Marcin, Lester Jenny, Lubiński Jan, Mateoiu Constantina, Orsulic Sandra, Ruebner Matthias, Schoemaker Minouk J, Shah Mitul, Sharma Raghwa, Sherman Mark E, Shvetsov Yurii B, Singh Naveena, Rinda Soong T, Steed Helen, Sukumvanich Paniti, Talhouk Aline, Taylor Sarah E, Vierkant Robert A, Wang Chen, Widschwendter Martin, Wilkens Lynne R, Winham Stacey J, Anglesio Michael S, Berchuck Andrew, Brenton James D, Campbell Ian, Cook Linda S, Doherty Jennifer A, Fasching Peter A, Fortner Renée T, Goodman Marc T, Gronwald Jacek, Huntsman David G, Karlan Beth Y, Kelemen Linda E, Menon Usha, Modugno Francesmary, Pharoah Paul D P, Schildkraut Joellen M, Sundfeldt Karin, Swerdlow Anthony J, Goode Ellen L, DeFazio Anna, Köbel Martin, Ramus Susan J, Bowtell David D L, Garsed Dale W
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Department of Obstetrics and Gynecology, Bern University Hospital and University of Bern, Bern, Switzerland.
medRxiv. 2023 Nov 10:2023.11.09.23298321. doi: 10.1101/2023.11.09.23298321.
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 and (). 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 pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.
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 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 in HGSC cell lines with and without 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 loss.
RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, = 6.8 ×10), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, = 0.0140). Germline mutations and RB1 loss co-occurred in HGSC ( < 0.0001). Patients with both RB1 loss and germline mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, = 5.2 ×10) 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 ( < 0.01) and paclitaxel ( < 0.05) was seen in mutated cell lines with knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined 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 -deficient HGSC with co-loss of .
Co-occurrence of RB1 loss and mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
肿瘤抑制因子RB1的体细胞缺失是输卵管卵巢高级别浆液性癌（HGSC）中的常见事件，常与包括 和 （）在内的同源重组DNA修复基因改变同时出现。我们研究了RB1的肿瘤表达是否与不同组织学类型的卵巢癌（HGSC、子宫内膜样癌（ENOC）、透明细胞癌（CCOC）、黏液性癌（MOC）、低级别浆液性癌（LGSC））患者的生存率相关，以及种系 致病性变异与RB1缺失的共同出现如何影响一大系列HGSC患者的长期生存。
通过免疫组织化学对参与卵巢肿瘤组织分析联盟的20项研究中的7436例患者的上皮性卵巢癌进行RB1蛋白表达模式分类，并评估其与总生存期（OS）的相关性，同时考虑诊断时的患者年龄和国际妇产科联盟（FIGO）分期。我们在1134例HGSC患者的亚组中检测了RB1表达和种系 状态，并将基因型与生存率、肿瘤浸润性CD8 +淋巴细胞计数和转录组亚型相关联。使用CRISPR-Cas9，我们在有或无 突变的HGSC细胞系中删除 ，以模拟共同缺失与治疗反应的关系。我们还对126例原发性HGSC进行了基因组分析，以探索同时存在的同源重组缺陷和 缺失的分子特征。
RB1蛋白缺失在HGSC中最常见（16.4%），且与 mRNA表达高度相关。RB1缺失与HGSC患者的OS延长相关（风险比[HR] 0.74，95%置信区间[CI] ：0.66 - 0.83， = 6.8 × 10），但与ENOC患者的预后较差相关（HR 2.17，95% CI 1.17 - 4.03， = 0.0140）。种系 突变与RB1缺失在HGSC中共同出现（ < 0.0001）。与单独发生任何一种改变的患者相比，同时存在RB1缺失和种系 突变的患者具有更好的OS（HR 0.38 , 95% CI 0.25 - 0.58 , = 5.2 × 10），他们的中位OS是非携带者（肿瘤保留RB1表达）的三倍（9.3年对3.1年）。在 敲除的 突变细胞系中观察到对顺铂（ < 0.01）和紫杉醇（ < 0.05）的敏感性增强。在126例有全基因组和转录组序列数据的患者中， 缺失与同源重组缺陷的基因组证据相结合，与原发性HGSC中增强的干扰素反应、细胞周期失调和上皮-间质转化减少的转录标志物相关。CD8 +淋巴细胞在 和 共同缺失的 缺陷HGSC中最为普遍。
RB1缺失和 突变的共同出现与HGSC患者的超长生存期相关，这可能归因于更好的治疗反应和免疫刺激。
