Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada.
School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
Cancer. 2023 Mar 1;129(5):697-713. doi: 10.1002/cncr.34582. Epub 2022 Dec 26.
Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.
Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.
High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.
This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
细胞周期蛋白 E1（CCNE1）是 tubo-ovarian 高级别浆液性癌（HGSC）的潜在预测标志物和治疗靶点。较小的研究表明 CCNE1 扩增和 CCNE1 过表达与生存不良相关，但迄今为止尚未进行大规模、组织特异性验证。假设高水平的 CCNE1 扩增和 CCNE1 过表达，以及两者的组合，与 HGSC 的总生存期缩短有关。
在卵巢肿瘤组织分析联盟内，对 3029 例 HGSC 病例的扩增状态和蛋白水平以及 2419 例样本的 mRNA 表达进行了研究。
HGSC 中发现高水平扩增（染色体原位杂交>8 拷贝）占 8.6%，过表达（免疫组织化学至少 5%显示强强度的>60%）占 22.4%。多变量生存分析调整年龄和分期后，CCNE1 高水平扩增和过表达均与总生存期缩短相关，研究分层的危险比（HR）分别为 1.26（95%CI，1.08-1.47，p=0.034）和 1.18（95%CI，1.05-1.32，p=0.015）。在合并高水平扩增/过表达的病例中也是如此（HR，1.26；95%CI，1.09-1.47，p=0.033）。CCNE1 mRNA 表达与总生存期无关（HR，每增加 1-SD 增加 1.00；95%CI，0.94-1.06；p=0.58）。CCNE1 高水平扩增与种系 BRCA1/2 致病性变异的存在互斥，与 RB1 缺失呈负相关。
本研究提供了大规模的验证，证明 CCNE1 高水平扩增与生存缩短相关，支持其作为 HGSC 预后生物标志物的应用。
