Department of Gynecology and Oncology, Jagiellonian University, 21 Kopernika Street, 30-501, Krakow, Poland.
Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.
BMC Cancer. 2018 Apr 13;18(1):418. doi: 10.1186/s12885-018-4333-6.
The expression of DNA fragmentation factor 45 (DFF45) and B-cell lymphoma 2 (BCL2) in glands of the normal human endometrium is related to phases of the menstrual cycle and decreases after menopause, whereas the expression of DNA fragmentation factor 40 (DFF40) is stable. Moreover, DF45, BCL2 and DFF40 underexpression has been reported in numerous malignancies, including uterine leiomyosarcomas. In this study, we aimed to investigate DFF45, BCL2 and DFF40 expression in endometrioid and non-endometrioid types of endometrial cancers (ECs). We also evaluated the correlations between DFF45, BCL2 and DFF40 expression levels and clinicopathological parameters and determined the value of these three proteins as prognostic markers of disease-free survival (DFS) and overall survival (OS).
Immunohistochemistry was performed to evaluate DFF45, BCL2 and DFF40 expression in 342 cases of ECs. Student's t-test, the Mann-Whitney U-test, and the chi-squared test were used for the statistical analyses as appropriate. The Cox-Mantel test, Cox's proportional hazard model, and relative risk analyses were used to evaluate associations between DFF40, DFF45, and BCL2 expression and clinicopathological characteristics.
DFF40 and BCL2, but not DFF45, were significantly underexpressed in non-endometrioid and high-grade endometrioid ECs compared with low- and moderate-grade endometrioid ECs. Women with DFF40- and BCL2-negative tumors had higher risks of disease recurrence, lymph node involvement, lympho-vascular space infiltration, and deep myometrial invasion compared with women with DFF40- and BCL2-positive tumors. Additionally, women with DFF40- and BCL2-negative tumors had significantly lower OS and DFS than women with DFF40- and BCL2-positive tumors. A multivariable analysis of the model, including the clinicopathological characteristics and immunohistochemical results, showed that negative BCL2 expression, lymph node involvement, and high-stage and high-grade disease were independent predictors of OS, whereas negative BCL2 expression, lymph node involvement, and high-stage disease were independent predictors of DFS.
Compared with low- and moderate-grade endometrioid ECs, non-endometrioid and high-grade endometrioid ECs showed significant DFF40 and BCL2 underexpression. The absence of DFF40 and BCL2 expression negatively affects DFS and OS. Further prospective studies are warranted to assess the potential utility of DFF40 and BCL2 as targets in the diagnosis or treatment of ECs.
在正常人类子宫内膜的腺体中，DNA 片段化因子 45（DFF45）和 B 细胞淋巴瘤 2（BCL2）的表达与月经周期的各个阶段有关，并在绝经后下降，而 DNA 片段化因子 40（DFF40）的表达则保持稳定。此外，DF45、BCL2 和 DFF40 的表达不足已在许多恶性肿瘤中报道，包括子宫平滑肌肉瘤。在这项研究中，我们旨在研究在子宫内膜样癌（EC）和非子宫内膜样癌中 DFF45、BCL2 和 DFF40 的表达。我们还评估了 DFF45、BCL2 和 DFF40 表达水平与临床病理参数之间的相关性，并确定这三种蛋白质作为无病生存（DFS）和总生存（OS）的预后标志物的价值。
对 342 例 EC 患者进行免疫组织化学法评估 DFF45、BCL2 和 DFF40 的表达。根据需要使用 Student's t-test、Mann-Whitney U-test 和 chi-squared test 进行统计学分析。Cox-Mantel 检验、Cox 比例风险模型和相对风险分析用于评估 DFF40、DFF45 和 BCL2 表达与临床病理特征之间的关联。
与低级别和中级别子宫内膜样癌相比，非子宫内膜样癌和高级别子宫内膜样癌中 DFF40 和 BCL2 的表达明显不足，而非 DFF45。与 DFF40 和 BCL2 阳性肿瘤相比，DFF40 和 BCL2 阴性肿瘤的患者疾病复发、淋巴结受累、淋巴管血管空间浸润和深肌层浸润的风险更高。此外，与 DFF40 和 BCL2 阳性肿瘤的患者相比，DFF40 和 BCL2 阴性肿瘤的患者 OS 和 DFS 显著降低。包括临床病理特征和免疫组织化学结果的模型的多变量分析显示，BCL2 表达阴性、淋巴结受累、高分期和高级别疾病是 OS 的独立预测因素，而 BCL2 表达阴性、淋巴结受累和高分期疾病是 DFS 的独立预测因素。
与低级别和中级别子宫内膜样癌相比，非子宫内膜样癌和高级别子宫内膜样癌显示出明显的 DFF40 和 BCL2 表达不足。DFF40 和 BCL2 表达缺失会对 DFS 和 OS 产生负面影响。需要进一步进行前瞻性研究，以评估 DFF40 和 BCL2 作为 EC 诊断或治疗靶点的潜在效用。
