High GATA-4 expression associates with aggressive behavior, whereas low anti-Mullerian hormone expression associates with growth potential of ovarian granulosa cell tumors
High GATA-4 expression associates with aggressive behavior, whereas low anti-Mullerian hormone expression associates with growth potential of ovarian granulosa cell tumors
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DOI：
10.1210/jc.2005-0921
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发表时间：
2005-12-01
影响因子：
5.8
通讯作者：
Heikinheimo, M
中科院分区：
文献类型：
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作者：
Anttonen, M;Unkila-Kallio, L;Heikinheimo, M
背景：颗粒细胞瘤（GCTs）是一种产生雌激素、雌激素和抗苗勒管激素（AMH）的卵巢恶性肿瘤。GCTs的分子发病机制可能涉及卵泡发生过程中调节正常颗粒细胞增殖的基因缺陷。目的：本研究的目的是检测调节正常颗粒细胞功能的因子，即AMH、α-珠蛋白、SF-1的作用。（类固醇生成因子-1）和加塔转录因子在GCT的病理生物学和临床行为中的作用。我们随机选择了1971-2003年期间在我们大学医院接受治疗的80例GCT患者，通过免疫组织化学分析了包埋在组织芯片上的肿瘤样本中的蛋白质表达，并将数据与临床和组织病理学参数相关联。我们发现，与正常颗粒细胞相比，GCTs中的α-氨基丁酸、加塔- 6、FOG-2（加塔-2的朋友）或SF-1的免疫反应性水平无显著差异。然而，69%的GCT中AMH表达较低（即减少），且与肿瘤大小呈负相关（P = 0.0025）。相反，加塔- 4在44%的GCT中高表达（即类似于正常颗粒细胞），并与临床分期和复发呈正相关（分别为P = 0.0232和P = 0.0038）。80例患者中有50例随访至少10年，其中13例复发。在复发的多变量分析中，高加塔- 4表达仍然是唯一的独立因素（风险比，9.2; 95%置信区间，2.0-43.3; P = 0.0048）。结论：侵袭性越强的GCT保留高加塔- 4表达，而较大的肿瘤则失去增殖抑制AMH表达。加塔- 4在GCT中的高表达可作为预后不良的标志。
Context: Granulosa cell tumors (GCTs) are ovarian malignancies that produce estrogens, inhibins, and anti-Mullerian hormone (AMH). The molecular pathogenesis of GCTs is likely to involve defects in the genes regulating normal granulosa cell proliferation during folliculogenesis.Objective: The objective of this study was to test the role of factors regulating the normal granulosa cell function, i.e. AMH, inhibin-alpha, SF-1 (steroidogenic factor-1), and GATA transcription factors in the pathobiology and clinical behavior of GCTs.Design: We selected randomly a cohort of 80 GCT patients treated at our university hospital during 1971-2003, analyzed protein expression in the tumor samples embedded on a tissue microarray by immunohistochemistry, and correlated the data to clinical and histopathological parameters.Results: We found no significant differences in the immunoreactivity levels of inhibin-alpha, GATA- 6, FOG-2 (friend of GATA-2), or SF-1 in GCTs compared with normal granulosa cells. AMH expression was, however, low (i.e. reduced) in 69% of GCTs and correlated inversely with tumor size (P = 0.0025). In contrast, GATA- 4 expression was high (i.e. resembled normal granulosa cells) in 44% of GCTs and correlated positively with clinical stage and recurrence (P = 0.0232 and P = 0.0038, respectively). Fifty of the 80 patients had a follow-up for at least 10 yr, and 13 of them had recurrence(s). In multivariate analysis of recurrence, the high GATA- 4 expression remained the only independent factor ( risk ratio, 9.2; 95% confidence interval, 2.0-43.3; P = 0.0048).Conclusions: The more aggressive GCTs retain a high GATA- 4 expression, whereas the larger tumors lose the proliferation-suppressing-AMH-expression. The high GATA- 4 expression in GCTs may serve as a marker of poor prognosis.