Sabah Muna, Cummins Robert, Leader Mary, Kay Elaine
Department of Histopathology, Education and Research Centre, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin 9, Ireland.
Hum Pathol. 2006 Jun;37(6):648-55. doi: 10.1016/j.humpath.2006.01.023.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract. The prediction of the malignant potential of GISTs is still difficult. Altered cell cycle regulation may underlie the tumorigenesis and/or the progression of human malignancies. Although p53 and Bcl-2 have been extensively investigated in GISTs, little is known about the frequency of expression and possible clinical implications of alterations of other cell cycle regulatory proteins in these neoplasms. We have previously investigated the role of loss of p16(INK4A) by loss of heterozygosity and immunohistochemistry in the progression of GISTs and found that loss of heterozygosity of 9p and loss of p16 expression are confined to malignant GISTs. This has led us to investigate the role of other cell cycle regulatory proteins in these tumors. Twenty-three cases of GIST (9 low malignant potential [LMP], 10 primary malignant, and 4 intra-abdominal recurrences) were examined. All cases were strongly positive for KIT (CD117). Immunohistochemical stains were carried out on tissue microarrays to evaluate the expression of proteins involved in the G(1)-S transition and proteins that regulate apoptosis including Rb, E2F1, cyclin D1, CDK4, CDK6, p27(KIP1), p21(WAF1/CIP1), p53, Mdm2, Bcl-2, and Bax. The positive phenotypes identified were as follows: Rb, 39.1%; E2F1, 69.6%; cyclin D1, 30.4%; CDK4, 100%; CDK6, 30.4%; 39.1%; p27(KIP1), 47.8%; p21(WAF1/CIP1), 39.1%; p53, 43.5%; Mdm2, 17.4%; Bcl-2, 91.3%; and Bax, 100%. Malignant GISTs are more likely to be associated with a positive E2F1 and p53 phenotype and a negative p16 and p27(KIP1) phenotype. It was concluded that aberration of the cell cycle regulators is a frequent finding and may be a contributing factor to the pathogenesis of GISTs. While some alterations are seen in LMP and malignant GISTs and therefore may represent an early event in molecular tumorigenesis of GISTs, other alterations are more common in malignant GISTs than LMP and therefore have potential utility as complementary tools for the prognostication of GISTs.
胃肠道间质瘤（GISTs）是消化道最常见的间叶性肿瘤。预测GISTs的恶性潜能仍然困难。细胞周期调控异常可能是人类恶性肿瘤发生和/或进展的基础。尽管p53和Bcl-2在GISTs中已被广泛研究，但对于这些肿瘤中其他细胞周期调节蛋白表达改变的频率及其可能的临床意义却知之甚少。我们之前通过杂合性缺失和免疫组织化学研究了p16（INK4A）缺失在GISTs进展中的作用，发现9p杂合性缺失和p16表达缺失仅限于恶性GISTs。这促使我们研究其他细胞周期调节蛋白在这些肿瘤中的作用。我们检查了23例GIST（9例低恶性潜能[LMP]、10例原发性恶性和4例腹腔内复发）。所有病例KIT（CD117）均呈强阳性。在组织微阵列上进行免疫组织化学染色，以评估参与G1-S转换的蛋白以及调节细胞凋亡的蛋白的表达，包括Rb、E2F1、细胞周期蛋白D1、细胞周期蛋白依赖性激酶4（CDK4）、细胞周期蛋白依赖性激酶6（CDK6）、p27（KIP1）、p21（WAFI/CIP1）、p53、Mdm2、Bcl-2和Bax。所确定的阳性表型如下：Rb为39.1%；E2F1为69.6%；细胞周期蛋白D1为30.4%；CDK4为100%；CDK6为30.4%；p27（KIP1）为47.8%；p21（WAFI/CIP1）为39.1%；p53为43.5%；Mdm2为17.4%；Bcl-2为91.3%；Bax为100%。恶性GISTs更可能与E2F1和p53阳性表型以及p16和p27（KIP1）阴性表型相关。研究得出结论，细胞周期调节因子的异常是常见现象，可能是GISTs发病机制的一个促成因素。虽然在LMP和恶性GISTs中都观察到一些改变，因此可能代表GISTs分子肿瘤发生的早期事件，但其他改变在恶性GISTs中比LMP中更常见，因此具有作为GISTs预后补充工具的潜在用途。
