Molecular carcinogenesis of endometrial cancer.
Molecular carcinogenesis of endometrial cancer.
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DOI：
10.1016/s1028-4559(08)60102-3
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发表时间：
2007-03-01
影响因子：
2.1
通讯作者：
Liu, Fu-Shing
中科院分区：
文献类型：
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作者：
Liu, Fu-Shing
1983年，Bokhman在临床观察和临床病理对照的基础上提出了子宫内膜肿瘤发生的二元模型。大多数子宫内膜癌(约70%-80%)被指定为I型癌，遵循雌激素相关的途径。组织学上，大多数I型肿瘤似乎发生在增生性子宫内膜的背景下，表现为子宫内膜样分化，并且级别较低。在临床上，他们的总体特征是良好的行为。另有10%-20%的子宫内膜癌，被称为II型癌，遵循雌激素无关的途径，发生在萎缩的子宫内膜背景下。II型肿瘤通常发生在年龄较大的年龄，大约比I型肿瘤晚5-10年。它们是典型的非子宫内膜样分化的高级别癌，最常见的是浆液性癌，较少见透明细胞。II型癌表现为侵袭性的临床病程，预后差。大约十年后，这种二元论模型得到了分子研究的支持。目前，子宫内膜样癌和浆液性癌分别代表I型和II型子宫内膜癌的主要表型，具有不同类型的遗传不稳定性和分子改变的特点。在子宫内膜样癌中，PTEN抑癌基因沉默、错配修复基因突变引起的微卫星不稳定性、K-ras原癌基因突变和β-catenin基因改变是导致子宫内膜样癌发生的四个主要基因改变。另一方面，P53突变和Her2/neu癌基因的过度表达是浆液性和透明细胞(II型)癌的两个主要基因改变。然而，就像在任何模型中一样，也有例外的证据。许多子宫内膜癌位于灰色地带，与I型和II型子宫内膜癌的临床、形态、免疫组织化学和分子特征重叠。最后，发现一小部分子宫内膜癌是遗传性的。它被认为是遗传性非息肉病性结直肠癌(Lynch综合征)最常见的结外恶性肿瘤，是一种常染色体显性遗传性癌症易感性疾病。错配修复基因MSH2和MSH6的失活似乎在肿瘤的发生中起着核心作用。
In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.