[The mitogen-activated protein kinase (MAPK) signaling pathway in papillary thyroid cancer. From the molecular bases to clinical practice].
[The mitogen-activated protein kinase (MAPK) signaling pathway in papillary thyroid cancer. From the molecular bases to clinical practice].
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DOI：
10.1016/s1575-0922(09)70982-9
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发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Obiols, Gabriel
中科院分区：
文献类型：
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作者：
Zafon, Carles;Obiols, Gabriel
近年来，在阐明各种人类肿瘤中促进肿瘤发生的遗传基础方面取得了重大进展。丝裂原活化蛋白激酶（MAPK）信号通路的组成性激活是甲状腺乳头状癌（PTC），最常见的内分泌恶性肿瘤的癌变过程中的一个主要事件。受影响的元件包括RET/PTC重排以及Ras和BRAF基因的点突变。这些基因的突变在超过70%的PTC中被发现。染色体RET重排，称为RET/PTC，导致RET激酶的组成型配体非依赖性激活，这是在PTC中检测到的第一个遗传异常，在5-70%的肿瘤样品中发现。尽管不太常见，但其他酪氨酸激酶受体（如NTRK 1、c-Met或EGFR）的激活也在PTC中有报道。BRAF突变是PTC中最常见的遗传变异。超过90%的BRAF突变导致位置600处的缬氨酸变为谷氨酸（V600 E）。最后，Ras是途径中受影响最小的分子。已经提出了临床行为和这些遗传改变之间的关系。因此，BRAF突变与更具侵袭性的PTC表型相关，并与较差的结局相关。然而，RET/PTC和临床特征之间没有明确的联系。这些改变的发现为新的治疗策略开辟了道路，特别是治疗那些常规治疗无效的患者。一些新药正在测试中，如小分子酪氨酸激酶抑制剂。这些最近开发的药物中的一些已经开始使用，并取得了令人鼓舞的结果。
In recent years, significant progress has been made in elucidating the genetic bases promoting tumorigenesis in various human neoplasms. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is a major event in the carcinogenesis of papillary thyroid carcinoma (PTC), the most prevalent endocrine malignancy. Affected elements include RET/PTC rearrangements and point mutations of the Ras and BRAF genes. Mutations in these genes are found in over 70% of PTC. Chromosomal RET rearrangements, called RET/PTC, result in constitutive ligand-independent activation of RET kinase, which was the first genetic anomaly detected in PTC and is found in 5-70% of tumoral samples. Although less frequent, the activation of other tyrosine kinase receptors, such as NTRK1, c-Met or EGFR, has also been reported in PTC. The BRAF mutation represents the most common genetic alteration found in PTC. More than 90% of BRAF mutations lead to a change of a valine to a glutamic acid at position 600 (V600E). Finally, Ras is the least affected molecule in the pathway. A relationship between clinical behavior and these genetic alterations has been proposed. Thus, the BRAF mutation is associated with a more aggressive PTC phenotype and is correlated with poorer outcomes. However, no clear association has been found between RET/PTC and clinical features. The discovery of these alterations opens the way to new therapeutic strategies, especially to treat those patients in whom conventional therapy is not effective. Several new drugs are being tested, such as small molecule tyrosine kinase inhibitors. Some of these recently developed agents have begun to be used with promising results.