Baudry D, Hamelin M, Cabanis M O, Fournet J C, Tournade M F, Sarnacki S, Junien C, Jeanpierre C
INSERM U383, Hôpital Necker-Enfants Malades, Université René Descartes, Paris France.
Clin Cancer Res. 2000 Oct;6(10):3957-65.
Hereditary and sporadic forms of tumors are generally related to germ-line and somatic mutations of the same tumor suppressor gene. Unexpectedly, in Wilms' tumor, somatic mutations of the WT1 gene were found only occasionally in sporadic cases, although constitutional mutations of this gene are clearly associated with predisposition. It has been suggested that abnormal splicing may be another mode of somatic WT1 alteration. However, this idea was based on the analysis of a small series of tumors, precluding accurate evaluation of the frequency of such changes. To investigate WT1 changes at the somatic level in more detail, we analyzed the levels of the four isoform transcripts produced by alternative splicing events in a large series of 50 tumors, normal mature kidneys, and fetal kidneys. We characterized splicing alterations in 63% of sporadic Wilms' tumors. Moreover, taking into account the decreased and increased overall levels of WT1 mRNA, the percentage of sporadic tumors with changes in WT1 expression reached 90%. Whether and how these alterations of expression play a role in the tumorigenic process remain to be evaluated.
遗传性和散发性肿瘤通常与同一肿瘤抑制基因的种系突变和体细胞突变有关。出乎意料的是，在肾母细胞瘤中，尽管该基因的胚系突变与易感性明显相关，但在散发性病例中仅偶尔发现WT1基因的体细胞突变。有人提出异常剪接可能是体细胞WT1改变的另一种方式。然而，这一观点是基于对一小系列肿瘤的分析，无法准确评估此类变化的频率。为了更详细地研究体细胞水平上的WT1变化，我们分析了50个大系列肿瘤、正常成熟肾脏和胎儿肾脏中由可变剪接事件产生的四种异构体转录本的水平。我们在63%的散发性肾母细胞瘤中鉴定出剪接改变。此外，考虑到WT1 mRNA总体水平的降低和升高，WT1表达发生变化的散发性肿瘤的百分比达到90%。这些表达改变是否以及如何在肿瘤发生过程中发挥作用仍有待评估。
