Abstract
Overgrowth syndromes such as Perlman syndrome and associated pediatric cancers, including Wilms tumor, arise through genetic and, in certain instances, also epigenetic changes. In the case of the Beckwith-Wiedemann overgrowth syndrome and in Wilms tumor, increased levels of IGF2 have been shown to be causally related to the disease manifestation. In the previous issue of Genes & Development, Hunter and colleagues (pp. 903-908) investigated the molecular mechanisms by which mutations in the gene encoding the RNA degradation component DIS3L2 lead to Perlman syndrome. By analyzing nephron progenitor cells derived from their newly created Dis3l2 mutant mouse lines, the investigators showed that DIS3L2 loss of function leads to up-regulation of IGF2 independently of the let7 microRNA pathway. In a second study in this issue of Genes & Development, Chen and colleagues (pp. 996-1007) show that microRNA processing gene mutations in Wilms tumor lead to an increase in the levels of transcription factor pleomorphic adenoma gene 1 (PLAG1) that in turn activates IGF2 expression. Thus, augmented IGF2 expression seems to be a common downstream factor in both tissue overgrowth and Wilms tumor through several alternative mechanisms.
Highlights
Translocations, loss of imprinting, duplication, or mutations resulting in altered expression of key developmental genes
Recent genetic evidence has shown microRNA processing gene (MIRPG) mutations associated with Wilms tumor (Rakheja et al 2014; Torrezan et al 2014; Walz et al 2015; Wegert et al 2015), characterized by dysregulated microRNA levels
Bharathavikru and Hastie tumor suppressor in a mouse model through inhibition of the oncogenic target lin28, which is overexpressed in Wilms tumor (Viswanathan et al 2009; Urbach et al 2014)
Summary
Translocations, loss of imprinting, duplication, or mutations resulting in altered expression of key developmental genes. Work with animal models has provided evidence that increased IGF2 expression is an important contributing factor in both BWS and Wilms tumor (Caspary et al 1999; Hu et al 2011; Huang et al 2016). Two studies, Chen et al (2018) in this issue and Hunter et al (2018) in the previous issue of Genes & Development, highlight the significance of IGF2 up-regulation in the context of Perlman syndrome and Wilms tumor, respectively.
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