Overgrowth syndromes and pediatric cancers: how many roads lead to IGF2?

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 have been shown to be causally related to the disease manifestation. In the previous issue of, 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 mutant mouse lines, the investigators showed that DIS3L2 loss of function leads to up-regulation of independently of the let7 microRNA pathway. In a second study in this issue of , 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 expression. Thus, augmented expression seems to be a common downstream factor in both tissue overgrowth and Wilms tumor through several alternative mechanisms.

TRIM28 variants and Wilms' tumour predisposition

“…WTs originate from a developmental arrest during nephrogenesis [1–3]. Manifestations of this developmental arrest include nephrogenic rests, which are embryonic remnants found in the surrounding kidney tissue of ~40% of WTs (~100% in bilateral cases) and are considered to be WT precursor lesions.…”

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

“…There are multiple events that lead to WT, including the perturbation of the IGF2 signalling pathway (Bharathavikru and Hastie, 2018). This occurs through genetic and/or epigenetic mechanisms including paternal disomy or loss of imprinting of the maternal allele.…”

Modeling the developmental origins of pediatric cancer to improve patient outcomes

“…Pediatric cancers also disproportionately carry alterations in epigenetic factors ( Huether et al, 2014 ) and developmental signaling pathways such as WNT, Notch, TGF-beta and Hedgehog ( Filbin and Monje, 2019 ), which can represent novel targets but also introduce therapeutic complexity owing to the importance of these factors in normal, developing tissues in children ( Chheda and Gutmann, 2017 ; Gajjar et al, 2013 ; Morinello et al, 2014 ; Zwergel et al, 2018 ). The theme of early development is further apparent in the strong linkage between cancer predisposition and developmental syndromes, such as Noonan and Costello RASopathy syndromes, or overgrowth syndromes such as Beckwith-Wiedemann or Perlman's syndromes ( Bharathavikru and Hastie, 2018 ; Cizmarova et al, 2013 ). Pediatric cancers arise during a time period of profound changes in tissue patterning and organ development.…”