Multiple mechanisms of MYCN dysregulation in Wilms tumour

Abstract

Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.

Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes

“…Interestingly, a connection with the Rho pathway has also been reported, where RhoB modulated cMyc stability via GSK‐3 . The p.P44L MYCN mutation found in the current study has been reported in a few NB cases without MYCN amplification, and is also recently suggested to be an activating mutation driving tumorigenesis in Wilms tumor . N‐myc is regulated by MAX , and the finding of recurrent MAX mutations, and now recurrent MYCN mutations, confirms the importance of MYCN/MAX deregulation in the development and progression of PCC/PGL and other neural tumors.…”

“…Recurrent mutations in MYCN , MYO5B or VCL is a novel finding in PCC/PGL tumors, and variants of these genes were exclusively found in malignant PGL harboring germline SDHB mutations (CPN3, CPN6, CPN7, CPN8, Table ). The p.P44L is a well‐known MYCN mutation reported in several cancer, while the p.T58M was a novel finding affecting a well‐conserved phosphorylation site of Myc proteins. In MYO5B , one mutation was located in the myosin head domain responsible for actin binding (p.L578P), while the second was positioned in the Rab11a‐binding tail domain of Myo5b (p.G1611S; Fig.…”

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

“…Germline changes at these loci have also been reported in patients presenting with WT and therefore WT risk should also be considered in patients with germline MYCN copy number gains (2p24.3) or 2q37 microdeletions (65,66). The incidence of patients with these genetic changes is rare and the actual incidence of WT in these populations needs further study.…”

Biomarkers to Detect Wilms Tumors in Pediatric Patients: Where are We Now?

“…MYCN appears to be mutated in around 4% WTs, however, has recently shown to be dysregulated by multiple mechanisms, including activating mutation, copy number gain, DNA methylation or by dysregulation of genes that regulate MYCN, in other words, deletion/mutation of FBXW7 or MAX, and therefore the overall number of tumors that overexpress MYCN may be greater [13,22]. Point mutations and copy number gains were shown to occur frequently with no preference for pretreated (SIOP) histological subtype in one study, however, outcome was not assessed [13].…”

“…Point mutations and copy number gains were shown to occur frequently with no preference for pretreated (SIOP) histological subtype in one study, however, outcome was not assessed [13]. Another study showed that for pretreated tumors with MYCN copy number gain, a poorer outcome was observed with gain occurring frequently in tumors with diffuse anaplasia (30% compared with 11% in nonanaplastic tumors) [22].…”