Subtype-Specific FBXW7 Mutation and MYCN Copy Number Gain in Wilms' Tumor

Abstract

Purpose: Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP).Experimental Design: We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation-dependent Probe Amplification, or fluorescence in situ hybridization.Results: We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in ∼4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%).Conclusions: Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor. Clin Cancer Res; 16(7); 2036-45. ©2010 AACR.

The yin and yang of kidney development and Wilms’ tumors

“…High expression and copy number gain of MYCN have been associated with Wilms' tumor for a long time (Nisen et al 1986;Norris et al 1988;Williams et al 2010), and, recently, mutations in MYCN were identified by exome sequencing (Rakheja et al 2014), including a recurrent mutation (P44L) previously identified in neuroblastoma and believed to be a gain-of-function mutation . MYCN is a target of ubiquitination and degradation by FBXW7, which is deleted or mutated in ;4% of tumors .…”

Molecular profiling reveals frequent gain of MYCN and anaplasia‐specific loss of 4q and 14q in wilms tumor

“…We have recently described focal deletions that include the FBXW7 gene on 4q31.3 in postchemotherapy epithelial-type tumors (Williams et al, 2010). We examined the individual profiles of AH samples in which some degree of 4q loss was measured on the 32k platform for evidence of specific events at this locus.…”

“…Significant discriminator genes have also been identified in a study that compared 8 high risk tumors, including four with anaplasia, with 52 intermediate risk samples (Zirn et al, 2006). In a study of 104 tumors, we have recently shown that diffuse anaplasia is associated with MYCN gain in samples profiled at resection after a course of neoadjuvant chemotherapy (Williams et al, 2010).…”

Prognostic Significance of Promoter DNA Methylation in Patients with Childhood Neuroblastoma

“…Hypermethylation of this gene has also been observed in pediatric brain tumors and Wilms' tumors and in ovarian cancers that displayed chemotherapeutic resistance (25,27,28). Although these cancers are biologically different from neuroblastoma, amplification of the proto-oncogenes, such as c-myc, MYCN, or L-myc have been observed in a small proportion of these tumors (29)(30)(31), suggesting a possible interaction between proto-oncogenes and methylation that may contribute to the tumorigenesis of these cancers.…”