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Clin Cancer Res. 2010 Apr 1;16(7):2036-45. doi: 10.1158/1078-0432.CCR-09-2890. Epub 2010 Mar 23.

Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor.

Author information

1
Section of Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, United Kingdom.

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 approximately 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.

PMID:
20332316
PMCID:
PMC5122447
DOI:
10.1158/1078-0432.CCR-09-2890
[Indexed for MEDLINE]
Free PMC Article

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