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1.  TP53 Mutational Status Is a Potential Marker for Risk Stratification in Wilms Tumour with Diffuse Anaplasia 
PLoS ONE  2014;9(10):e109924.
Purpose
The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information.
Patients and Methods
We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling.
Results
From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26–16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36–31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes.
Conclusion
This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.
doi:10.1371/journal.pone.0109924
PMCID: PMC4196953  PMID: 25313908
2.  The IGF signalling pathway in Wilms tumours - A report from the ENCCA Renal Tumours Biology-driven drug development workshop 
Oncotarget  2014;5(18):8014-8026.
It is hypothesised that Wilms tumour (WT) results from aberrant renal development due to its embryonic morphology, associated undifferentiated precursor lesions (termed nephrogenic rests) and embryonic kidney-like chromatin and gene expression profiles. From the study of overgrowth syndrome-associated WT, germline dysregulation was identified in the imprinted region at 11p15 affecting imprinted genes IGF2 and H19. This is also detected in ~70% sporadic cases, making this the most common somatic molecular aberration in WT. This review summarises the critical discussion at an international workshop held under the auspices of The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium, where the potential for drug development to target IGF2 and the WT epigenome was debated. Here, we consider current cancer treatments which include targeting the IGF pathway and the use of methylation agents alone or in combination with other drugs in clinical trials of paediatric cancers. Finally, we discuss the possibility of the use of these drugs to treat patients with WT.
PMCID: PMC4226664  PMID: 25478630
IGF2; IGF signalling pathway; Wilms tumour; targeted therapy; DNA methylation
3.  Is Wilms tumor a candidate neoplasia for treatment with WNT/β-catenin pathway modulators? – A report from the Renal Tumors Biology-driven drug development workshop 
Molecular cancer therapeutics  2013;12(12):10.1158/1535-7163.MCT-13-0335.
The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium organized a workshop in Rome, in June 2012, on “Renal Tumor Biology Driven Drug Development” to discuss the current knowledge in pediatric renal cancers and to recommend directions for further research. Wilms tumor (WT) is the most common renal tumor of childhood and represents a success of pediatric oncology, with cure rates of over 85% of cases. However, a substantial minority (~25%) responds poorly to current therapies and requires ‘high risk’ treatment or relapse. Moreover, the successfully treated majority are vulnerable to the late effects of treatment, with nearly one quarter reporting severe chronic health conditions by 25 years of follow up. Main purposes of this meeting were: to advance our understanding on the molecular drivers in WT, their heterogeneity and interdependencies; to provide updates on the clinic-pathologic associations with biomarkers; to identify eligible populations for targeted drugs; and to model opportunities to use preclinical model systems and prioritize targeted agents for early phase clinical trials. At least three different pathways are involved in WT; this review represents the outcome of the workshop discussion on the WNT/β-catenin pathway in Wilms tumorigenesis.
doi:10.1158/1535-7163.MCT-13-0335
PMCID: PMC3858246  PMID: 24258344
Wilms tumor; WNT/β-catenin pathway; WNT/β-catenin pathway modulators; therapeutic strategies
4.  A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing 
PLoS ONE  2014;9(5):e96531.
Background
Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.
Methods and Findings
We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.
Conclusion
The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
doi:10.1371/journal.pone.0096531
PMCID: PMC4014518  PMID: 24810334

Results 1-5 (5)