Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences.

Filippo Spreafico,Federica Torri,Sara Ciceri,Paola Collini,Beatrice Gamba,Monica Terenziani,Fabio Macciardi,Paolo Radice,Daniela Perotti

doi:10.18632/oncotarget.6950

Abstract

Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures.Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.

Highlights

Thanks to an effective integration of surgery, chemotherapy and, in selected cases, radiotherapy, the overall survival rate for patients affected with Wilms tumor (WT), the most frequent pediatric renal tumor, exceeds 90%
Whole-genome chromosomal anomalies were examined by single nucleotide polymorphism (SNP) array analysis in a set of paired primary tumors and corresponding recurrences (Figure 1)
In the present study we describe the findings observed in a cohort of eight pairs of primary/recurrent WTs analyzed by whole-genome SNP array, and we investigated the role in tumor progression of a group of genes, previously reported to be associated with poor outcome in this malignancy [12, 13]

Summary

Introduction

Thanks to an effective integration of surgery, chemotherapy and, in selected cases, radiotherapy, the overall survival rate for patients affected with Wilms tumor (WT), the most frequent pediatric renal tumor, exceeds 90%. Only approximately half of children who suffer from tumor relapse reach second durable remission. Aiming at tailoring therapeutic intensification at relapse, an international consensus has recognized three post-relapse risk groups according to the initial treatment received (which in turn is largely dictated by tumor stage and histology) [1]. The clinical behavior within the different risk subgroups has www.impactjournals.com/oncotarget yet to be established, since the probability of response to conventional therapies at recurrence is extremely variable [2]. The understanding of molecular features underlying recurrent tumors could help to develop effective treatments. The generation of early-phase clinical trials, initially conducted in the context of resistant/recurrent tumors, will probably rely on molecular-targeted drugs

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Conclusion