Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences
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Filippo Spreafico1,*, Sara Ciceri2,*, Beatrice Gamba2, Federica Torri3, Monica Terenziani1, Paola Collini4, Fabio Macciardi5, Paolo Radice2, Daniela Perotti2
1Pediatric Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Genomics and Bioinformatics Unit, University of Milan–Fondazione Filarete, Milan, Italy
4Department of Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA
*These authors contributed equally to this work
Daniela Perotti, e-mail: firstname.lastname@example.org
Paolo Radice, e-mail: email@example.com
Keywords: Wilms tumor, recurrence, chromosomal anomalies, SIX1, miRNA processor genes
Received: June 08, 2015 Accepted: December 08, 2015 Published: January 20, 2016
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.
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