title: Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences.
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.
authors.affiliation: Pediatric Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Spreafico
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ciceri
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gamba
authors.affiliation: Genomics and Bioinformatics Unit, University of Milan-Fondazione Filarete, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Torri
authors.affiliation: Pediatric Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Terenziani
authors.affiliation: Department of Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Perotti
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics*; D015996:Survival Rate; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C099236:SIX1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III
keywords: SIX1; Wilms tumor; chromosomal anomalies; miRNA processor genes; recurrence