Genetic and epigenetic analyses guided by high resolution whole-genome SNP array reveals a possible role of CHEK2 in Wilms tumour susceptibility
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Sara Ciceri1, Beatrice Gamba1, Paola Corbetta1, Patrizia Mondini1, Monica Terenziani2, Serena Catania2, Marilina Nantron3, Maurizio Bianchi4, Paolo D’Angelo5, Federica Torri6, Fabio Macciardi6, Paola Collini7, Martina Di Martino8, Fraia Melchionda9, Andrea Di Cataldo10, Filippo Spreafico2, Paolo Radice1,*, Daniela Perotti1,* and on behalf of the AIEOP study group**
1Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
2Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
3Department of Hematology and Oncology, Istituto G. Gaslini, Genova, Italy
4Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Torino, Italy
5Pediatric Oncology Unit, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Palermo, Italy
6Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA
7Soft Tissue and Bone Pathology, Histopathology, and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
8Pediatric Oncology Unit, Pediatric Department, II University, Naples, Italy
9Pediatric Hematology and Oncology Unit, Bologna University, Bologna, Italy
10Pediatric Hematology and Oncology Unit, Catania University, Catania, Italy
*These authors have contributed equally to this work
Daniela Perotti, email: [email protected]
Keywords: Wilms tumor; SNP array; CHEK2
Received: June 19, 2018 Accepted: September 01, 2018 Published: September 25, 2018
Wilms tumour (WT), the most frequent malignant childhood renal tumour, shows a high degree of genetic and epigenetic heterogeneity. Loss of imprinting on chromosome 11p15 is found in a large fraction of cases and mutations in a few genes, including WT1, CTNNB1, WTX, TP53 and, more recently, SIX1, SIX2 and micro RNA processing genes (miRNAPGs), have been observed. However, these alterations are not sufficient to describe the entire spectrum of genetic defects underlying WT development. We inspected data obtained from a previously performed genome-wide single nucleotide polymorphism (SNP) array analysis on 96 WT samples. By selecting focal regions commonly involved in chromosomal anomalies, we identified genes with a possible role in WT development, based on the prior knowledge of their biological relevance, including MYCN, DIS3L2, MIR562, HACE1, GLI3, CDKN2A and CDKN2B, PALB2, and CHEK2. The MYCN hotspot mutation c.131C>T was detected in seven cases (7.3%). Full sequencing of the remaining genes disclosed 16 rare missense variants and a splicing mutation. Most of these were present at the germline level. Promoter analysis of HACE1, CDKN2A and CDKN2B disclosed partial methylation affecting HACE1 in a consistent fraction of cases (85%). Interestingly, of the four missense variants identified in CHEK2, three were predicted to be deleterious by in silico analyses, while an additional variant was observed to alter mRNA splicing, generating a functionally defective protein. Our study adds additional information on putative WT genes, and adds evidences involving CHEK2 in WT susceptibility.
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