Genetic and epigenetic analyses guided by high resolution whole-genome SNP array reveals a possible role of CHEK2 in Wilms tumour susceptibility

Abstract

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.

MicroRNA Profiling in Wilms Tumor: Identification of Potential Biomarkers

“…In conclusion, WT is a heterogeneous cancer (20), in which epigenetic alterations influence its biologic behavior. In this study, several miRNAs were found to be differentially expressed between non-neoplastic kidney tissue and WT tissue, and these differences were especially pronounced in DAWT and metastatic tumor tissues.…”

“…Wilms tumor presents a high degree of genetic and epigenetic heterogeneity. Although structural alterations in numerous genes have been associated with WTs, several cases have been identified where no mutations are present, suggesting that other mechanisms may be involved in WT etiology (20). MiRNAs are known to play roles in the epigenetic mechanisms involved in tumor development and are involved in numerous cellular pathways through their interactions with a wide variety of transcription factors.…”

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…Unexpectedly, Gadd and colleagues identified germline CHEK2 variants in 3/117 (2.6%) and 8/651 (1.2%) patients with Wilms tumors in their discovery and validation sets, respectively [ 220 ]. Another report by Ciceri et al [ 221 ] found five carriers of rare missense or splicing CHEK2 variants among 96 Wilms tumor patients from Italy. While evidence of the association of CHEK2 germline mutations with an increased RCC risk is currently mounting, larger case control studies in RCC patients are required to confirm and refine the magnitude of the associated risk.…”

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

“…MYCN amplification enhances promoted the development of Wilms tumor through multiple mechanisms [9]. Moreover, numerous gene polymorphisms have been found to predispose to Wilms tumor [10][11][12], including WTX [13], P53 [14], CTNNB1 [15], BARD1 [16], HACE1 [17], LIN28B [18], XPD [19], hOGG1 and FEN1 gene [20], KRAS [21]. Although quite a few of predisposing genetic factors have been found, they are far from enough to explicitly explain the genetic pathogenesis of Wilms tumor.…”