Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

Abstract

Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤ 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.

Multiple mechanisms of MYCN dysregulation in Wilms tumour

“…One recurrent focal copy number gain on 2p24.3, encompassing the MYCN locus, has been observed in several previous WT studies [11, 19-23]. The MYCN gene encodes a proto-oncogenic MYC family transcription factor, MYCN.…”

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

“…While the majority of genomic imbalances confined to subclones were low-frequency aberrations in their respective tumour subtypes according to previous studies, there were indeed also examples of highly recurrent, potential drivers, emerging as part of microdiversity landscapes. In nephroblastomas these included copy number neutral imbalance of 11p and trisomy 8 (Case 2), as well as 1q gain and 1p/16q loss (Case 7)-all of which are highly prevalent and characteristic abnormalities in this tumour type 15 .…”

“…These tumours uniformly exhibit an immature cellular phenotype, reflecting their origin from early embryonic populations such as sympathoadrenal progenitors for neuroblastoma and metanephric progenitors for nephroblastoma. While many SRBCT subtypes exhibit characteristic chromosomal rearrangements [12][13][14][15][16] , next-generation sequencing studies have shown relatively few DNA sequence mutations in childhood cancers compared with adult neoplasms 8 . The present study of intratumoral heterogeneity in SRBCTs therefore focused on genomic aberrations larger than point mutations, that is, those detectable by high-resolution genotyping arrays.…”

Biomarkers to Detect Wilms Tumors in Pediatric Patients: Where are We Now?

“…Copy number analysis of paired primary and recurrent WTs identified acquired alterations occurring in more than one relapsed sample including gain of 5p, 8p12, 15q (including IGF1R), 16p and 20q and loss of 17p (including TP53) [36]. Another study found copy number gains at 1q21.1-q31.3 which significantly associated with relapse [37]. By analyzing gene expression profiles, a gene expression signature was identified in relapsed tumors and included genes involved in apoptosis, Wntsignaling, the IGF signaling pathway and epigenetic mechanisms [38].…”