Gain of 1q is a marker of poor prognosis in Wilms' tumors

Abstract

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age (< or > 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one-third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow-up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event-free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema.

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

“…In this case, independent mutation events, with different chromosomal breakpoints, led to repeated occurrence of both 1p and 16q loss of heterozygosity over time. This is particularly interesting as both these aberrations are strongly associated with high-risk morphology and poor outcome 22,23,33 . Genome profiles in metastases frequently derived from subclones that were part of a microdiversity landscape.…”

“…This protocol consists of both pre-and postoperative chemotherapy 21 , and all biopsies were obtained from tumournephrectomy specimens obtained B7 days after the last chemotherapy cycle. Our cohort was representative of nephroblastoma with regard to the panorama of genomic imbalances and had survival statistics that stratified according to established clinicopathological parameters (Supplementary Figs 5 and 6a-c) 22,23 . High-resolution genome array analysis showed microdiversity in 45% (20/44) of the tumours (Supplementary Fig.…”

Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor

“…Lastly, several studies from Europe and North America have both demonstrated and validated the prognostic impact of 1q gain in patients with FHWT who were treated with adjuvant chemotherapy. 12,13,14 The impact of 1q gain has not been previously examined in patients with VLRWT.…”

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

“…Biopsy: copy number array Can assess microdiversity which is associated with poor outcome [39] SIX1/SIX2 protein in blood/urine SIX1/SIX2 is overexpressed in Wilms tumors; SIX2 expression is associated with blastemal histology [12] Genomic copy number changes in blood/urine Detection of adverse outcome/relapse associated changes (1q/1p/16q/15q/17p). Overcomes intratumoral heterogeneity, can identify tumors with adverse prognosis [8,52] Detection of tumor-specific methylated DNA in blood/urine Feasibility shown, needs expanding to more patients to assess use in diagnosis or tumor monitoring [43] Analysis of Let-7 in tumor or blood/urine Let-7 is dysregulated in several tumors but a relationship with outcome is unknown [12,23,53] Analysis of seven miRNAs in circulation Associated with high-risk histology independent of chemotherapy [30] Expression of 'oncomir' miRNAs in tumor tissue Correlated with higher stage and metastatic disease [29] SIX1/SIX2 mutation in tumor/circulation Poor response to chemotherapy [13] TP53 mutation in tumor/circulation Anaplasia, poor outcome [19] CTNNB1/WT1 mutation in tumor/circulation Favorable histology (stromal) [54] SIX1/2 mutation + miRNA processing mutation in tumor/circulation…”