Abstract 3268: Gene expression associated to relapsing disease in Wilms tumor indicates a more differentiated phenotype unveiling a distinct transformation process for patients with a higher risk of relapse
Authors: Fiorino Antonio , De Cecco Loris , Gamba Beatrice , Marchesi Edoardo , Collini Paola , Pession Andrea , Nantron Marilina , Bianchi Maurizio , Spreafico Filippo , Canevari Silvana , Radice Paolo , Perotti Daniela 
Published: August 2015

Wilms Tumor (WT), originating through perturbation of developmental processes in embryonic kidney, is the most frequent pediatric genitourinary malignancy. Despite its overall survival rate has reached 90%, several patients develop relapses and, among them, approximately 50% will suffer of fatal disease. Hence, reduction of the relapse burden is key to improve WT outcome, and incorporation of novel prognostic markers is currently explored to achieve this goal. Chromosomal alterations and gene expression signatures in WT cohorts are thus examined to identify patients with risk disease.

By evaluating gene expression profiles of 58 untreated primary tumor tissues from patients enrolled in the AIEOP multicenter protocol, we could identify four WT subtypes displaying enrichment for genes that were differentially expressed, and divergent clinical outcome. These patterns were validated against a previously published large WT cohort, confirming the accuracy of the prediction. A correlation analysis based on the expression of WT1, which deregulation is a crucial event in this disease, allowed us to verify known WT1 targets and to identify novel potential effectors implicated in this disease. However, although the majority or primary tumors from relapsing patients (7 out of 11) features lower WT1 level and increased 11p13 copy number (CN) losses, its expression did not significantly correlate with specific pathological parameters, confirming its poor prognostic impact as an independent disease predictor.

Therefore, in order to reliably associate the risk of recurrence to a specific gene signature, we performed class comparison analysis of primary tumors between relapsing and non-relapsing patients. Unexpectedly, the pattern of genes up-regulated in relapsing tumors showed a negative enrichment of genes expressed in early embryonic kidney structures, such as the metanephric and cap mesenchyme, and a positive enrichment for genes expressed in nephrogenic structures developed upon mesenchymal-to-epithelial transition. These findings underscore the clinical heterogeneity of the disease and indicate that disruption of post-inductive renal processes occurs in high-risk WTs. Moreover, a few transcripts mapping at chromosome 1q21-44, with CN gain or allelic imbalance in 5/11 relapsing vs. 6/47 non-relapsing tumors, were found up-regulated in these patients. Remarkably, a few genes known to be implicated in metastatic disease in adult cancers, including SPP1, MUC1, MYC, CLDN1, and MAOA, showed up-regulation in relapsing WTs. Overall, our data suggests a gene signature associated to naive primary recidivant tumors, to be exploited as a potential predictor of disease at higher risk of relapse.

Citation Format: Antonio Fiorino, Loris De Cecco, Beatrice Gamba, Edoardo Marchesi, Paola Collini, Andrea Pession, Marilina Nantron, Maurizio Bianchi, Filippo Spreafico, Silvana Canevari, Paolo Radice, Daniela Perotti. Gene expression associated to relapsing disease in Wilms tumor indicates a more differentiated phenotype unveiling a distinct transformation process for patients with a higher risk of relapse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3268. doi:10.1158/1538-7445.AM2015-3268