Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines

Abstract

Treatment of Wilms tumor has a high success rate, with some 85% of patients achieving long-term survival. However, late effects of treatment and management of relapse remain significant clinical problems. If accurate prognostic methods were available, effective risk-adapted therapies could be tailored to individual patients at diagnosis. Few molecular prognostic markers for Wilms tumor are currently defined, though previous studies have linked allele loss on 1p or 16q, genomic gain of 1q, and overexpression from 1q with an increased risk of relapse. To identify specific patterns of gene expression that are predictive of relapse, we used high-density (30 k) cDNA microarrays to analyze RNA samples from 27 favorable histology Wilms tumors taken from primary nephrectomies at the time of initial diagnosis. Thirteen of these tumors relapsed within 2 years. Genes differentially expressed between the relapsing and nonrelapsing tumor classes were identified by statistical scoring (t test). These genes encode proteins with diverse molecular functions, including transcription factors, developmental regulators, apoptotic factors, and signaling molecules. Use of a support vector machine classifier, feature selection, and test evaluation using cross-validation led to identification of a generalizable expression signature, a small subset of genes whose expression potentially can be used to predict tumor outcome in new samples. Similar methods were used to identify genes that are differentially expressed between tumors with and without genomic 1q gain. This set of discriminators was highly enriched in genes on 1q, indicating close agreement between data obtained from expression profiling with data from genomic copy number analyses.

Value and difficulties of a common European strategy for recurrent Wilms’ tumor

“…To date, expression profiling studies have provided inconsistent results, perhaps due to the cellular heterogeneity found in WT, whereas genomic copy number analyses look more promising to discriminate relapsing tumors [20][21][22]. This is consistent with the predictive value of allele loss at chromosomes 1p and 16q found in the large NWTS-5 trial, although the critical genes or pathways remain to be defined [23].…”

Current Therapy for Wilms’ Tumor

“…Other promising prognostic markers are an increase in gene copy number or expression at chromosome 1q [28,29] and telomerase expression level [30,31]. Gene expression profiling also shows promise to identify new prognostic factors [32][33][34].…”

Late recurrence of Wilms’ tumour with exclusive skeletal muscle phenotype 23 years after primary diagnosis

“…Approximately 15-20% of cases of Wilms tumour relapse, more frequently within the first 2-5 years following the primary diagnosis; in these cases, the risk of recurrence is mainly related to the morphological and molecular features of the previous tumour [12,8,18,7,14].…”

“…The association of chemotherapy and radiotherapy to radical nephrectomy has increased the overall survival rate up to 85-90% [3,6];however, in spite of these therapeutic improvements, tumour relapses in a subset of patients (15-20%) [12].Numerous studies have demonstrated that the risk of recurrence can be associated to different features such as histological tumour pattern and loss of heterozygosis (LOH) at 1p and/or 16q, as well as gain of chromosome 1 and other recently described alterations [8,18,7,14]. The recurrence risk is greater within the first 2 years after primary diagnosis (in these patients the percentage of survival approximaly ranges from 24% to 43%) but late relapses have occasionally been reported [1,10].…”