Multicenter study identified molecular blood‐born protein signatures for Wilms Tumor

Abstract

Wilms Tumor (WT) is the most common renal childhood tumor. Recently, we reported a cDNA microarray expression pattern that varied between WTs with different risk histology. Since the Societé Internationale d'Oncologie Pédiatrique (SIOP) in Europe initiates treatment without a histological confirmation, it is important to identify blood-born markers that indicate WT development. In a multicenter study, we established an autoantibody signature by using an array with 1,827 recombinant E. coli clones. This array was screened with sera of patients with WT recruited by SIOP or the Children's Oncology Group (COG). We report an extended number of antigens that are reactive with autoantibodies present in sera from patients with WT. We established an autoantibody signature that separates untreated patients with WT recruited in SIOP from non-WT controls with a specificity of 0.83 and a sensitivity of 0.82 at standard deviations of 0.02 and 0.04, respectively. Likewise, patients recruited in the COG in the United States were separated from the controls with an accuracy of 0.83 at a standard deviation of 0.02. Proteins that were most significant include zinc finger proteins (e.g., ZFP 346), ribosomal proteins and the protein fascin that has been associated with various types of cancer including renal cell carcinoma. Our study provides first evidence for autoantibody signatures for WTs and suggests that these may be most informative before chemotherapy. We present the first multicenter study of autoantibody signatures in patients with WT. We established an autoantibody signature that separates patients with WT from controls.Wilms Tumor (WT) is the most common renal childhood tumor.1 More than 75% of nephroblastomas are diagnosed before the age of 5 years. The overall survival rate greatly improved over the last decades to over 90%. The progress in treatment of nephroblastoma was largely due to interdisciplinary approaches accomplished by cooperative study groups including the Children's Oncology Group (COG) in North America and the Societé Internationale d'Oncologie Pédiatri-que (SIOP) in Europe. While the COG treatment protocol starts with primary nephrectomy, the SIOP treatment of children older than 6 months is initiated by preoperative chemotherapy.2,3 The primary aims of both protocols are risk-stratified therapies, improved patient outcome and diminished toxicity.Several genetic lesions have been reported for WTs including numerical and structural changes of chromosomes 1, 11, 16 as well as several others. 4 Few genes have been associated with the pathogenesis of nephroblastoma including WT1 on 11p13 that is deleted or mutated in 10-30% of WTs. 5,6 Further WT associated gene loci include WT2 at 11p15.5 and proposed familial predisposition loci at 17q12-q21 (FWT1) and 19q13.4 (FWT2). 7,8

Diagnostic Potential of Zinc Finger Protein-Specific Autoantibodies and Associated Linear B-Cell Epitopes in Colorectal Cancer

“…In addition, autoantibodies to the zinc finger protein ZNF638 were previously identified in sera of patients with cutaneous T-cell lymphoma using the SEREX (serological identification of recombinantly expressed genes) approach [ 22 ]. A more recent study further confirmed our discovery of ZNF346 autoantibodies when sera of renal cancer patients were analysed [ 23 ]. Autoantibodies to other zinc finger proteins were also frequently detected in cancer [ 24 ] and autoimmune disease [ 25 – 27 ]; however, there is a paucity of literature on autoantibodies specific to zinc finger proteins ZNF700 and ZNF768.…”

Systematic review of the immunological landscape of Wilms tumors

“…72 In WT patients not subjected to neoadjuvant chemotherapy, the autoantibodies contributing the most to the identification of WT patients were directed to the proteins ZFP 346 and fascin. 73 Surprisingly, fascinand ZFP 346-specific autoantibodies were not found in previously treated patients, suggesting that specific changes in the autoantibody repertoire occurred under chemotherapy. Since, according to the SIOP protocol, WT patients are treated without a previous diagnostic biopsy, autoantibody signatures may aid radiological and clinical identification of nephroblastoma.…”

“…Tumor-associated autoantibodies can be used as diagnostic tools. Despite that nephroblastomas have a much lower expression of autoantibodies than neuroblastomas, 72 , 73 differential autoantibody signatures allowed separation between WT patients, neuroblastoma patients, and healthy controls with sensitivity and specificity of more than 86%. 72 In WT patients not subjected to neoadjuvant chemotherapy, the autoantibodies contributing the most to the identification of WT patients were directed to the proteins ZFP 346 and fascin.…”

Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy

“…It has been established that Zinc can bind to certain proteins to form zinc finger proteins. Studies have confirmed that ZFP346, ZNF224 and other zinc finger proteins act as transcriptional cofactors of WT1 in WT, leukemia and other cancers, and they could have significant influence on cancer progression (34,35). Furthermore, it was observed that red blood cells from children with nephroblastoma have higher concentration of zinc and this is associated with zinc superoxide dismutase activity.…”

“…Sorafenib is an oral small molecule inhibitor, helpful in the treatment of rhabdomyosarcoma, nephroblastoma and hepatocellular carcinoma (HCC) (32,33). Studies have confirmed that ZFP346, ZNF224 and other zinc finger proteins act as transcriptional cofactors of WT1 in WT, leukemia and other cancers, and affect cancer progression (34,35). In addition, copper-bound monoamine oxidase (AOC1) is activated by WT1 and mediates polyamine breakdown, playing a key role in cell growth and proliferation of embryonic kidney and gonads (36).…”