Moleculaar evidence of the independent origin of multiple wilms tumors in a case of WAGR syndrome

Background. This study investigated the genetic events leading to tumorigenesis in a patient affected with WAGR syndrome who developed multiple distinct Wilms tumors (WTs). Procedure and Results. At 1 year of age, the child developed two synchronous bilateral WTs that were resected by partial nephrectomy. Histologically, these tumors were fetal rhabdomyomatous nephroblastomas. Immunohistochemical study revealed the absence of nuclear expression of WT1 protein, while β-catenin protein was expressed at nuclear level by the large majority of tumor cells. Molecular investigations of WT1 gene and exon 3 of β-catenin (CTNNB1) gene detected no mutations. At 4 years of age, 28 months after the chemotherapy completion, a third WT was diagnosed in the left kidney, and surgically removed before any further chemotherapy. Nine months after surgery, a metastasis was detected in the left lung. Both the third renal tumor and the lung metastasis showed a blastema-predominant morphology. Immunohistochemistry confirmed the lack of expression of WT1 protein, while β-catenin protein was expressed at nuclear level by the large majority of tumor cells. Molecular analysis of the third renal tumor and the lung metastasis revealed a 4 bp deletion in exon 7 of WT1 gene, leading to a frameshift of the reading frame and to a premature stop of the translation (c.925_928delACTC, p.T309LfsX71); no mutations in the exon 3 of the β-catenin gene were documented. Conclusions. These data demonstrate that multiple WTs can arise as a consequence of different genetic events in a patient with genetic predisposition, such as WAGR syndrome.