Wnt signaling pathway analysis in renal cell carcinoma in young patients

Abstract

Renal cell carcinomas in young patients constitute a morphologically and genetically heterogeneous group. Twenty percent belong to the newly recognized Xp11.2 translocation-associated family and rare tumors arise from nephroblastoma. Aberrant Wnt signaling through b-catenin mutation has been implicated in nephroblastoma pathogenesis and has been found to synergize with WT1 mutations. To characterize Wnt signaling activity in renal cell carcinomas in young patients, we gathered 34 tumors (three clear cell, ten Xp11.2 translocation associated, five papillary, two chromophobe, two collecting duct, one neuroblastoma associated, eight unclassified renal cell carcinomas, and three carcinomas combined with nephroblastoma) from patients less than 22 years. Expression of b-catenin, its homologue c-catenin, and of WT1 was assessed by immunohistochemistry in 30 tumors, and sequence analysis of CTNNB1, CTNNG1, and WT1 genes was performed in 25 tumors. Cytoplasmic b-catenin accumulation was demonstrated in two papillary carcinomas, one neuroblastoma-associated carcinoma, and two carcinomas arising from nephroblastoma. The pattern of c-catenin expression paralleled that of b-catenin but its signal intensity was lower in 22, equal in 7, and stronger only in 1 tumor, respectively. Four tumors showed nuclear WT1 expression. One Xp11.2 translocationassociated carcinoma presented a rare intronic CTNNB1 single nucleotide polymorphism and cytoplasmic b-catenin accumulation. There were no further CTNNB1 or CTNNG1 sequence alterations. A WT1 mutation was found in the nephroblastoma component of a carcinoma arising from nephroblastoma. These findings suggest Wnt signaling pathway activation only in a minority of renal cell carcinomas in young patients. CTNNB1 mutations are rare events. Cytoplasmic b-catenin accumulation in an Xp11.2-associated carcinoma suggests potential interaction of Wnt signaling components with microphthalmia transcription factor family also in Xp11.2 translocation carcinomas. WT1 mutation in the nephroblastoma component of a mixed-type renal cell carcinoma provides direct evidence for clonal independence of nephroblastoma and carcinoma components in this exceptional tumor.

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“…In other model transmembrane proteins, it has been demonstrated that the minimal distance from the transmembrane domain to a luminal glycosylation site must be between 12 to 15 residues in order for N-linked glycosylation to take place (46). Therefore, it is not surprising that the potential glycosylation site at N53 is not modified since it puts this amino acid within 11 residues from the predicted first transmembrane domain (4,7,52). Similarly, the potential glycosylation site at N945 (Fig.…”

Impact of an Altered Wnt1/β-Catenin Expression on Clinicopathology and Prognosis in Clear Cell Renal Cell Carcinoma

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