7849

PAX8

-;paired box 8;PAX8;paired box 8

paired box protein Pax-8|paired domain gene 8

2q13

protein-coding

The paired box-8 protein (Pax-8) has been observed in the nucleus of normal adult thyroids, follicular adenomas, follicular thyroid cancers, and papillary thyroidcancers (PTC) but not undifferentiated thyroid cancers. To our knowledge, Pax-8 has not been studied in pediatric thyroid cancer. Because of the more favorable prognosis for PTC in children compared to young patients, we hypothesized that Pax-8 expression might be different in pediatric thyroid cancers. To test this, we stained 47 thyroid lesions from children and young patients for Pax-8. Pax-8 was located in the cytoplasm (cPAX) or nucleus (nPAX) in the majority of samples. There was no significant difference in nPAX between benign and malignant lesions. However, cPAX was more commonly seen in PTC than autoimmune diseases (p = 0.01) and the intensity of cPAX staining correlated with tumor size (p = 0.041), metastasis, age, completeness of resection, local invasion, and tumor size (MACIS) scores (p = 0.045), and the presence of invasion, metastasis, recurrence, or persistence (p = 0.012). disease-free survival was significantly reduced for cancers with intense cPAX staining (p = 0.0003). These data show that cPAX is common in PTC, and although limited by small sample size, suggest an associationwith higher MACIS scores, an aggressive clinical course, and an increased risk of clinically evident recurrence for children and young patients.

Wilms' tumor (WT) is a childhood renal neoplasm with histological features resembling fetal kidney development. Two members of the paired box family of genes, PAX2 and PAX8, are expressed in WT and are potentially involved in its induction. A zinc finger gene, WT1, which is involved in WT induction, encodes aDNA binding protein, and like PAX2 and PAX8 proteins is a transcription factor with an important role in kidney development. We have compared the expression patterns of PAX2, PAX8, and WT1 in fetal kidney and WTs by in situ hybridization. The PAX2, PAX8, and WT1 genes were transcribed in the condensed mesenchyme and early stages of epithelial differentiation in fetal kidney. WT1 gene transcription was observed in the glomeruli of fetal kidney until a later stage in development than PAX genes. In WTs ALL three genes were expressed in the condensed blastema, but WT1 expression was not detectable in the epithelial structures in two WTs. No evidence of attenuation of PAX gene expression was found in WT. These results suggest that in some WTs the expression of WT1 is attenuated in structures that continued to express PAX genes. It is unlikely that both PAX2 and PAX8 genes would be mutated in WT. However, failure of PAX gene expression to attenuate in WTs may result from mutations involved in the onset of the tumor.

Wilms' tumor (WT) is an embryonal renal neoplasm with features resembling fetal kidney development. A family of genes potentially involved in WT induction is called the paired box (PAX) gene family. In this study we examined by Northern blot analysis the expression of several PAX genes in a variety of WTs and other childhood neoplasms. RNA was isolated from four primary WTs and 12 WTs propagated in nude mice (heterotransplant), as well as from a variety of other childhood renal and nonrenal embryonal tumors. RNA samples were electrophoretically separated in 1.2% agarose gels, transferred to nylon membranes, and hybridized to random primer-labeled PAX2, PAX8, and WT1 probes. Membranes were then exposed tox-ray films at -70 degrees C with intensifying screens. PAX2 and WT-1 expressionwere seen in ALL four primary WTs; PAX8 was seen in three of the four primary WTs. Of the 12 heterotransplant Wilms' tumors, PAX2, PAX8, and WT1 were concomitantly expressed in seven tumors. Another heterotransplant WT expressed WT1 alone. expression of these three genes, with one exception, was not seen in the other childhood renal and nonrenal solid tumors. The PAX genes are transcriptional regulators; their protein products bind to specific DNA segmentsand control gene expression. Their role in the pathogenesis of Wilms' tumor and their interaction with WT1 are unclear. Elucidation of the functional significance of the PAX genes will provide important insights into not only the pathogenesis of WT but also the molecular control of the developing kidney.