7291

TWIST1

ACS3|BPES2|BPES3|CRS1|SCS|TWIST|bHLHa38;twist homolog 1 (Drosophila);TWIST1;twist homolog 1 (Drosophila)

B-HLH DNA binding protein|H-twist|TWIST homolog of drosophila|class A basic helix-loop-helix protein 38|twist-related protein 1

7p21.2

protein-coding

Saethre-Chotzen syndrome (SCS) is a craniosynostosis syndrome characterized by facial and limb abnormalities caused by mutations in the TWIST1 gene on 7p21, resulting in variable loss of function. The transcription factor TWIST1 has alsobeen shown to promote tumor growth and has been linked to the formation of metastases in breast cancers. One suggestive case of inherited SCS and malignancy in childhood has been reported previously. Here, we present immunological and genetic investigations including the determination of a new stop codon mutation in the TWIST1 gene in SCS associated with malignancy in childhood.

Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiationand remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive extracellular matrix (ECM)molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced inhuman pediatric and adult diseased heart valves. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sites. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation (ChIP) assays, and binding was detected in ECCs but not latestage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo, which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsiveto Twist1 transcriptional function, and contain Twist1-responsive regulatory sequences.

Nested stromal epithelial tumor of the liver is a rare neoplasm of early childhood and adolescence with a characteristic nested morphology of spindle andepithelioid cells. Histogenesis and pathogenesis of this neoplasm are, however, still unclear. Because the characteristic nested morphology with spindle mesenchymal and epithelioid cells is suggestive of altered mesenchymal-epithelial transition and beta-catenin mutations are rather common in other liver tumors such as hepatoblastomas, we investigated the beta-catenin gene in 2 nested stromal epithelial tumors of the liver and analyzed additional factors involved in mesenchymal-epithelial transition, such as E-cadherin, vimentin, c-Met, TWIST, SNAIL, and SLUG by molecular genetic and immunohistochemical methods. mutation analysis of both cases revealed large deletions in exon 3 of the beta-catenin gene (155 and 228 base pairs), resulting in an accumulation of beta-catenin in the cytoplasm and nuclei of tumor cells, as evidenced by immunohistochemistry. The expression of the mesenchymal-epithelial transition factors SNAIL, SLUG, TWIST, c-Met, vimentin, and beta-catenin was generally increased, whereas E-cadherin was decreased. Morphological and immunohistochemical analysis, however, showed a variable expression pattern of various epithelial and mesenchymal markers both in the spindle and epithelioid cell compartments of thetumors, thus illustrating the transitional status of the tumor cells. In conclusion, our data clearly identify protein stabilizing mutations of the beta-catenin gene as a common feature of nested stromal epithelial tumors of theliver, similarly as in hepatoblastomas. Therefore, nested stromal epithelial tumors of the liver may be regarded as a variant of hepatoblastoma, despite differing from it in clinical and morphological aspects. The characteristic epithelioid-spindle morphology along with the incomplete epithelial differentiation proposes impaired mesenchymal-epithelial transition as a possible pathogenetic mechanism of this rare tumor. However, because only 2 cases were studied, this hypothesis awaits further validation.#CI- Copyright (c) 2012 Elsevier Inc. ALL rights reserved.