4233

MET

AUTS9|HGFR|RCCP2|c-Met;met proto-oncogene (hepatocyte growth factor receptor);MET;met proto-oncogene (hepatocyte growth factor receptor)

HGF receptor|HGF/SF receptor|SF receptor|hepatocyte growth factor receptor|met proto-oncogene tyrosine kinase|oncogene MET|proto-oncogene c-Met|scatter factor receptor|tyrosine-protein kinase Met

7q31

protein-coding

The hepatocyte growth factor (HGF)/MET pathway plays a critical role in the development of the nervous system and has been implicated in medulloblastoma pathogenesis. Recent studies have shown a role for gene amplification of activators of this pathway, as well as silencing of its inhibitors in medulloblastoma pathogenesis. We analyzed exon array data from a cohort of 103 primary medulloblastomas to show that HGF/MET pathway elements are dysregulated in tumors compared to normal cerebellum. To determine if mutation of HGF/MET pathway genes is a mechanism for pathway dysregulation, we conducted a mutational analysis by exon resequencing of three key components of this pathway, includingserine protease inhibitor Kunitz-type 1 (SPINT1), serine protease inhibitor Kunitz-type 2 (SPINT2), and MET, in 32 primary human medulloblastoma specimens. From this analysis, we identified multiple coding synonymous and nonsynonymous single nucleotide polymorphisms in these genes among the 32 tumor samples. Interestingly, we also discovered two unreported sequence variants in SPINT1 andSPINT2 in two tumors that resulted in Arginine to Histidine amino acid substitutions at codons 418 and 233, respectively. However, conservation assessment and functional assays of these two variants indicate that they involve nonconserved residues and that they do not affect the function of SPINT1 and SPINT2 as tumor suppressor genes. In conclusion, our data suggest that mutation alone plays a minor role in causing aberrancies of the HGF/MET pathway in medulloblastoma in comparison with other malignancies such as breast, hepatocellular, renal, and lung carcinomas.#CI- Copyright (c) 2012 Wiley Periodicals, Inc.

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.