Faculty Bibliography

Tuberous sclerosis complex (TSC) is a genetically heterogeneous disease caused by mutations of TSC1 or TSC2 genes. It involves multiple organ systems resulting in mild to lethal hamartoma formation due to gene mutation in the germ line and loss of heterozygosity (LOH) in somatic cells. Hamartin (TSC1) and tuberin (TSC2) are expressed broadly. However, little is known about tissue susceptibility to hamartomas when equal or similar amounts of TSC gene expression are present. In this study, we present a 19-week gestational age fetus with pathological features of TSC, which was confirmed by finding LOH of TSC2 in a cardiac rhabdomyoma. Developmental expression of hamartin and tuberin in the TSC fetus, an age-matched non-TSC fetus, and a 26-week gestational age non-TSC fetus were analyzed by immunohistochemistry. We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues. In general, hamartin and tuberin are mainly expressed in epithelial cells, myocytes, and neural tissues. By comparing the incidence of the hamartomas in early childhood and gene expression in tissues, it appears that tissues with co-expression of hamartin and tuberin are prone to a higher incidence of hamartomas than those expressing only one protein, or two proteins but in different patterns of cellular localization

Gastrointestinal stromal tumor (GIST), a stromal tumor of the gastrointestinal tract defined as CD117 (c-kit)-positive neoplasm, occurs primarily in adults. GIST with CD117 (c-kit) mutation and certain cytogenetic abnormalities is associated with malignancy, though a definite relationship between prognosis and molecular alterations remains to be elucidated. We report the cytologic features of an epithelioid GIST arising in the stomach of a child and metastatic to the liver, and the molecular mutational analysis of both the primary gastric tumor and the liver metastasis. Literature of pediatric GISTs was also reviewed. Fine needle aspiration of the liver metastasis, processed by Ultrafast Papanicolaou stain, showed fragments of cohesive small epithelioid cells with bland oval nuclei and unipolar cytoplasm transected by capillaries. Immunohistochemically, all nodules in the stomach and liver expressed CD117 (c-kit). Interestingly, some of the gastric tumor clusters were uniformly CD34 positive, whereas others were uniformly CD34 negative, suggesting heterogeneity of tumor clones. The presence of neurosecretory granules further subtyped the tumor into gastric autonomic nerve tumor (GANT). Molecular mutational analysis, performed in both the gastric tumor and the liver metastasis, showed no sequence abnormality in exons 9, 11, and 13 of CD117 (c-kit). Cytogenetic study revealed normal karyotype. These features might suggest a different molecular mechanism leading to malignancy in certain GISTs arising in children

The fine-needle aspiration cytologic findings of Wilms' tumor occurring in a 20-yr-old female patient and a 35-yr-old male patient showing blastemal, spindled sarcomatous and rare epithelial components are reported. The male patient had the typical presentation of renal mass with metastasis to lung and pleura, whereas the female patient had an unusual presentation with the tumor originated from the subcapsular nephrogenic zone of the kidney, extending into the liver without invasion into the renal cortex. Cytogenetic analysis of this case identified: 90, XXXX, +2x3-4, -5, -15, -16, -17, -17, i (17)(q10) x2. This finding may represent a genetic change associated with Wilms' tumor of older pediatric and young adult patients. To the best of our knowledge, this case is the sixth case with cytogenetic study and the first case revealing isochromosome 17q of an adult Wilms' tumor

Identifying genes upregulated in lead-resistant cells should give insight into lead toxicity and cellular protective mechanisms and may also result in identification of proteins that may be useful as biomarkers. Glial cells are thought to protect neurons against heavy metals. Rat glioma C6 cells share many properties of normal glial cells. To identify and analyze genes upregulated in a lead-resistant variant, PbR11, suppression subtractive hybridization (SSH) between mRNAs of wild-type and PbR11 cells was performed. Sequencing and database searches identified three genes, thrombospondin-1, heparin sulfate 6-sulfotransferase, and neuropilin-1, which play important roles in angiogenesis and axon growth during development. Two genes, HSP90 and UBA3, are involved in the ubiquitin-proteosome system. One gene was identified as that of a rat endogenous retrovirus and another, 2C9, is a transcript expressed in fos-transformed cells. PbR11 also overexpresses c-fos. Expression of these genes and effects of short-term lead exposure (24 h, up to 600 microM) on their expression in C6 cells was examined. The rat endogenous retrovirus and 2C9 are expressed only in PbR11 cells, and show no expression, either constitutive or lead-induced, in wild-type C6 cells. HSP90 is expressed at low level constitutively in C6 cells, but can be induced in a dose-dependent manner by lead. In contrast, thrombospondin-1 is repressed in a dose-dependent manner by lead. The other genes (HS6ST, neuropilin, and UBA3) show low constitutive expression and are neither upregulated nor downregulated by exposure to lead. We suggest that neuropilin-1, heparin sulfate 6-sulfotransferase, and thrombospondin-1 may be important targets for lead-induced developmental neurotoxicity

A yeast two-hybrid assay has identified an androgen-dependent interaction of androgen receptor (AR) with amino-terminal enhancer of split (AES), a member of the highly conserved Groucho/TLE family of corepressors. Full-length AR, as well as the N-terminal fragment of AR, showed direct interactions with AES in in vitro protein-protein interaction assays. AES specifically inhibited AR-mediated transcription in a well-defined cell-free transcription system and interacted specifically with the basal transcription factor (TFIIE) in HeLa nuclear extract. These observations implicate AES as a selective repressor of ligand-dependent AR-mediated transcription that acts by directly interacting with AR and by targeting the basal transcription machinery