²Ä¤@³¡¥÷ Nasopharyngeal carcinoma¡]NPC¡^ is a malignant tumor which occurs at high incidence in southern China. Several risk factors have now been recognized, but the molecular mechanism of this disease is not well understood. To investigate the c-myc¡Bcyclin D1¡Bp16¡Bp27 and Rb gene expression in NPC at protein level, 46 cases of nasopharyngeal carcinoma in southern Taiwan were detected by immunohistochemistry. There was no detectable p16 in 31/45 cases¡]69¢M¡^¡F 34/46 cases¡]73.9¢M¡^had intense staining for the Rb protein¡F 29¡]70.7¢M¡^of 41 cases had c-myc protein expression¡Fcyclin D1 was not overexpression in nasopharyngeal carcinoma¡F 32¡]69.6¢M¡^of 46 cases had high level expression of p27, which was inverse correlation with other tumors. No expression of c-myc protein correlated with higher neck metastasis¡]P¡Õ0.05¡^. No correlation was found between other proteins and any of the clinicopathological parameters. ²Ä¤G³¡¥÷ To better understand nasopharyngeal carcinoma¡]NPC¡^, we have newly established two NPC cell lines. Biopsy specimens from NPC patients were collected, primary culture were set up. Two NPC cell lines were established¡GNPCGK 01 was derived from differentiated carcinoma and NPCGK 02 was derived from undifferentiated carcinoma. Two cell lines have been passaged for more than 25 times. Two cell lines had telomerase activity¡Fstrong expression of hTERT gene and keratin-19 gene were also observed. TGF£] RI protein expression of these NPC cell lines is higher than normal epithelial cell.The oncogenes, c-myc¡Bc-fos and cyclin D1 were overexpressed. The Rb protein was expressed stronger than normal epithelial cells. NPCGK 01 that was derived from differentiated carcinoma had p16 down-regulation and p27 gene not expression, but p21 protein had excess expression. In short, two cell lines had cancer cell characteristics, oncoproteins were overexpression and tumor suppressor proteins were abnormal expression. This result may lead to tumorigenesis of nasopharyngeal carcinoma.

Deletion of the long arm of chromosome 6 is one of the most common genetic alterations in human malignant melanoma. Recently, a reciprocal translocation between chromosomes 6q and 17p was detected in a melanoma cell line, UACC-930, using arm painting probes of 6p and 6q. Reciprocal translocation is seldom observed in solid tumors. Upon further characterization of the translocation marker using techniques such as Southern blotting, genomic library screening and DNA sequencing, a complex rearrangement including two inversions of 6q and a translocation between the inverted 6q and 17p, [der(6)inv(6)(q21q22)(q22q27)t(6;17)(q27;p13)], was detected. An NCBI blast search revealed 3 genes being interrupted by the breakpoints: prenyl diphosphate synthase subunit 2 (PDSS2) at 6q21, Parkin at 6q27 and p53 at 17p13. Down-regulation of PDSS2 was commonly observed in 59/87 (67.8%) primary melanomas, which was significantly higher than that in benign nevi (7/66, 10.6%, p<0.001), indicating the tumor-suppressive potential of PDSS2 in melanoma development. To characterize the function of PDSS2 in tumorigenesis, PDSS2 was stably transfected into a highly tumorigenic melanoma cell line, UACC-903. The tumor-suppressive function of PDSS2 was demonstrated by both in vitro and in vivo assays. The results showed that PDSS2 could inhibit tumor cell growth, decrease the colony-forming ability in soft agar, and totally abrogate the tumorigenicity of UACC-903 in nude mice. PDSS2 is the first enzyme involved in the CoQ10 biosynthesis pathway. Other studies have demonstrated PDSS2 mutations can cause severe CoQ10 deficiency and markedly reduced ATP production because of respiratory chain dysfunction. Interestingly, proteomics analysis revealed 7 out of 11 identified proteins (HSPA8, GAPDHS, TPI1, HSPA5, PGK1, ENO1, and ATP5B) differentially expressed in PDSS2-overexpressing cells were related to energy metabolism. Further studies are required to determine how PDSS2 could alter the energy supply in tumor cells. Taken together, these results support the proposal that PDSS2 is a novel tumor suppressor gene which may play an important role in the development of malignant melanoma via altering tumor metabolism.

Des mutations acquises du gène TET2 ont été décrites dans les hémopathies malignes humaines. La fréquence de ces anomalies dans les hémopathies myéloïdes est de 10 à 20%, atteignant 50% dans les échantillons de leucémies myélo-monocytaires chroniques (LMMC). Les mutations observées sont inactivatrices, ce qui suggère que TET2 est un gène de type suppresseur de tumeur et que les mutations retrouvées conduisent à une perte de fonction de la protéine. Ce gène code pour une enzyme capable de modifier les cytosines méthylées. Il participerait ainsi au contrôle de la méthylation de l'ADN et donc à la régulation épigénétique de l’expression génique. Afin de mieux comprendre son rôle au cours de l’hématopoïèse, deux modèles murins d'inactivation du gène Tet2 ont été développés. Des expériences de greffe de cellules médullaires dans des souris syngéniques montrent que les cellules déficientes pour ce gène présentent un avantage compétitif par rapport aux cellules sauvages. L’analyse des souris invalidées pour ce gène montre une amplification des populations hématopoïétiques immatures, ainsi que des anomalies de la différenciation des lignages myéloïdes et également des lignages lymphoïdes. Une fraction des souris invalidées pour Tet2 âgées de plus de six mois développe des hémopathies malignes ressemblant à la LMMC humaine. Des anomalies équivalentes sont retrouvées dans les souris hémizygotes pour Tet2 et dans des souris portant un allèle hypomorphe du gène. L’ensemble de ces résultats montre qu’une dérégulation de l'activité de Tet2 conduit à des anomalies précoces de l'hématopoïèse, mais n'entraine pas directement la transformation des cellules progénitrices immatures. La latence du développement de ces tumeurs suggère la nécessité d'une coopération avec d'autres évènements oncogéniques, comme des anomalies d’autres acteurs épigénétiques / Acquired loss-of-function mutations of TET2 gene are frequently observed in patients with myeloid malignancies, including acute myeloblastic leukemia, myeloproliferative neoplasm, myelodysplastic syndrome, and chronic myelomonocytic leukemia (CMML). The Ten-Eleven-Translocation (TET) family proteins are 2-oxoglutarate/Fe(II)-dependent dioxygenases that catalyze the conversion of 5-methyl-cytosine into 5-hydroxymethyl-cytosine, which is proposed to constitute a first step toward cytosine demethylation. To study the function of Tet2 in murine hematopoiesis, we developed two mouse models in which the catalytic domain of the protein is disrupted. In both models, Tet2 deficiency leads to the progressive expansion of the immature hematopoietic compartment that includes stem cell and multipotent progenitors. In addition, both Tet2-deficient animals display abnormalities of erythroid, megakaryocytic, myelo-monocytic and lymphoid lineages, recapitulated in competitive transplantation assays. With age, Tet2-deficient mice develop bona fide myeloid tumors. All these properties were shown to be cell-autonomous by bone marrow cells transplantation and in vitro assays. Together these data suggest that TET2 activity is essential for normal homeostasis of the hematopoietic system. Its inactivation results in the development of hematologic disorders resembling human CMML myeloid disorders. TET2 deficiency endows the cells with a competitive advantage over wild type cells, induces hematopoietic differentiation abnormalities but is not responsible for full cellular transformation. The latency observed for CMML development in mouse models of Tet2 deficiency suggests a requirement for cooperating mutations, such other epigenetic regulator alterations.

IFN-α has been applied in medical treatment of various neuroendocrine (NE) tumors, either alone or combination with somatostatin analogues. They can improve clinical symptoms in 50-70% of patients but a significant tumor reduction is only observed in 5-15% patients. Vasostatin (vaso) is believed to be an angiogenic inhibitor. The aim of this study is to evaluate the feasibility to use IFN-α and vasostatin gene therapy in NE tumors. We constructed plasmid vectors carrying human IFN-α2 (hIFN-α2) gene and human vasostatin gene, which were transfected into BON I cell to obtain stable gene-expressing cell lines. We found that in animal tumor model and cell experiments gene transfer of vasostatin caused a faster cell growth and tumor development via down-regulation of the tumor suppressor gene and p27. Cell adhesion, spreading, migration and invasion ability were increased in vaso-expressing BON I cells. Transfecting chicken vinculin could reverse the malignant behavior and restored expression of tumor suppressor genes. Moreover, vinculin knockdown could result in a faster cell growth and an increased colony formation. Condition medium taken from hIFN-α2-expressing BON I cells showed significant antiproliferative effects both on the NE tumor cells, BON I and LCC18, and the endothelial cells, PAE. It also suppressed cell adhesion and cell invasion and inhibited angiogenesis on CAM assay. Mice implanted with a mixture of WT BON cells and hIFN-α2-expressing BON cells (1:1) demonstrated significantly lower tumor incidence and longer tumor doubling time. Furthermore, long-acting IFN-α2b (PEGIntron®) demonstrated a better anti-tumor effect in contrast with IFN-α2b (IntronA®). Intratumoral injection of hIFN-α2 plasmids significantly inhibited NE tumor growth and caused tumor regression. We concluded that gene transfer of vasostatin into BON I cells might cause an enhanced malignant tumor behavior. Therefore, vasostatin therapy can not be recommended for patients with NE tumors. Vinculin might play an important role in NE tumor development and growth regulation. Gene therapy by using plasmid DNA carrying hIFN-α2 gene is feasible and promising in NE tumors.

WW domain-containing oxidoreductase (WWOX) is a novel tumor suppressor gene discovered few years ago. Many researches indicate that expression of WWOX is reduced in a variety of cancers including heptocellular carcinoma (HCC). A recent report suggests that WWOX is implicated in Wnt/£]-catenin pathway which is frequently affected in HCC. In this study, we used immunohistochemical (IHC) staining to analyze the expression of WWOX and Wnt/£]-catenin pathway components in HCC and adjacent non-tumor tissues. Our result showed that WWOX was significantly downregulated in poor differentiated HCC. In addition, downregulation of WWOX was significantly correlated with cytoplasmic £]-catenin expression. We also found that TCF4 was strongly expressed in HCC tissues and the expression was associated with tumor grade and stage. Consequently, our result implied that downregulation of WWOX in HCC might lead to accumulation of £]-catenin in the cytoplasm and the subsequent activation of Wnt/£]-catenin signaling pathway.

Mosaicism occurs due to postzygotic genetic alterations during early embryonic development. The phenomenon is common, present in all humans, animals, and plants, and is associated with phenotypic variability and heterogeneity. Mosaic pathogenic gene variants result in a mosaic disease state, in which the individual can present with mild, generalized disease, a localized disease phenotype in specific organs and tissue regions, or full-blown clinical features which are indistinguishable from the heterozygous disease state. Multiple studies have described the prevalence and clinical correlations associated with low-level mosaicism for various genetic disorders, including several tumor suppressor gene (TSG) syndromes, which are well-known to display mosaicism. However, the extent of mosaicism research varies widely between TSG syndromes. Currently there is no comprehensive, up to date review covering multiple TSGs and focusing on mosaicism prevalence, diagnostic strategies and transmission risk. Here, in this literature review, I focus on 8 common tumor suppressor genes NF1, NF2, TSC1, TSC2, RB1, PTEN, VHL, and TP53; reporting the following disease aspects: • Role and function of each tumor suppressor gene, disease prevalence, inheritance pattern, penetrance/expressivity pattern, age of onset clinical features, organs affected, and benign or malignant tumors seen • Different types of mosaicism, including critical review of recent, representative publications for each tumor suppressor gene syndrome • Established criteria for clinical diagnosis of inherited versus mosaic disease, molecular diagnosis, and current methods of genetic analysis Then more extensively, this thesis discusses the most informative, representative original studies for each TSG and provides a summary which covers: • The number of mosaic patients analyzed and the spectrum of clinical features of the cohort they were sampled from • The spectrum of variant allele frequency (VAF), tissue types analyzed, and different analysis methods performed • Whether or not the mosaic patients met clinical criteria for diagnosis of inherited disease • The number of patients who were persistently classified as no mutation identified (NMI) after genetic analysis • Spectrum and type of mosaic mutational event(s) identified • Age of onset and age range of mosaic patients • Patient ascertainment and family history (sporadic or familial cases) and • Type of mosaicism seen Furthermore, it compares and discusses disease severity, possibility of malignancy, and genotype-phenotype correlations for each TSG. Ultimately, by juxtaposing these TSGs, this review aims to centralize existing knowledge about mosaicism and provide insight into how molecular techniques can be broadly applied for better diagnosis of mosaic disease. / 2022-11-10T00:00:00Z

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