Papers - YAMAMOTO HIDETAKA

Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Reviewed International journal

Teiyu Izumi, Yoshinao Oda, Tadashi Hasegawa, Yukihiro Nakanishi, Hiroshi Iwasaki, Hiroshi Sonobe, Hiroaki Goto, Hidenari Kusakabe, Tomonari Takahira, Chikashi Kobayashi, Ken-Ichi Kawaguchi, Tsuyoshi Saito, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   19 ( 6 )   820 - 31   2006.6

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Dysadherin is a cancer-associated cell membrane glycoprotein, which downregulates E-cadherin and promotes metastasis. We studied the clinicopathological features in 72 cases of epithelioid sarcoma and in six cases of malignant rhabdoid tumor, and also assessed the immunohistochemical expression of dysadherin, E-cadherin and MIB-1 in epithelioid sarcoma and malignant rhabdoid tumor cases. In addition, we compared dysadherin mRNA expression between epithelioid sarcoma and malignant rhabdoid tumor cell lines, using RT-PCR and real-time quantitative RT-PCR analysis. Immunohistochemical dysadherin expression was more frequently observed in proximal-type epithelioid sarcoma (71%) in comparison with distal-type epithelioid sarcoma (36%) (P = 0.037). Furthermore, seven proximal-type epithelioid sarcoma cases mimicking malignant rhabdoid tumor (histologically classified as the large cell type, accompanied by frequent rhabdoid cells and located in deep soft tissue) were all positive for dysadherin (100%), whereas dysadherin expression was not detected at all in any of the true six malignant rhabdoid tumors (0%). Cell lines established from proximal-type epithelioid sarcoma revealed significantly higher levels of dysadherin mRNA expression, compared with the levels seen in malignant rhabdoid tumor cell lines by real-time quantitative RT-PCR (P = 0.0433). Epithelioid sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P = 0.001). In multivariate analysis, dysadherin immunopositivity (P = 0.0004) was one of the two independent adverse prognostic factors. We conclude that dysadherin expression in epithelioid sarcoma is a significant poor prognostic factor and that it is a powerful diagnostic marker for distinguishing epithelioid sarcoma, including the proximal-type epithelioid sarcoma, from malignant rhabdoid tumor. In epithelioid sarcoma, especially in proximal-type epithelioid sarcoma, increased cell disadhesion and motility by dysadherin plays an important role to acquire aggressive biological behavior. However, in malignant rhabdoid tumor, cell growth cycle that is regulated by hSNF5/INI1 gene seems to be critical to lethal biological behavior rather than dysadherin.

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Nuclear beta-catenin correlates with cyclin D1 expression in spindle and pleomorphic sarcomas but not in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Hidetaka Yamamoto, Ken-Ichi Kawaguchi, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology   37 ( 6 )   689 - 97   2006.6

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Nuclear beta-catenin staining in soft tissue sarcomas (STSs) has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis. Frequent activation of Wnt signaling pathway has been also shown in synovial sarcoma (SS), suggesting a specific role of this pathway in SS. We examined roles of nuclear beta-catenin staining within soft tissue sarcomas. Immunohistochemical detection of nuclear beta-catenin accumulation correlated with cyclin D1 overexpression in spindle cell and pleomorphic sarcomas (P = .037), and the expression of these proteins evenly distributed throughout each section. In some cases, strong beta-catenin nuclear staining was observed in highly pleomorphic and mitotic cells. Furthermore, tumors with nuclear beta-catenin accumulation showed statistically significant increasing cyclin D1 mRNA expression level compared with those without (P = .023). Cyclin D1 mRNA expression levels were statistically higher in tumors with cyclin D1 overexpression than in tumors without (P = .037), suggesting that cyclin D1 overexpression is due to transcriptional activation. However, these correlations could not be detected in SS. In biphasic SS, beta-catenin nuclear staining was observed in spindle cells, whereas cyclin D1 nuclear staining was seen in glandular areas where beta-catenin kept membranous expression. Mutations in exon 3 of the beta-catenin gene and in the mutation cluster region of adenomatous polyposis coli gene were absent in this series of cases. Thus, cyclin D1 could be considered as one of the targets of the nuclear beta-catenin in spindle cell and pleomorphic sarcomas. A possible association between beta-catenin accumulation and spindle cell morphogenesis may exist in SS.

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CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis. Reviewed International journal

Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Kazuhiro Tanaka, Ryohei Yokoyama, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   19 ( 5 )   738 - 45   2006.5

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The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was also evaluated. CXCR4 expression (primary, 33.3% positive vs metastatic, 66.6% positive; P = 0.0097) and MVD (primary, 29.86 +/- 6.87/0.26 mm2 vs metastatic, 43.32 +/- 8.65/0.26 mm2; P = 0.0015) in the metastatic site were both significantly increased compared with those in the primary site, whereas no difference between primary and metastatic sites was observed with regard to VEGF expression. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (P = 0.0269). In total population, the MIB-1-labeling index (LI) was significantly higher in tumors, which showed immunoreactivity for VEGF (MIB-1-LI in VEGF-positive tumors, 24.29 +/- 5.4 vs VEGF-negative tumors, 18.33 +/- 4.16; P = 0.034). Furthermore, those patients with VEGF-positive primary tumors had a significantly worse prognosis compared with the patients with VEGF-negative primary tumors (P = 0.0053). Our results suggested that CXCR4 expression was associated with metastatic progression, and immunohistochemical VEGF expression in the primary site had predictive value for the osteosarcoma patients, who developed lung metastasis.

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Aberrant expression of CHFR in malignant peripheral nerve sheath tumors. Reviewed International journal

Chikashi Kobayashi, Yoshinao Oda, Tomonari Takahira, Teiyu Izumi, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Tomomi Yamada, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   19 ( 4 )   524 - 32   2006.4

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Mitotic checkpoint maintains genomic integrity before mitosis. Numerous observations have suggested that mitotic abnormalities produce chromosomal instability and aneuploidy. In MPNST, complex karyotypes showing numerical and structural aberrations have been described. 'Checkpoint with forkhead-associated domain and ring finger' (CHFR) was recently identified as defining a new early mitotic checkpoint. We examined the expression of CHFR in 96 cases of MPNST by immunohistochemical and molecular methods. We found reduced (score, < or = 3) expression of CHFR in 63 out of 96 (66%) cases of MPNST, and such alteration was significantly correlated with a high mitotic count, a high Ki-67-labeling index, and a poor prognosis. In addition, MPNST with normal karyotype showed a strong (score, =5) expression of CHFR. Our results support the assertion that CHFR functions as an inhibitor of tumor proliferation.

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Chromosomal aberrations and microsatellite instability of malignant peripheral nerve sheath tumors: a study of 10 tumors from nine patients. Reviewed International journal

Chikashi Kobayashi, Yoshinao Oda, Tomonari Takahira, Teiyu Izumi, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Tomomi Yamada, Shinya Oda, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Cancer genetics and cytogenetics   165 ( 2 )   98 - 105   2006.3

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Malignant peripheral nerve sheath tumor (MPNST) is an uncommon soft tissue neoplasm with a poor prognosis, occurring sporadically or associated with neurofibromatosis type 1 (NF1); however, the histogenesis of MPNST remains unclear, especially in sporadic tumors. There are two major forms of genomic instability in human cancer: chromosomal instability (CIN) and microsatellite instability (MSI). An inverse relationship has recently been demonstrated between CIN and MSI in colorectal cancers. CIN and MSI are suggested to be individual pathways, which are involved in the pathogenesis and which may lead to specific clinical and pathological characteristics. To elucidate the chromosomal aberration as a consequence of CIN and MSI status of MPNST, we karyotyped 10 MPNSTs from nine patients, and examined the MSI of seven microsatellite markers using high-resolution fluorescence microsatellite analysis; 2 out of 10 cases (20%) had normal karyotypes, and 8 out of 10 cases (80%) revealed structural and numerical chromosomal aberrations. Three of the 10 cases (30%) showed near triploidy. The most frequent aberration was -22 (40%), followed by +2, +14, -13, -17, and -18 (30% each). An MSI-low status was observed in 30% of cases; the remaining cases showed microsatellite stability. These findings suggest that chromosomal aberration as a consequence of CIN has a greater role in the pathogenesis of MPNST than does that due to MSI.

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Malignant perivascular epithelioid cell tumor of the colon: report of a case with molecular analysis. Reviewed International journal

Hidetaka Yamamoto, Yoshinao Oda, Takashi Yao, Toshio Oiwa, Chikashi Kobayashi, Sadafumi Tamiya, Ken-ichi Kawaguchi, Okio Hino, Masazumi Tsuneyoshi

Pathology international   56 ( 1 )   46 - 50   2006.1

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Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm, and malignant cases are extremely rare. A case of malignant PEComa arising in the colon is described herein. The patient was a 43-year-old Japanese woman without a history of tuberous sclerosis complex. The tumor occurred in the abdominal cavity attached to the serosal side of the descending colon. Histologically, the tumor consisted of sheets or closely packed nests of epithelioid cells with clear or eosinophilic cytoplasms. The tumor cells were positive for HMB-45 but negative for S-100 protein and cytokeratins by immunohistochemical staining. Ki-67 labeling index was 2.9%. Peritoneal dissemination of tumor occurred at 20 months and the patient died of tumor at 38 months after the initial operation. This was considered to be a case of malignant PEComa, based on the histological and clinical features. Tumor cells showed overexpression of cyclin D1 but lacked the loss of heterozygosity of the TSC1 and TSC2 genes. The result suggests that the overexpression of cyclin D1 may play an important role in the tumorigenesis of PEComa. Because PEComas can behave in an aggressive manner, careful follow up is warranted.

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DNA hypermethylation status of multiple genes in soft tissue sarcomas. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Chikashi Kobayashi, Sadafumi Tamiya, Naomi Tateishi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   19 ( 1 )   106 - 14   2006.1

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The aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in soft tissue sarcomas, we examined the promoter methylation status of 10 tumor-related genes in 65 soft tissue sarcomas and 19 adjacent non-neoplastic tissues by methylation-specific PCR. The methylation frequencies of tumor-related genes tested in soft tissue sarcomas were 17 (26%) for RASSF1A, 11 (17%) for DAP kinase, 10 (15%) for MGMT, nine (14%) for GSTP1, eight (12%) for PTEN, six (9%) for p16 and hMLH1, five (8%) for hMSH2, two (3%) for p14, and one (2%) for RB. Promoter methylation of these genes was not recognized in non-neoplastic tissues. All those cases of soft tissue sarcoma that had MGMT methylation, with the exception of one case of malignant peripheral nerve sheath tumor, showed large tumor size (> or = 10 cm) or recurrence. Moreover, eight of 10 cases with MGMT methylation revealed high American Joint Committee on Cancer stage. Seven of 10 cases (70%) with MGMT methylation showed a loss of MGMT expression by immunohistochemistry. In addition, MGMT methylation status had a statistically significant correlation with a loss of MGMT expression (P=0.014). In conclusion, although methylation of tumor-related genes was a relatively rare event in soft tissue sarcomas, methylation was tumor-specific. Of 10 tumor-related genes, cases with MGMT methylation had a tendency to be aggressive behavior. Moreover, MGMT methylation was closely associated with a loss of MGMT expression. Although our findings need to be extending to a large series, promoter methylation of tumor-related genes is likely to have an association with the pathogenesis of soft tissue sarcomas. Furthermore, MGMT methylation may be associated with tumor aggressiveness and the inactivation of MGMT gene.

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Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis. Reviewed International journal

Yoshinao Oda, Hidetaka Yamamoto, Tomonari Takahira, Chikashi Kobayashi, Kenichi Kawaguchi, Naomi Tateishi, Yoko Nozuka, Sadafumi Tamiya, Kazuhiro Tanaka, Shuichi Matsuda, Ryohei Yokoyama, Yukihide Iwamoto, Masazumi Tsuneyoshi

The Journal of pathology   207 ( 4 )   410 - 21   2005.12

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In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G1 to S-phase check-point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB-1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16(INK4a)/p14(ARF) genes were also investigated, using concordant paraffin-embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over-expression of p53 protein (p = 0.01366) and the reduced expression of p14 (p < 0.0001) and p16 (p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14(ARF) gene promoter (p = 0.0176) and over-expression of p53 protein (p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly (p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site (p = 0.0251), the presence of an RC component (p = 0.0113), high MIB-1 labelling index (p = 0.0005) and p53 missense mutation (p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14(ARF)/p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour.

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Alterations of the RB1 gene in dedifferentiated liposarcoma. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Chikashi Kobayashi, Teiyu Izumi, Kensaku Ito, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   18 ( 11 )   1461 - 70   2005.11

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Dedifferentiated liposarcoma is a malignant adipocytic neoplasm containing a non-lipogenic sarcoma of variable histological grade that arises against the background of a pre-existing well-differentiated liposarcoma. The phenomenon of dedifferentiation is considered to be time-dependent, but the mechanism is not well known. The retinoblastoma protein, encoded by the RB1 gene located at 13q14, is a key regulator of proliferation, development, and differentiation of certain cell types, including adipocytes. In the current study, we investigated the genetic alterations of the RB1 gene, such as mutation (the essential promoter region and the protein-binding pocket domain; exons 20-24) and methylation of the promoter region, in addition to pRB expression and loss of heterozygosity (LOH) status, in two morphologically distinct areas (non-lipogenic dedifferentiated and well-differentiated components) in 27 patients. As a control, 11 undifferentiated high-grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma samples and 11 well-differentiated liposarcoma samples were also evaluated. Dedifferentiated components showed LOH (15/25; 60%) and abnormal retinoblastoma protein expression (18/27; 66.7%) more frequently than noted in the well-differentiated components (3/24; 12.5% and 9/27; 33.3%, respectively). Five and four out of the 27 dedifferentiated components harbored mutations and promoter methylation, respectively, whereas none of these alterations were seen in the well-differentiated components. These results suggest that retinoblastoma protein has a major role to play in dedifferentiation and that a 'two-hit' mechanism is involved in the altered retinoblastoma protein expression in dedifferentiated liposarcoma.

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Microsatellite instability and proliferating activity in sinonasal carcinoma: molecular genetic and immunohistochemical comparison with oral squamous cell carcinoma. Reviewed International journal

Hideoki Uryu, Yoshinao Oda, Hideki Shiratsuchi, Shinya Oda, Hidetaka Yamamoto, Shizuo Komune, Masazumi Tsuneyoshi

Oncology reports   14 ( 5 )   1133 - 42   2005.11

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Sinonasal carcinomas arise from the respiratory epithelium that lines the nasal and paranasal cavities, and are histologically composed of either squamous or cylindrical cell carcinoma. However, molecular analysis with the purpose of distinguishing sinonasal carcinomas from other head and neck squamous cell carcinomas (HNSCCs), which arise from squamous epithelium, has been limited. Moreover, a wide range of frequency of microsatellite instability (MSI) in HNSCC has been reported. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 34 patients with sinonasal carcinoma. As a control, 24 oral squamous cell carcinomas were used. MSI was detected in 14 patients with sinonasal carcinoma (41%), but not in any with oral squamous cell carcinoma (p=0.002). Furthermore, in sinonasal carcinoma, 11 out of 17 (65%) T1-T3 sinonasal carcinomas demonstrated MSI, whereas only 3 out of 15 (20%) T4 tumors demonstrated MSI. Immunohistochemically, sinonasal carcinoma showed a higher MIB-1-labeling index and more frequently showed cytokeratin 18 expression when compared with oral squamous cell carcinoma. These findings suggest that sinonasal carcinoma and HNSCC have quite different molecular backgrounds regarding carcinogenesis, and the role of MSI is relatively minor in cases of advanced sinonasal carcinoma.

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Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Reviewed International journal

Norimoto Nakamura, Hidetaka Yamamoto, Takashi Yao, Yoshinao Oda, Ken-ichi Nishiyama, Masakazu Imamura, Tomomi Yamada, Hajime Nawata, Masazumi Tsuneyoshi

Human pathology   36 ( 7 )   828 - 37   2005.7

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Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.

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ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas. Reviewed International journal

Yoshinao Oda, Tsuyoshi Saito, Naomi Tateishi, Yoshihiro Ohishi, Sadafumi Tamiya, Hidetaka Yamamoto, Ryohei Yokoyama, Takeshi Uchiumi, Yukihide Iwamoto, Michihiko Kuwano, Masazumi Tsuneyoshi

International journal of cancer   114 ( 6 )   854 - 62   2005.5

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The phenomenon of multidrug resistance (MDR) in various malignant neoplasms has been reported as being caused by one or multiple expressions of ATP-binding cassette (ABC) superfamily protein, including P-glycoprotein/multidrug resistance (MDR) 1 and the MDR protein (MRP) family. However, their expression levels and distribution within soft tissue sarcomas remain controversial. In 86 cases of surgically resected soft tissue sarcoma, intrinsic mRNA levels of MDR1, MRP1, MRP2 and MRP3 were assessed using a quantitative reverse transcriptase-PCR (RT-PCR) method. Moreover, immunohistochemical protein expressions of P-glycoprotein (P-gp), MRP1, MRP2, MRP3 and p53 protein were evaluated in concordant paraffin-embedded material. The mRNA expression and immunohistochemical expression of ABC superfamily transporters were compared to clinicopathologic parameters and proliferative activities as evaluated by the MIB-1-labeling index (LI). Among the various histologic types, malignant peripheral nerve sheath tumor (MPNST) showed significantly high levels of MDR1 (p=0.017) and MRP3 (p=0.0384) mRNA expression, compared to the other tumor types. When the immunohistochemical method was compared to the RT-PCR technique to assess ABC transported expression at the protein and mRNA levels, a significantly close relationship was found between the 2 methods (p<0.05). P-gp expression was significantly correlated with large tumor size (> or =5 cm, p=0.041) and high AJCC stage (stages III and IV) (p=0.0365). Furthermore, cases with nuclear expression of p53 revealed significantly higher levels of MDR1 mRNA expression, compared to those with negative immunoreaction for p53 (p=0.0328). Our results suggest that MDR1/P-gp expression may have an important role to play in tumor progression in the cases of soft tissue sarcoma, and p53 may be one of the active regulators of the MDR1 transcript. In addition, the high levels of both MDR1 and MRP3 mRNA expression in MPNST may help to explain the poor response of this tumor to anticancer-drugs.

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Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Tomonari Takahira, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology   36 ( 4 )   357 - 63   2005.4

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The PTEN/MMAC1 ( PTEN ) gene was identified as a tumor suppressor gene encoding a cytoplasmic protein that controls cellular processes. To investigate the potential role and the alteration of the PTEN gene in soft tissue sarcomas (STSs), we searched for homozygous deletion and promoter hypermethylation in a series of 48 STSs that was composed of malignant fibrous histiocytoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, including 2 cases with a mutation that we previously reported; differential polymerase chain reaction and methylation-specific polymerase chain reaction, respectively, were used for the analyses. Furthermore, to determine whether PTEN gene alterations are involved in the down-regulation of PTEN expression, we examined the expression of PTEN protein in 38 cases in which paraffin-embedded tissues were available for immunohistochemical analysis. In addition to our previous results showing that 2 (4%) of 51 cases had a PTEN mutation, promoter methylation was recognized in 6 (13%) of 48 cases, and homozygous deletion was detected in 1 (2%) of 48 cases in the current study. Of 6 cases with promoter methylation of PTEN gene, 5 were malignant peripheral nerve sheath tumor. Decreased expression of PTEN protein was recognized in 11 (29%) of 38 STS cases. Of 9 cases with PTEN alterations (6 cases with promoter methylation, 2 with mutation, and 1 with homozygous deletion), 3 (33%) showed decreased expression of PTEN protein. Furthermore, decreased expression of the PTEN gene showed a statistically significant correlation with high MIB-1 labeling index in 38 STS cases examined ( P = .0441). In conclusion, promoter methylation and homozygous deletion of the PTEN gene were found to be relatively rare events in cases of STS, as is mutation of the gene. Of 9 cases with a PTEN alteration, 3 (33%) showed a decrease in PTEN expression, indicating that PTEN gene alterations seem to play a minor role in the inactivation of PTEN in these tumors. Furthermore, although a further detailed analysis of a larger number of cases is still necessary, the present results suggest that PTEN expression may be a useful indicator of cell proliferation in patients with STS.

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Microsatellite instability and hMLH1 and hMSH2 expression analysis in soft tissue sarcomas. Reviewed International journal

Ken-Ichi Kawaguchi, Yoshinao Oda, Tomonari Takahira, Tsuyoshi Saito, Hidetaka Yamamoto, Chikashi Kobayashi, Sadafumi Tamiya, Shinya Oda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Oncology reports   13 ( 2 )   241 - 6   2005.2

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Alterations of the size of microsatellite DNA sequences, namely microsatellite instability (MSI), have been demonstrated in some types of malignancies. We analyzed the MSI of five microsatellite markers in 40 cases of soft tissue sarcoma (STS) using high resolution fluorescent microsatellite analysis. In addition, we examined the expression of hMLH1 and hMSH2 proteins of DNA mismatch repair (MMR) genes by immunohistochemistry, and promoter methylation of the hMLH1 gene by methylation-specific PCR (MSP). MSI was recognized in 10 of 40 STS cases (25%), which consisted of 2 MSH-high (MSI-H) tumors and 8 MSI-low (MSI-L) tumors. A loss of hMLH1 expression was recognized in 7 of 40 STS cases (18%), and loss of hMSH2 expression was recognized in 3 of 40 STS cases (8%). One case showed a loss of both hMLH1 and hMSH2 expression. Promoter hypermethylation of the hMLH1 gene was detected in only 3 of 40 STS cases (8%). Of 10 cases with MSI, 5 (50%) showed a loss of hMLH1 and/or hMSH2 expression. There was a statistically significant correlation between MSI-positive tumors and the loss of hMLH1 and/or hMSH2 expression (p=0.0286). Although the frequency of MSI (25%) or a loss of hMLH1 and/or hMSH2 expression (23%) was relatively low in STS cases, a loss of hMLH1 and/or hMSH2 was recognized in 5 out of 10 MSI-positive cases (50%). These findings suggest that the inactivation of MMR gene expression might be the cause of MSI in STS cases.

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Clinical value of serum squamous cell carcinoma antigen in the management of sinonasal inverted papilloma Reviewed

R Yasumatsu, T Nakashima, M Masuda, Y Kuratomi, H Shiratsuchi, N Hirakawa, K Tomita, T Yamamoto, S Komune

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK   27 ( 1 )   44 - 48   2005.1

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Background, Although sinonasal inverted papilloma (IP) is a rare benign tumor, it has a tendency to recur and is sometimes associated with squamous cell carcinoma (SCC). Therefore, postoperative long-term follow-up of these patients is recommended. We previously reported that serum SCC antigen might be a useful tumor marker for sinonasal IP. In this study, we investigated whether serum SCC antigen level has a correlation with disease status and is useful in the early detection of recurrent disease.
Methods. Blood samples for the analysis of serum SCC antigen were taken from 28 IP patients before and after surgical treatment.
Results. Twenty-five (89%) of 28 cases showed evaluated serum SCC antigen levels above the upper limit. This marker level decreased in all cases after surgical resection. Four of these patients had a recurrence. None of the patients with recurrent tumor showed symptoms at the time of detection of their recurrent tumor, and recurrence was discovered from elevated levels of SCC antigen.
Conclusions, Serum SCC antigen level has a correlation with disease status of IP and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management of sinonasal IPs. (C) 2004 Wiley Periodicals, Inc.

DOI： 10.1002/hed.20115

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E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Keishi Sugimachi, Hidetaka Yamamoto, Naomi Tateishi, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Marc Ladanyi, Masazumi Tsuneyoshi

Oncogene   23 ( 53 )   8629 - 38   2004.11

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We have recently reported frequent E-cadherin gene mutations in synovial sarcoma (SS), suggesting mutational inactivation of E-cadherin as a potential mechanism of spindle cell morphology in SS, a spindle cell sarcoma that shows areas of glandular epithelial differentiaton in some cases (biphasic SS) and only pure spindle cell morphology in most cases (monophasic SS). However, the mechanism of downregulation of E-cadherin in SS remains unknown. To further address this issue, we analysed the mechanisms of E-cadherin silencing in 40 SS. Genetic and epigenetic changes in the E-cadherin gene, and the expression level of its transcriptional repressor Snail were examined by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP), methylation-specific PCR, and real-time quantitative PCR, respectively. Expression of E-cadherin was examined by RT-PCR and immunohistochemistry. We also examined ELF3, a transcription factor associated with epithelial differentiation in SS in a previous cDNA microarray, by RT-PCR. E-cadherin and ELF3 transcripts were detected, respectively, in 27/40 (67.5%) and in 25/40 (62.5%) of SS, and these epithelial-related genes were almost always coexpressed. Hypermethylation of the promoter of the E-cadherin gene was detected in five cases (12.5%) in SS; however, E-cadherin was silenced at mRNA level in only one of the five cases. E-cadherin missense mutations were observed in five cases (12.5%) of SS. In SS, all five cases with E-cadherin missense mutations had the SYT-SSX1 fusion and were monophasic tumors, suggesting a relationship between the SYT-SSX fusion type and E-cadherin missense mutation (P=0.07). E-cadherin mRNA expression in SS was associated with reduced Snail expression level (P=0.03). E-cadherin membranous expression was observed in 14/40 (35.0%) of SS, and was also correlated with SYT-SSX1 fusion type and biphasic histology. ELF3 was confirmed to be more highly expressed in biphasic than monophasic SS by real-time quantitative PCR. These results suggest that in SS the loss of E-cadherin expression occurs either by Snail trans-repression or by inactivating mutations. Thus, E-cadherin downregulation is associated with the loss or absence of glandular epithelial differentiation in certain SS.

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Death-associated protein kinase (DAP kinase) alteration in soft tissue leiomyosarcoma: Promoter methylation or homozygous deletion is associated with a loss of DAP kinase expression. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology   35 ( 10 )   1266 - 71   2004.10

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The death-associated protein kinase (DAP kinase) was initially identified as a positive mediator of programmed cell death induced by interferon-gamma. To investigate the potential role and the alteration of the DAP kinase gene in soft tissue leiomyosarcoma (LMS), we first searched for homozygous deletion and promoter hypermethylation in 45 LMSs for which genomic DNA was available, using differential PCR and methylation-specific PCR, respectively. Promoter methylation was recognized in 10 of 45 cases (22%), and homozygous deletion was detected in 3 of 45 cases (7%). p53 mutation was detected in 11 of 45 LMS cases (24%). Cases with DAP kinase alteration or p53 mutation showed a close correlation with high French Federation of Cancer Centers grade or with poor prognosis (P = 0.0244, P = 0.0491, respectively). Next, to determine that DAP kinase promoter methylation or homozygous deletion is involved in the down-regulation of DAP kinase expression, we examined the expression of DAP kinase protein by immunohistochemistry. Decreased expression of DAP kinase protein was recognized in 13 of 45 LMS cases (29%). Seven of 13 cases (54%) with decreased expression of DAP kinase protein revealed promoter methylation or homozygous deletion of DAP kinase, and the methylation status or homozygous deletion of its gene showed a close correlation with decreased DAP kinase expression (P = 0.0300). In conclusion, although DAP kinase alteration was relatively rare, DAP kinase alteration and/or p53 mutation may associate with tumor progression in soft-tissue LMSs. Furthermore, although further detailed analyses are necessary, promoter methylation or homozygous deletion status of DAP kinase may present a major alternative mechanism of a loss of or decrease in DAP kinase expression.

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Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kawaguchi, Chikashi Kobayashi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Cancer science   95 ( 8 )   651 - 5   2004.8

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Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a poor prognosis. It has become apparent through immunohistochemical, ultrastructural, and microarray analyses that CCS is a soft tissue melanocytic neoplasm. Alterations in the p16INK4a/p14ARF gene are common in malignant melanoma, which is the prototypical melanocytic neoplasm. In the present study, we performed a clinicopathologic analysis and investigated p16 and cyclin D1 expression by immunohistochemistry in 14 cases. Furthermore, we investigated genetic changes of various tumor suppressor genes and an oncogene, including p16INK4a/p14ARF, p53, beta-catenin, and APC, in 11 cases. The 5-year overall survival rate in all the patients was 33.3%. A high mitotic rate was a significant adverse prognostic factor (P = 0.004). Decreased expression of p16 was observed in 4 (28.6%) of 14 cases. Overexpression of cyclin D1 was observed in 9 cases (64.3%). SSCP analysis followed by DNA direct sequencing revealed point mutations of the p16INK4a gene in 2 of 11 cases (18.2%). In addition, one case with the p14ARF mutation and 2 cases with the p53 mutation were observed. None of the cases harbored mutation of the beta-catenin or APC gene. Homozygous deletion of the p16INK4a/p14ARF gene was detected in one case. Methylation-specific PCR did not reveal hypermethylation of the p16INK4a/p14ARF promoter region in any of the cases. Three cases harbored genetic alterations of the p16INK4a/p14ARF gene (27.3%). All tumors with genetic alterations of the p16INK4a/p14ARF or p53 gene showed a high mitotic rate or tumor necrosis. These alterations were considered to be influential in the poor prognosis of CCS patients.

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Low-grade fibromyxoid sarcoma versus low-grade myxofibrosarcoma in the extremities and trunk. A comparison of clinicopathological and immunohistochemical features

Y Oda, T Takahira, K Kawaguchi, H Yamamoto, S Tamiya, S Matsuda, K Tanaka, Y Iwamoto, M Tsuneyoshi

HISTOPATHOLOGY   45 ( 1 )   29 - 38   2004.7

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Aims: Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive variant of fibrosarcoma and has been reported to have metastatic potential despite its low-grade histological findings. Low-grade myxofibrosarcoma (MFS) is an important differential diagnosis of LGMFS, because it shows different biological behaviour. Of 75 MFSs in the extremities and trunk, we defined 22 grade 1 tumours as low-grade MFS according to the French Federation of Cancer Centres grading system and compared the clinicopathological factors and immunohistochemical expression of cell cycle regulators with those of 11 LGFMSs.
Methods and results: The two entities could be distinguished on histological grounds. Low-grade MFS was characterized by the presence of prominent elongated, curvilinear capillaries and pseudolipoblasts, accompanied by an abundant myxoid matrix. It had no extensive solid areas. LGFMS was composed of bland spindle cells arranged in a whorled pattern with alternating myxoid and fibrous stroma. Curvilinear capillaries were not prominent and cytological atypia was absent. No tumour necrosis was observed in any of the 11 LGFMSs, whereas only one case showed tumour necrosis in less than 50% of the tumour in 22 low-grade MFSs. The patients with low-grade MFS were significantly older than those with LGFMS (low-grade MFS average, 60.1 years; LGFMS average, 31.5 years; P &lt; 0.0001) and low-grade MFS occurred more frequently in a superficial location (low-grade MFS 14/20; LGFMS 2/11; P = 0.0077). As for cell cycle regulator expression, the MIB-1 labelling index (LI) (14.76 on average) and cyclin E LI (11.55 on average) in low-grade MFS were significantly higher than those (MIB-1 LI, 4.68 on average; cyclin E LI, 3.38 on average) of LGFMS, while p21 LI (25.53 on average) and p27 LI (42.68 on average) in low-grade MFS were significantly lower than those (p21 LI, 42.74 on average; p27 LI, 57.28 on average) of LGFMS.
Conclusions: We conclude that low-grade MFS and LGFMS are distinctly different clinicopathological entities and the assessment of the immunohistochemical expression of MIB-1, cyclin E, p21 and p27 as well as conventional clinicopathological features may be helpful to distinguish low-grade MFS from LGFMS.

DOI： 10.1111/j.1365-2559.2004.01886.x

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Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. Reviewed International journal

Yukiko Takahashi, Yoshinao Oda, Ken-Ichi Kawaguchi, Sadafumi Tamiya, Hidetaka Yamamoto, Sachiyo Suita, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   17 ( 6 )   660 - 9   2004.6

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Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

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