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Papers - KANAI Yae

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Correlation of DNA hypomethylation at pericentromeric heterochromatin regions of chromosomes 16 and 1 with histological features and chromosomal abnormalities of human breast carcinomas.

Tsuda H, Takarabe T, Kanai Y, Fukutomi T, Hirohashi S.

Am J Pathol (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 161 ( 3 ) 859 - 866 2002

Accepted, ISSN 00029440

Changes in DNA methylation status are not only important for regulating gene expression but are also suggested to induce chromosome instability. To reveal the correlation of DNA methylation status in heterochromatin regions with tumor histology and with chromosome alterations, DNA methylation status was examined by Southern blot analysis, and numerical and structural chromosome alterations, including the formation of der(16)t(1;16)/der(1;16), were examined by fluorescence in situ hybridization at the two loci in the pericentromeric satellite 2 regions of chromosomes 16 and 1 in 39 human breast carcinomas. DNA hypomethylation at the D16Z3 and the D1Z1 loci was detected in 31% (12 of 39) and 36% (12 of 33) of carcinomas, respectively, and mostly concurred. DNA hypomethylation was more frequent in the carcinoma group of more aggressive histological types or grade 3 than in the carcinoma of less aggressive histological types or grades 1 and 2, and tended to be more frequent in carcinomas with greater than or equal to4 copies of chromosomes 16 and/or 1 than in carcinomas with less than or equal to3 copies of any of these chromosomes. The frequency of DNA hypomethylation at the D16Z3 and the D1Z1 loci was 45% (10 of 22) and 53% (9 of 17) in carcinomas without der(16)t(1;16)/der(1;16), formation, but only 12% (2 of 17) and 19% (3 of 16) in carcinoma with der(16)t(1;16)/der(1;16), respectively (P = 0.036 and 0.070). The 16q breakage was almost equally detected between carcinoma groups with and without the DNA hypomethylation. DNA hypomethylation in the satellite 2 regions was suggested to be associated with the accumulation of a large number of numerical chromosome alterations and involved in the development of breast carcinomas of aggressive histological features. on the contrary, chromosome instability induced by mechanisms other than DNA hypomethylation in heterochromatin regions might cause the formation of der(16)t(1;16)/der(1;16) and less aggressive breast carcinomas.

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DNA methylation

Kanai Y

Nippon rinsho. Japanese journal of clinical medicine (Nippon rinsho. Japanese journal of clinical medicine) 59 Suppl 6 142 - 146 2001.10

ISSN 00471852

DNA methyltransferase expression and DNA methylation of CpG islands and peri-centromeric satellite regions in human colorectal and stomach cancers.

Kanai Y, Ushijima S, Kondo Y, Nakanishi Y, Hirohashi, S.

Int J Cancer (International Journal of Cancer) 91 ( 2 ) 205 - 212 2001

Accepted, ISSN 00207136

We evaluated the significance of aberrant DNA methyltransferase expression in human carcinogenesis by examining 32 colorectal and 34 stomach cancers. Levels of mRNAs encoding DNA methyltransferases were measured by reverse transcription, followed by real-time quantitative detection of PCR products. The DNA methylation state of CpG islands and peri-centromeric satellite regions was examined by bisulfite modification and Southern blotting, respectively. The average level of mRNA for DNMTI and DNMT3b in colorectal and stomach cancers was significantly higher than in corresponding non-cancerous mucosae, whereas the average level of mRNA for DNMT2 was significantly lower in colorectal and stomach cancers than in non-cancerous tissue. Over-expression of DNMT3b in stomach cancer was significantly higher in cases with lymph node metastasis than in cases without. DNA hypermethylation on the p16, human Mut L homologue-1 and thrombospondin-1 genes and the methylated in tumor (MINT) 1, 2, 12, 25 and 31 clones was found in 23%, 27%, 9%, 23%, 20%, 23%, 20% and 10% of the colon cancers and in 9%, 19%, 30%, 25%, 34%, 19%, 81% and 3% of the stomach cancers, respectively. Criteria for identification of the CpG island methylator phenotype (CIMP) were met in 23% of colorectal cancers and 31% of stomach cancers. DNA hypomethylation on satellites 2 and 3 was detected in 0% and 8% of colorectal and stomach cancers, respectively. Over-expression of DNMTI mRNA was significantly associated with CIMP, whereas the level of DNMT3b mRNA was not associated with CIMP or DNA hypomethylation of pericentromeric satellite regions. These data suggest that both over-expression of the maintenance DNA methyltransferase DNMTI and over-expression of a newly identified de novo DNA methyltransferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms. © 2001 Wiley-Liss, Inc.

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Intraductal papillary components in invasive ductal carcinoma of the pancreas are associated with long-term survival of patients.

Fukushima N, Sakamoto M, Mukai K, Kanai Y, Shimada K, Kosuge T, Hirohashi S.

Hum Pathol (W B SAUNDERS CO) 32 ( 8 ) 834 - 841 2001

Accepted, ISSN 00468177

Most patients with pancreatic ductal carcinoma have a poor prognosis. However, in certain cases, 5-year survival can be achieved after surgical resection. Analysis of the pathologic findings associated with good survival rates will assist in identifying the optimum treatment. The clinicopathologic features of 67 patients who underwent surgical resection of ductal adenocarcinoma of the pancreas between 1990 and 1996 were reviewed and correlated with survival rates. There were 42 men and 25 women, with a mean age of 62.1 years (range, 44 to 82 years). The mean greatest diameter of the tumor was 4.3 cm (range, 1.5 to 11 cm). Nineteen patients (29.4%) survived more than 3 years, and 9 (13.2%) survived more than 5 years after surgical resection. The intraductal papillary component (IDPC) of the carcinoma was the main focus of the pathologic observations. IDPC was defined as intraductal papillary proliferative lesions seen in the tumor nodule with proliferative cells consistent with carcinomatous cellular atypia. IDPC was clearly present (++) in 24 patients and vaguely present (+) in 9 patients. Using the Mantel-Cox test, a statistically significant correlation was found between the presence of IDPC (either + or ++) and postoperative patient survival (P = .002). IDPC is a morphologic feature associated with longer patient survival and should be taken into consideration in assessing the pathway of tumor progression. HUM PATHOL 32;834-841. (C) 2001 by W.B. Saunders Company.

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Expression of cadherins and their undercoat proteins (α-, β-, and γ-catenins and p120) and accumulation of β-catenin with no gene mutations in synovial sarcoma.

Sato H, Hasegawa T, Kanai Y, Tsutsumi Y, Osamura Y, Abe Y, Sakai H, Hirohashi S.

Virchows Arch (Virchows Archiv) 438 ( 1 ) 23 - 30 2001

Accepted, ISSN 09456317

E-cadherin, the major intercellular adhesion molecule of epithelial cells, is important in determining the architecture of sarcomas, especially those showing epithelioid features. In addition to its role in cell adhesion, β-catenin, a cadherin undercoat protein, has been shown to function as a downstream transcriptional activator of the Wnt/Wingless signaling pathway. In order to evaluate the significance of the cadherin cell adhesion system and the Wnt/Wingless signaling pathway in the morphogenesis and/or tumorigenesis of synovial sarcoma (a major type of sarcoma with epithelioid features), immunoreactivity for pan-cadherin, E-cadherin, and their undercoat proteins (α-, β-, and γ-catenins and p120) was evaluated in 15 synovial sarcomas. Immunoreactivity for pan-cadherin, E-cadherin, α-catenin, β-catenin, and p120 was observed in all 15 specimens. Immunoreactivity for pan-cadherin was stronger than that for E-cadherin. Expression of γ-catenin was detected in ten specimens. Although β-catenin was observed only at the cell-cell boundaries in four specimens, it was present in the nucleus and cytoplasm and at the cell-cell boundaries in the other 11, suggesting constitutional activation of the Wnt/Wingless signaling pathway in synovial sarcoma. Direct sequencing for exon 3 of the β-catenin gene, however, revealed no mutations in any of the 15 specimens. In conclusion, other types of cadherin besides E-cadherin, together with cadherin undercoat proteins, may play a role in cell adhesion in synovial sarcoma. Furthermore, mechanisms other than mutation of exon 3 of the β-catenin gene may activate the Wnt/Wingless signaling pathway in this type of tumor.

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Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis.

Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S.

Hepatology (W B SAUNDERS CO) 33 ( 3 ) 561 - 568 2001

Accepted, ISSN 02709139

To evaluate the significance of alterations in DNA methylation during human hepatocarcinogenesis, we examined levels of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and the DNA methylation status in 67 hepatocellular carcinomas (HCCs), The average level of mRNA for DNMT1 and DNMT3a was significantly higher in noncancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal liver tissues, and was even higher in HCCs. Significant overexpression of DNMT3b and reduced expression of DNMT2 were observed in HCCs compared with the corresponding noncancerous liver tissues. DNA hypermethylation on CpG islands of the p16 (8% and 66%) and hMLH1 (0% and 0%) genes and methylated in tumor (MINT) 1 (6% and 34%), 2 (24% and 58%), 12 (21% and 33%), 25 (0% and 5%), and 31 (0% and 23%) clones, and DNA hypomethylation on satellites 2 and 3 (18% and 67%), were detected in noncancerous liver tissues and HCCs, respectively. There was no significant correlation between the expression level of any DNA methyltransferase and DNA methylation status. Reduced expression of DNA repair protein, MBD4, was significantly correlated with poorer tumor differentiation and involvement of portal vein. Slightly reduced expression of MBD2 was detected in HCCs, and the expression of MeCP2 was particularly reduced in HCCs with portal vein involvement. These data suggest that overexpression of DNMT1 and DNMT3a, DNA hypermethylation on CpG islands, and DNA hypomethylation on pericentromeric satellite regions are early events during hepatocarcinogenesis, and that reduced expression of MBD4 may play a role in malignant progression of HCC.

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mRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers.

Kanai Y, Ushijima S, Saito Y, Nakanishi Y, Sakamoto M, Hirohashi S.

J Cancer Res Clin Oncol (SPRINGER-VERLAG) 127 ( 12 ) 697 - 706 2001

Accepted, ISSN 01715216

Objective: We attempted to identify tumor-related genes whose expression is affected by DNA methylation and that participate in the determination of the biological characteristics of human cancers. Methods and materials: We used the differential display method in ten 5-azacytidine-treated human cancer cell lines. Time-dependent induction of mRNA expression of Wip1. TROP2, B4-2 protein, BRCA-2 region transcription unit CG005, cofilin, ROCK, CD44, and interferon-inducible protein 6-16 was observed during 5-azacytidine treatment. We then evaluated the mRNA expression of these genes in 26 stomach and 32 colorectal cancers and 44 hepatocellular carcinomas (HCCs) and in the corresponding non-cancerous tissues. Results Significantly reduced rn RNA expression of Wip1, B4-2, and cofilin in stomach cancers, of Wip1, B4-2, BRCA-2 region transcription unit CG005, cofilin, and ROCK in colorectal cancers, and of TROP2, B4-2, and BRCA-2 region transcription unit CG005 in HCCs, was observed in comparison with the corresponding non-cancerous tissues, whereas overexpression of TROP2 was detected in colorectal cancers. Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement. Expression of TROP2 mRNA was significantly higher in chronically diseased liver from HCC patients compared with histologically normal liver, but was reduced in progressed HCCs. Reduced expression of B4-2 protein was observed in association with hepatitis B virus infection of HCC patients. Conclusions: These data suggest that DNA methylation may play a role in human multistage carcinogenesis through direct or indirect regulation of multiple tumor-related genes.

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Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis.

Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Hirohashi S.

Cancer Lett (Cancer Letters) 148 ( 1 ) 73 - 80 2000

Accepted, ISSN 03043835

The aim of this study was to examine the significance of aberrant DNA methylation, the participation of which in genetic instability is controversial, in hepatocarcinogenesis. The DNA methylation status of the region around the promoter of the E-cadherin tumor suppresser gene, which is located on 16q22.1, and the allelic status at the D16S421 locus, which is adjacent to the E-cadherin locus, were examined using microdissected liver specimens from 38 hepatocellular carcinoma (HCC) patients. Almost all of the non-cancerous liver tissues showed histological findings compatible with chronic hepatitis and cirrhosis, which are considered to be precancerous conditions. DNA hypermethylation was detected in 61% of the non-cancerous liver tissues. The incidence of DNA hypermethylation in the non-cancerous liver tissues of patients with HCCs also showing DNA hypermethylation (72%) was significantly higher than that of patients without DNA hypermethylation in their HCCs (53%, P<0.05). Loss of heterozygosity (LOH) at the D16S421 locus was detected in 35% of the non-cancerous liver tissues. The incidence of LOH in the non-cancerous liver tissues of patients with HCCs also showing LOH was 78%, whereas LOH was not detected in non-cancerous liver tissues of patients without LOH in their HCCs. Fifty-two percent of the non-cancerous liver tissues showed both or neither of DNA hypermethylation and LOH; the incidence of DNA hypermethylation alone in non-cancerous liver tissue was 41%. The incidence of LOH alone in non-cancerous liver tissue (7%) was significantly lower compared to those of the former two cases (P<0.0001). These data suggest that aberrant DNA methylation participates in the precancerous stage of hepatocarcinogenesis by preceding, or causing, LOH. Copyright (C) 2000 Elsevier Science Ireland Ltd.

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GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas.

Tchou JC, Lin X, Freije D, Isaacs WB, Brooks JD, Rashid A, De Marzo AM, Kanai Y, Hirohashi S, Nelson WG.

Int J Oncol 16 663 - 676 2000

Accepted

Signet-ring cell carcinoma of the urinary bladder associated with transitional cell carcinoma of the right ureter.

Kume H, Kanai Y, Tobisu K, Fujimoto H, Tomita K, Kakizoe T.

Scand J Urol Nephrol 34 278 - 279 2000

Accepted

Multistep carcinogenesis and DNA methylation.

Hirohashi S, Kanai Y.

Princess Takamatsu Symp 31 5 - 10 2000

Aberrant expression of β-catenin and mutation of exon 3 of the β-catenin gene in renal and urothelial carcinomas.

Zhu X, Kanai Y, Saito A, Kondo Y, Hirohashi S.

Pathol Int (Pathology International) 50 ( 12 ) 945 - 952 2000

Accepted, ISSN 13205463

The present study attempted to clarify the significance of aberrant expression of β-catenin protein and mutation of exon 3 of the β-catenin gene in renal and urothelial carcinogenesis. β-Catenin expression was examined immunohistochemically and mutation of the β-catenin gene was analyzed by polymerase chain reaction-single strand conformation polymorphism (SSCP) and direct sequencing. β-Catenin immunoreactivity was observed at the cell membrane in all 30 renal cell carcinomas (RCC) examined, and no RCC showed a mobility-shifted SSCP band. Of 46 transitional cell carcinomas (TCC) examined, there was reduced expression of β-catenin, as compared with its expression in non-cancerous transitional epithelium, in 22 cases (48%) and catenin accumulation in the nucleus in five cases (11%). Of four renal pelvis TCC examined, point mutation of exon 3 of the β-catenin gene at codon 45 resulting in amino acid substitution (Ser to Phe) was detected in one (25%). The incidence of reduced expression of β-catenin correlated significantly with the growth pattern (superficial type vs invasive type) of TCC (P < 0.05). These data indicate that: (1) aberrant β-catenin expression may be at least partly involved in urothelial carcinogenesis, but less significantly so in renal carcinogenesis, and (2) it may be associated with the progression of TCC showing invasive growth.

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Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis--A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from ---

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S.

Hepatology 32 970 - 979 2000

Accepted

Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis - A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma

Kondo Y., Kanai Y., Sakamoto M., Mizokami M., Ueda R., Hirohashi S.

Hepatology (Hepatology) 32 ( 5 ) 970 - 979 2000

ISSN 02709139

A study was conducted to examine the significance of genetic instability and aberrant DNA methylation during hepatocarcinogenesis. Genomic DNA was extracted from 196 microdissected specimens of noncancerous liver tissue that showed no marked histologic findings or findings compatible with chronic hepatitis or cirrhosis, and 80 corresponding microdissected specimens of hepatocellular carcinoma (HCC) from 40 patients. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were examined by polymerase chain reaction (PCR) using 39 microsatellite markers, and DNA methylation status on 8 CpG islands was examined by bisulfite-PCR. In noncancerous liver tissues, LOH, MSI, and DNA hypermethylation were found in 15 (38%), 6 (15%), and 33 (83%) of 40 cases, respectively. The incidence of DNA hypermethylation in histologically normal liver was similar to that in chronic hepatitis and cirrhosis, although neither LOH nor MSI was found in histologically normal liver. In cancerous tissues, LOH, MSI, and DNA hypermethylation were found in 39 (98%), 8 (20%), and 40 (100%) of 40 cases, respectively. CpG islands of the p16 gene and methylated in tumor 1, 2, 12, and 31 clones were frequently methylated in cancerous tissues, although neither the thrombospondin-1 nor the human Mut L homologue (hMLH1) gene was methylated. Absence of silencing of the hMLH1 gene by DNA hypermethylation is consistent with the low incidence of MSI in HCCs. The results of this study indicate that LOH and aberrant DNA methylation contribute to hepatocarcinogenesis; DNA hypermethylation in particular, which precedes or may even cause LOH, is as an early event during hepatocarcinogenesis.

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Resection of liver metastases after pancreatoduodenectomy: Report of seven cases

Fujii K., Yamamoto J., Shimada K., Kosuge T., Yamasaki S., Kanai Y.

Hepato-Gastroenterology (Hepato-Gastroenterology) 46 ( 28 ) 2429 - 2433 1999.10

ISSN 01726390

There has been no English report of a long survivor after hepatectomy for metastasis from peri-ampullary malignancies, who had previously undergone pancreatoduodenectomy (PD) for primary disease. Herein, we report 7 patients of liver metastases who underwent 8 hepatectomies after PD for peri-ampullary malignancies. One patient whose liver metastasis was neuroendocrine tumor, survived 2 years and 6 months without recurrence after hepatectomy. Another patient who had 2 hepatectomies for metastasis from duodenal leiomyosarcoma survived for 3 years and 20 days after the first hepatectomy. Procedure of hepatectomy comprised 4 limited resections (including 1 second hepatectomy) and 4 lobectomies at the first resection. Hepatic inflow clamp was used in 6 out of 8 hepatectomies and 4 out of 8 hepatectomies did not require allogeneic blood transfusion. Bacterial contamination of the drained discharge from the cut surface of the liver, mostly representative of enteric organisms, was identified in all but 2 patients who were not examined. Subphrenic abscesses developed in 2 patients after removal of the drains. Thus, prophylactic use of abdominal drain is indispensable after hepatectomy for the patients with bilioenteric anastomosis.

DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis.

Kanai Y, Hui AM, Sun L, Ushijima S, Sakamoto M, Tsuda H, Hirohashi S.

Hepatology (Hepatology) 29 ( 3 ) 703 - 709 1999

Accepted, ISSN 02709139

To examine the significance of aberrant DNA methylation in hepatocarcinogenesis, the DNA methylation status at the D17S5 locus and mRNA expression of a candidate tumor suppressor gene, HIC-1 (hypermethylated-in- cancer), which was identified at the D17S5 locus, in primary hepatocellular carcinomas (HCCs) and their corresponding noncancerous liver tissues were assessed. DNA hypermethylation at the D17S5 locus was detected in 44% of the noncancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in noncancerous liver tissues showing no remarkable histological findings. The incidence of DNA hypermethylation at this locus was significantly higher in HCCs (90%) than noncancerous liver tissues (P < .001). Loss of heterozygosity at the D17S5 locus, which was preceded by DNA hypermethylation at the same locus, was detected in 54% of HCCs. The HIC-1 mRNA expression level of noncancerous liver tissues showing chronic hepatitis or cirrhosis was significantly lower than that of noncancerous liver tissues showing no remarkable histological findings (P < .01), and that of HCCs was even lower than that of noncancerous liver tissues (P < .05). Poorly differentiated HCCs showed lower expression levels than well- to moderately differentiated HCCs. Mutation of the p53 gene may be involved in HIC-1 inactivation. Moreover, wild-type p53 did not overcome DNA hypermethylation at the D17S5 locus to activate HIC-1 in HCCs. These data suggest that aberrant DNA methylation at this locus and reduced HIC-1 mRNA expression participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs.

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Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma.

Kuno T, Fukutomi T, Akashi-Tanaka S, Nanasawa T, Kanai Y, Tsuda H, Nomizu T, Miki Y.

Breast Cancer (Breast Cancer) 6 ( 1 ) 51 - 54 1999

Accepted, ISSN 13406868

A 34-year-old premenopausal woman developed asynchronous bilateral nonpalpable breast cancers at the age of 32 and 34 years. She had undergone amputation of her left lower leg because of osteosarcoma at the age of 16. Her mother had been diagnosed with breast cancer at the age of 45. The clinicopathological features of the two breast tumors in this patient closely resembled each other; both were nonpalpable, and detectable only by helical CT scan. Histologically, they consisted mainly of an intraductal component with small grade 3 invasive foci. In addition, both tumors estrogen receptor (ER) status was negative, and both were positive for c-erbB-2 protein on immunohistochemical staining. A missense germ line mutation of BRCA2 (exon 25 codon 3118; Met31 1 8Thr) was detected in this patient. These data may provide useful information on the carcinogenesis and biological behavior of breast cancers which develop in patients with BRCA2 germ line mutations.

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β-catenin accumulation and mutation of exon 3 of the β-catenin gene in hepatocellular carcinoma.

Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, Hirohashi S.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 90 ( 12 ) 1301 - 1309 1999

Accepted, ISSN 09105050

A study was conducted to clarify the contribution of β-catenin accumulation and mutation of the β-catenin gene to hepatocarcinogenesis. β-Catenin accumulation was examined immunohistochemically in 38 paired samples of hepatocellular carcinoma (HCC) and corresponding non-cancerous liver tissue. Gene mutation was analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing using intronic primers encompassing exon 3. Neither accumulation nor mutation was detected in non-cancerous liver tissues that showed no remarkable histological features, chronic hepatitis or liver cirrhosis. Accumulation of β-catenin was seen in the nucleus, cytoplasm or cell membrane in 15 of 38 (39%) HCC samples, and gene mutation was seen in 9 of 38 (24%) HCC samples. Although there was a significant correlation between accumulation and mutation (P < 0.01), six HCCs without mutation also showed accumulation. Samples of early HCC showed neither accumulation nor mutation, and accumulation and mutation were each correlated significantly with portal vein tumor involvement (P < 0.05). The present results indicate that (1) mutation of exon 3 of the β-catenin gene can lead to β-catenin accumulation, although other mechanisms of accumulation may also operate in HCC, and (2) β-catenin accumulation and mutation of the β-catenin gene are not early events in hepatocarcinogenesis, and may be associated with the malignant progression of HCC.

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Synovial sarcoma, histologically mimicking primitive neuroectodermal tumor/Ewing's sarcoma at distant sites.

Masui F, Matsuno Y, Yokoyama R, Nakanishi Y, Hasegawa T, Kanai Y, Beppu Y, Hirohashi S, Fujii K, Shimoda T.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 29 ( 9 ) 438 - 441 1999

Accepted, ISSN 03682811

We report a case of synovial sarcoma (SS) showing unusual histology at distant sites. A 47-year-old man was aware of a tumor on the sole of his left foot. After preoperative chemotherapy with a diagnosis of SS, wide excision was performed. During postoperative chemotherapy, multiple tumorous lesions developed in the bone (including the whole spine) and both lungs. The patient died 1 year later. Histologically, the excised tumor of the foot showed a biphasic cellular pattern typical of SS, whereas at autopsy the bone and lung lesions were composed only of undifferentiated small round cells with cytoplasmic fibrillar processes. Homer-Wright rosettes were also observed. Immunohistochemically, 80% of the bone and lung tumor cells expressed MIC2 protein homogeneously. To clarify whether the bone and lung round cell tumors were metastatic lesions or second malignancies, especially primary primitive neuroectodermal tumor (PNET)/Ewing's sarcoma (ES), we performed reverse transcription-polymerase chain reaction (RT-PCR) analysis of tumor type-specific fusion gene transcripts. The SYT/SSX fusion transcript was identified in both the foot and lung lesions, whereas the EWS/FLI1 transcript was not detected in either lesion. Therefore, we concluded that the multiple bone and lung tumors were poorly differentiated metastatic tumors, which arose from the SS of the foot. We also conclude that the identification of chimeric fusion transcripts can be successfully applied to poorly differentiated sarcomas and will help in the differential diagnosis of tumors that cannot be distinguished by conventional morphological examinations. Also, it should be remembered that cytoplasmic staining for MIC2 protein may occur in sarcomas other than PNET/ES. © 1999 Foundation for Promotion of Cancer Research.

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Microsatellite instability associated with hepatocarcinogenesis.

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi, S.

J Hepatol (Journal of Hepatology) 31 ( 3 ) 529 - 536 1999

Accepted, ISSN 01688278

Background/Aims: The biological and clinicopathological significance of microsatellite instability in hepatocellular carcinoma still remains to be determined. The aim of this study was to assess the role of microsatellite instability in hepatocarcinogenesis. Methods: Genomic DNA extracted from 38 fresh samples of hepatocellular carcinoma was amplified by polymerase chain reaction using 29 fluorescence-labeled microsatellite markers and analyzed using a semi-automated laser scanning system. Associations between the incidence of replication error and the clinicopathological features of hepatocellular carcinoma were evaluated. Since reference DNA was extracted from corresponding fresh samples of non-cancerous liver tissue, the incidence of microsatellite instability in non-cancerous liver tissues was not assessed in this study. Results: Four (11%) hepatocellular carcinomas had a replication error in one or two microsatellite markers; they were all poorly differentiated hepatocellular carcinomas. The incidence of replication error correlated significantly with the histological differentiation of the tumor (p<0.05) and with portal vein involvement (p<0.05). All four hepatocellular carcinomas with replication errors showed loss of heterozygosity in one or more of the 29 markers we examined. No replication errors were detected in six markers in the coding regions of the BAX, insulin-like growth factor II receptor, transforming growth factor-beta type II receptor, E2F-4, hMSH3 and hMSH6 genes. Conclusions: The results of this study indicate that: (1) microsatellite instability is a rare event during hepatocarcinogenesis and may be specifically associated with progression of hepatocellular carcinoma; and (2) frame-shift mutation in the above six genes is not a common mechanism involved in progression of this cancer.

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