Naoshi Nishida
Research interests
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InterestsHepatocellular carcinoma, Liver Cancer, Hepatitis B, Hepatitis C, Viral Hepatitis, HCV
Publications
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10.84Impact points
Characteristic pattern of DNA methylation alterations predict emergence of human hepatocellular carcinoma.
Hepatology (Baltimore, Md.). 03/2012;
We aimed to identify the specific subset of tumor suppressor genes (TSGs) that are methylation-silenced during the earliest steps of hepatocarcinogenesis, and to further evaluate whether these genes can serve as predictive biomarkers of HCC emergence. A total of 482 liver tissues including 177 pairs... [more] We aimed to identify the specific subset of tumor suppressor genes (TSGs) that are methylation-silenced during the earliest steps of hepatocarcinogenesis, and to further evaluate whether these genes can serve as predictive biomarkers of HCC emergence. A total of 482 liver tissues including 177 pairs of HCCs and matched non-tumor livers and 128 liver biopsies from chronic hepatitis C (CHC) patients were analyzed for quantitative methylation analysis in 24 tumor suppressor gene (TSG) promoters and 3 MINT loci. The tumors were classified as early, less-progressed, and highly-progressed HCCs using histology and radiological approaches. A subset of TSGs, which harbored distinctly high levels of methylation in early HCCs were selected. Based upon the methylation profiles of these genes, Kaplan-Meier analyses were performed to determine time-to-HCC occurrence in CHC patients. Subsequently, multivariate analysis was performed using age, gender, fibrosis stage and number of methylated TSGs as covariates. Among TSGs analyzed, a subset of 8 TSGs (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3 and PRDM2) demonstrated a distinct cluster by hierarchical clustering and receiver operating characteristic analyses. This subset of TSGs showed significantly higher methylation levels in the early HCCs (p < 0.0001). In the CHC patients, methylation frequencies in these TSGs were associated with shorter time-to-HCC occurrence (p < 0.0001), and number of methylated genes was an independent risk factor for HCC (hazard ratio = 5.21, 95% CI = 2.25 - 11.76, p = 0.0002). CONCLUSION: Epigenetic inactivation of a subset of TSGs plays a critical role in the earliest steps of hepatocarcinogenesis. Furthermore, epigenetic inactivation of these genes in CHC provides a prognostic value for determining the risk for developing HCC later in life. (HEPATOLOGY 2012.).
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1.08Impact points
Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review.
Current genomics. 04/2011; 12(2):130-7.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs emerge in the background of a chronic liver disease, such as chronic hepatitis and liver cirrhosis. The current understanding is th... [more] Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs emerge in the background of a chronic liver disease, such as chronic hepatitis and liver cirrhosis. The current understanding is that majority of HCCs evolve as a consequence of chronic inflammation and due to the presence of infection with hepatitis viruses. These underlying pathogenic stimuli subsequently induce a spectrum of genetic and epigenetic alterations in several cancer-related genes, which are involved in cell-cycle regulation, cell growth and adhesion. Such widespread genomic alterations cause disruption of normal cellular signaling and finally lead to the acquisition of a malignant phenotype in HCC. In general, the type of gene alterations, such as point mutations, deletion of chromosomal regions and abnormal methylation of gene promoters differ according to the individual targeted gene. In HCC, incidence of genetic alterations is relatively rare and is limited to a subset of few cancer-specific genes, such as the tumor suppressor p53, RB genes and oncogenes such as the CTNNB1. In contrast, epigenetic changes that involve aberrant methylation of genes and other post-transcriptional histone modifications occur far more frequently, and some of these epigenetic alterations are now being exploited for the development of molecular diagnostic signatures for HCC. In addition, recent findings of unique microRNA expression profiles also provide an evidence for the existence of novel mechanisms for gene expression regulation in HCC. In this review article, we will review the current state of knowledge on the activation of various oncogenic pathways and the inactivation of tumor suppressor pathways in HCC that result in the disruption of cancer-related gene function. In addition, we will specifically emphasize the clinical implication of some of these genetic and epigenetic alterations in the management of hepatocarcinogenesis.
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9.36Impact points
Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease.
Gut. 04/2010; 59(4):542-5.
We report a case of immunoglobulin G4 (IgG4)-related sclerosing disease involving the pancreas, liver and salivary glands. Massive infiltration of IgG4-expressing plasma cells was seen in the liver and submandibular lymph nodes. Interestingly, accumulation of IgG4-expressing plasma cells was also se... [more] We report a case of immunoglobulin G4 (IgG4)-related sclerosing disease involving the pancreas, liver and salivary glands. Massive infiltration of IgG4-expressing plasma cells was seen in the liver and submandibular lymph nodes. Interestingly, accumulation of IgG4-expressing plasma cells was also seen in the colon and terminal ileum. Peripheral blood mononuclear cells (PBMCs) isolated from this patient exhibited enhanced production of IgG4 and interleukin-10 upon stimulation with Toll-like receptor (TLR) ligands as compared with those from a healthy control. In contrast, production of tumour necrosis factor alpha and interferon gamma by PBMCs from this patient was markedly reduced. Since colonic mucosa is always exposed to TLR ligands derived from commensal organisms, the results of immunological studies suggest that enhanced T helper type 2 responses to intestinal microflora may underlie the immunopathogenesis in this patient with IgG4-related sclerosing disease.
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14.07Impact points
Analysis of Fecal DNA Methylation to Detect Gastrointestinal Neoplasia.
Journal of the National Cancer Institute. 08/2009;
Background The development of noninvasive screening tests is important to reduce mortality from gastrointestinal neoplasia. We sought to develop such a test by analysis of DNA methylation from exfoliated cancer cells in feces. Methods We first analyzed methylation of the RASSF2 and SFRP2 gene promot... [more] Background The development of noninvasive screening tests is important to reduce mortality from gastrointestinal neoplasia. We sought to develop such a test by analysis of DNA methylation from exfoliated cancer cells in feces. Methods We first analyzed methylation of the RASSF2 and SFRP2 gene promoters from 788 primary gastric and colorectal tissue specimens to determine whether methylation patterns could act as stage-dependent biomarkers of gastrointestinal tumorigenesis. Next, we developed a novel strategy that uses single-step modification of DNA with sodium bisulfite and fluorescence polymerase chain reaction methodology to measure aberrant methylation in fecal DNA. Methylation of the RASSF2 and SFRP2 promoters was analyzed in 296 fecal samples obtained from a variety of patients, including 21 with gastric tumors, 152 with colorectal tumors, and 10 with non-neoplastic or inflammatory lesions in the gastrointestinal lumen. Results Analysis of DNA from tissues showed presence of extensive methylation in both gene promoters exclusively in advanced gastric and colorectal tumors. The assay successfully identified one or more methylated markers in fecal DNA from 57.1% of patients with gastric cancer, 75.0% of patients with colorectal cancer, and 44.4% of patients with advanced colorectal adenomas, but only 10.6% of subjects without neoplastic or active diseases (difference, gastric cancer vs undiseased = 46.5%, 95% confidence interval (CI) = 24.6% to 68.4%, P < .001; difference, colorectal cancer vs undiseased = 64.4%, 95% CI = 53.5% to 75.2%, P < .001; difference, colorectal adenoma vs undiseased = 33.8%, 95% CI = 14.2% to 53.4%, P < .001). Conclusions Methylation of the RASSF2 and SFRP2 promoters in fecal DNA is associated with the presence of gastrointestinal tumors relative to non-neoplastic conditions. Our novel fecal DNA methylation assay provides a possible means to noninvasively screen not only for colorectal tumors but also for gastric tumors.
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4.72Impact points
Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis.
International journal of cancer. Journal international du cancer. 07/2008; 122(11):2429-36.
O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair gene which is frequently methylated in colorectal cancer (CRC). However, it remains controversial whether methylation of specific CpG sequences within MGMT promoter leads to loss of its protein expression, and if MGMT methylation correl... [more] O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair gene which is frequently methylated in colorectal cancer (CRC). However, it remains controversial whether methylation of specific CpG sequences within MGMT promoter leads to loss of its protein expression, and if MGMT methylation correlates with G to A transition mutations in KRAS. Two methylation sensitive regions (Mp and Eh region) of MGMT promoter were investigated in 593 specimens of colorectal tissue: 233 CRCs, 104 adenomatous polyps (AP), 220 normal colonic mucosa from CRC patients (N-C) and 36 normal colonic mucosa specimens obtained from subjects without colorectal neoplasia (N-N) by combined bisulfite restriction analysis (COBRA). The region-specific methylation data were compared to the MGMT protein expression, spectrum of KRAS mutations and other clinical features. Extensive (including both Mp and Eh) and partial (either Mp or Eh) MGMT methylation were found in 24.5% and 11.6% of CRCs, 3.8% and 27.9% of APs, 0.5% and 7.7% of C-Ns and 2.8% and 2.8% of N-Ns, respectively. Extensive methylation of MGMT promoter was primarily present in CRCs while partial methylation was common in APs. Extensive methylation of MGMT promoter was associated with loss/reduced protein expression (p < 0.0001), as well as with G to A mutations in KRAS (p = 0.0017). We herein provide first evidence that extensive methylation of MGMT promoter region is essential for methylation-induced silencing of this gene. Our data suggest that MGMT methylation may evolve and spread throughout the promoter in a stepwise manner as the colonic epithelial cells progress through the classical-adenoma-cancer multistep cascade.
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12.90Impact points
Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer.
Gastroenterology. 06/2008; 134(7):1950-60, 1960.e1.
BACKGROUND & AIMS: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies... [more] BACKGROUND & AIMS: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. METHODS: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. RESULTS: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P < .0001) or BRAF/KRAS wild-type tumors (0.7, P < .0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). CONCLUSIONS: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.
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10.84Impact points
Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma.
Hepatology (Baltimore, Md.). 03/2008; 47(3):908-18.
Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human l... [more] Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human liver tissue specimens. A total of 176 liver tissues, including 77 pairs of HCCs and matching noncancerous liver and 22 normal livers, were analyzed for methylation. Methylation of 19 epigenetic markers was quantified, and the results were correlated with different disease states and the presence or absence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Based on methylation profiles, the 19 loci were categorized into 3 groups. Normal liver tissues showed methylation primarily in group 1 loci (HIC-1, CASP8, GSTP1, SOCS1, RASSF1A, p16, APC), which was significantly higher than group 2 (CDH1, RUNX3, RIZ1, SFRP2, MINT31) and group 3 markers (COX2, MINT1, CACNA1G, RASSF2, MINT2, Reprimo, DCC) (P < 0.0001). Noncancerous livers demonstrated increased methylation in both group 1 and group 2 loci. Methylation was significantly more abundant in HCV-positive livers compared with normal liver tissues. Conversely, HCC showed frequent methylation at each locus investigated in all 3 groups. However, the group 3 loci showed more dense and frequent methylation in HCV-positive cancers compared with both HBV-positive cancers and virus-negative cancers (P < 0.0001). CONCLUSION: Methylation in HCC is frequent but occurs in a gene-specific and disease-specific manner. Methylation profiling allowed us to determine that aberrant methylation is commonly present in normal aging livers, and sequentially progresses with advancing stages of chronic viral infection. Finally, our data provide evidence that HCV infection may accelerate the methylation process and suggests a continuum of increasing methylation with persistent viral infection and carcinogenesis in the liver.
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7.54Impact points
Extensive methylation is associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct pathways of human hepatocarcinogenesis.
Cancer research. 05/2007; 67(10):4586-94.
Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with beta-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of ca... [more] Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with beta-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of cancer-related genes is another characteristic feature of HCCs. The aim of this study was to determine the contribution of the methylator phenotype to HCC and its relationship to genomic instability. Fractional allelic loss (FAL) was determined using 400 microsatellite markers in 81 HCCs and 77 corresponding noncancerous livers as a measure of CIN. Methylation of 21 genetic loci was quantitated using combined bisulfite restriction analysis. Using hierarchical clustering analysis based upon the quantification of methylation levels, all HCCs were segregated into two groups characterized by either limited or extensive methylation. Mutations in the beta-catenin and p53 genes were determined by DNA sequencing. We found that the methylation levels were significantly higher in the HCCs than in noncancerous livers in 18 of the 21 loci (P values ranged from 0.035 to <0.0001). Among 18 loci, elevated levels of methylation at nine loci were significantly associated with beta-catenin mutations (P values ranged from 0.02 to <0.0001). In addition, the presence of beta-catenin mutations was associated with HCCs in the extensive methylation group (P < 0.0001), whereas p53 mutations correlated with high FAL scores (P = 0.0036). These data suggest that HCCs can be classified into two distinct categories based upon promoter methylation, CIN, and mutations of cancer-related genes. HCCs with extensive methylation harbor frequent beta-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC.
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2.71Impact points
High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers.
Cancer biology & therapy. 05/2007; 6(4):525-33.
Chromosomal instability (CIN) is a common but not universal feature of colorectal cancer (CRC); however, the molecular basis for CIN is controversial and poorly understood. There are many plausible mechanisms proposed for CIN, including disruption of G1/S and G2/M checkpoint regulation, and alterati... [more] Chromosomal instability (CIN) is a common but not universal feature of colorectal cancer (CRC); however, the molecular basis for CIN is controversial and poorly understood. There are many plausible mechanisms proposed for CIN, including disruption of G1/S and G2/M checkpoint regulation, and alterations in the spindle checkpoint genes. However, mutations in individual growth regulatory genes are not commonly observed in CRC. Therefore, a more comprehensive analysis of the genes involved in each cell cycle checkpoint regulatory pathway might be required to evaluate a possible role for involvement in CIN. We investigated the presence of high copy amplification of the cyclin E, Aurora-A, Skp2 genes, mutation of ubiquitin ligase CDC4, and promoter methylation of Mad2L1, as well as the expression of the gene products in a panel of 11 human CRC cell lines as well as 48 human CRC specimens. In the cell lines with CIN, we found amplification of the Aurora-A, cyclin E and Skp2 genes, and a mutation in the CDC4 gene, all of which resulted in altered expression of the cognate proteins. In the human CRC tissues, amplification of Aurora-A was frequent (29%), while alterations were rarely observed in cyclin E, Skp2 or CDC4. Aurora-A amplification was strongly associated with a high fractional allelic loss score (p = 0.0001), but not with microsatellite instability, nor with the promoter methylation phenotype in these tumors. Our data confirm involvement in the CDC4-cyclin E pathway of the development of the CIN phenotype in human CRC, and find that amplification of the Aurora-A is a common target for disruption of this pathway.
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1.54Impact points
Genome-wide semiquantitative microsatellite analysis of human hepatocellular carcinoma: discrete mapping of smallest region of overlap of recurrent chromosomal gains and losses.
Cancer genetics and cytogenetics. 06/2006; 167(1):57-65.
Recurrent chromosomal gains at 1q, 6p, 8q, and 17q, or losses at 1p, 4q, 6q, 8p, 9p, 13q, 16q, and 17p are common features of human hepatocellular carcinoma (HCC). For precise determination of the shortest region of overlap (SRO), 49 HCC obtained at the time of surgery or autopsy were subjected to c... [more] Recurrent chromosomal gains at 1q, 6p, 8q, and 17q, or losses at 1p, 4q, 6q, 8p, 9p, 13q, 16q, and 17p are common features of human hepatocellular carcinoma (HCC). For precise determination of the shortest region of overlap (SRO), 49 HCC obtained at the time of surgery or autopsy were subjected to comprehensive microsatellite analysis by using 400 markers distributed at almost equal distances throughout the 22 autosomes and X chromosomes. Each allele showing imbalance was subjected to comparative duplex polymerase chain reaction using a retained allele as an internal control to determine whether the imbalance was the result of chromosomal gain or loss. The following SRO of recurrent chromosomal gains and losses were determined: -1p36.22 approximately p36.33, D1S450-D1S2893, 5.0 mega-base pairs (Mbp); +1q23.3 approximately q25.3, D1S2878-D1S2619, 16.9 Mbp; -4q21.2 approximately q24, D4S2964-D4S1572, 23.0 Mbp; -6q23.3 approximately qter, D6S292-qter, 34.7 Mb; -8p22 approximately p23.1, D8S549-D8S550, 4.8 Mbp; +8q12.2 approximately q24.13, D8S260-D8S514, 61.8 Mbp; -13q13.3 approximately q22.1, D13S218-D13S156, 35.6 Mbp; -16q22.1 approximately qter, D16S503-qter, 26.7 Mbp; and -17p12 approximately pter, D17S921-pter, 14.2 Mbp. Contrary to our initial expectations, many HCC showed major deletions or additions of chromosome arms, so that a number of genes were included in the SRO. Although some putative oncogenes or tumor suppressor genes mapped in these SRO may be important, relative copy number changes of numerous other genes may affect pathogenesis of HCC.
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1.54Impact points
Interferon-alpha improves bone resorption and osteopenia in patients with chronic hepatitis C.
Hepatology research : the official journal of the Japan Society of Hepatology. 04/2006; 34(4):222-227.
BACKGROUND: Interferon (IFN)-beta is known to be involved in the regulation of bone homeostasis. As IFN-alpha and -beta share the same receptor complex and signaling pathway, we speculated that treatment with IFN-alpha for chronic hepatitis C (CHC) may provide a beneficial effect on bone loss. METHO... [more] BACKGROUND: Interferon (IFN)-beta is known to be involved in the regulation of bone homeostasis. As IFN-alpha and -beta share the same receptor complex and signaling pathway, we speculated that treatment with IFN-alpha for chronic hepatitis C (CHC) may provide a beneficial effect on bone loss. METHODS: Urinary deoxypyridinoline (uDPD) of 41 patients with CHC who had been receiving IFN-alpha for 24 weeks was examined during the period of observation. Among them, eight patients showed a bone mineral density (BMD) of less than 0.850g/cm(2) before IFN therapy and they were examined a BMD again after completion of IFN administration. Relationships between the percentage difference of uDPD after discontinuation of IFN and various factors related to CHC were also examined. RESULTS: A mean uDPD of 7.1+/-3.4nM/mM creatinine before IFN therapy decreased to 4.5+/-2.4 in the 4th week and 4.2+/-2.7 in the 24th week of IFN therapy, respectively (p<0.0001). The reduction in uDPD was more prominent in cases with a lower viral load (p=0.0266). The BMD of the eight patients, which was less than 0.850g/cm(2) before IFN therapy, showed significant increase after the end of therapy (p=0.0172). CONCLUSION: IFN-alpha can improve bone resorption in CHC patients, especially in those with a lower viral load, and increased BMD. These effects are thought to be a result of direct action of IFN on bone homeostasis.
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1.60Impact points
Genome-wide microsatellite analysis of focal nodular hyperplasia: a strong tool for the differential diagnosis of non-neoplastic liver nodule from hepatocellular carcinoma.
Journal of hepato-biliary-pancreatic surgery. 02/2006; 13(5):416-20.
Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in hepatocellular carcinoma (HCC), but the significance of AI analysis in focal nodular hyperplasia (FNH) has not been fully clarified. We hypothesized, therefore, that comprehensive allelotyping of FNH ... [more] Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in hepatocellular carcinoma (HCC), but the significance of AI analysis in focal nodular hyperplasia (FNH) has not been fully clarified. We hypothesized, therefore, that comprehensive allelotyping of FNH could be a useful tool for differentiating FNH from HCC. A 27-year-old man was admitted to the hospital because of general fatigue. A computed tomography (CT) scan disclosed a hepatic nodule 8 cm in diameter. No definite diagnosis was made after imaging or by biopsy before surgery. Macroscopically and microscopically, the surgical specimen showed typical features of FNH. Comprehensive microsatellite analysis was carried out with 382 microsatellite markers distributed throughout all chromosomes. To detect AI effectively, the cutoff value of the AI index was set at 0.70. Among the 382 microsatellite markers, 212 loci were informative, but no AI was detected. The absence of gross chromosomal alterations strongly suggested that the large nodule was FNH rather than HCC, in terms of its genetic background. The patient's subsequent clinical course revealed the nodule to be benign. The results suggest that this genome-wide microsatellite analysis is a useful tool for the differential diagnosis of non-neoplastic liver nodules from HCC.
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1.54Impact points
Genotype stability and clonal evolution of hepatocellular carcinoma assessed by autopsy-based genome-wide microsatellite analysis.
Cancer genetics and cytogenetics. 10/2005; 161(2):164-9.
It is widely accepted that chromosomal instability is an essential feature of cancer cells including hepatocellular carcinoma (HCC) cells. For an accurate characterization of clonal evolution of HCC cells, we studied chromosomal alterations in various metastatic lesions in an autopsy case of HCC. Ti... [more] It is widely accepted that chromosomal instability is an essential feature of cancer cells including hepatocellular carcinoma (HCC) cells. For an accurate characterization of clonal evolution of HCC cells, we studied chromosomal alterations in various metastatic lesions in an autopsy case of HCC. Tissues from the main tumor, which consisted of 2 macroscopically distinct portions, and from intrahepatic metastasis, portal vein thrombus, epiploic lymph node metastasis, and pulmonary metastasis as well as from the non-tumorous liver were analyzed with comprehensive microsatellite analysis. Alleles showing imbalance of the main tumor were further subjected to comparative duplex PCR, with use of a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. A striking finding was that allelic imbalances detected in the main tumor and metastatic lesions were almost identical, showing -1p, +1q, -4q, -7, -8p, +8q, +9q, +10, -13q, -17p, +19p, -19q, and -X. Additional alterations of +2q and -16q were detected in one portion of the main tumor and the portal vein thrombus. In conclusion, clonal evolution of the HCC cells during metastatic progression seems rare, in contrast to many recurrent chromosomal aberrations that may have accumulated before the clinical manifestation.
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3.86Impact points
Discrete breakpoint mapping and shortest region of overlap of chromosome arm 1q gain and 1p loss in human hepatocellular carcinoma detected by semiquantitative microsatellite analysis.
Genes, chromosomes & cancer. 02/2005; 42(1):34-43.
Recurrent chromosomal gain at 1q is one of the most common features of human hepatocellular carcinoma (HCC), but how the gain at 1q contributes to hepatocarcinogenesis is still unclear. To identify the target genes, precise determination of the shortest region of overlap (SRO) and of breakpoints is ... [more] Recurrent chromosomal gain at 1q is one of the most common features of human hepatocellular carcinoma (HCC), but how the gain at 1q contributes to hepatocarcinogenesis is still unclear. To identify the target genes, precise determination of the shortest region of overlap (SRO) and of breakpoints is necessary. Similarly, the role of loss at 1p, which is also a major cytogenetic aberration in HCC, needs to be determined. Fifty HCCs were examined with the aid of 59 microsatellite markers distributed throughout both arms of chromosome 1. To detect allelic gain effectively, the cutoff value of the allelic imbalance index was set at 0.70. Alleles showing imbalance were subjected to multiplex PCR, using a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. The SRO of the gains was defined as D1S2878-D1S2619 (1q23.-q25.3, 16.9 Mb), which involved 36 cases (72%). Gains in the number of copies of certain oncogenes within this region seemed to be critical for the pathogenesis of HCC. In contrast, the centromeric breakpoints of these gains varied, but they tended to occur mainly in the pericentromeric region (26 of 50 cases, 52%). Rearrangement of specific genes associated with the gains is unlikely. On the other hand, the SRO of deletion was defined as D1S2893-D1S450 (1p36.32-p36.22, 5.1 Mb). Four known putative tumor-suppressor genes (TP73, RIZ1, NBL1/DAN, and CDKN2C) were outside the SRO, suggesting the presence of other candidate genes with critical roles in hepatocarcinogenesis.
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[Natriuretic peptides in liver cirrhosis and their clinical implication]
Nippon rinsho. Japanese journal of clinical medicine. 10/2004; 62 Suppl 9:131-4.
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2.91Impact points
Alteration of the p14(ARF) gene and p53 status in human hepatocellular carcinomas.
Journal of gastroenterology. 01/2004; 39(4):355-61.
BACKGROUND: The INK4a/ARF locus encodes p16INK4a and p14ARF, both of which are crucial for two tumor suppressor pathways, retinoblastoma (RB)/p16INK4a and p53/ARF. Inactivation of RB/p16INK4a was frequently reported, but alterations of the p14ARF gene in hepatocellular carcinoma (HCC) in the Japanes... [more] BACKGROUND: The INK4a/ARF locus encodes p16INK4a and p14ARF, both of which are crucial for two tumor suppressor pathways, retinoblastoma (RB)/p16INK4a and p53/ARF. Inactivation of RB/p16INK4a was frequently reported, but alterations of the p14ARF gene in hepatocellular carcinoma (HCC) in the Japanese population have been insufficiently analyzed. METHODS: To determine the role of p53/ARF alteration in hepatocarcinogenesis, we examined 44 HCCs for mRNA expression, deletion, mutation, and promoter hypermethylation of the p14(ARF) gene; alterations of p53 were also analyzed in the same series of HCCs. RESULTS: Homozygous deletion, spanning from exon 1 beta to exon 2, was found in 1 HCC mutations within exon 2 were found in 2 HCCs, but no promoter hypermethylation was detected. All 3 HCCs with p14(ARF) alteration were well differentiated. Twelve of the 44 HCCs (27.2%) showed immunohistochemical evidence of p53 alteration; however, only 1 of the tumors with p53 alteration was well differentiated. TaqMan polymarase chain reaction (PCR) indicated that the expression of p14(ARF) in HCCs was higher than in that in all but three of the corresponding non-tumorous tissues ( P < 0.0001), and increased expression of p14(ARF) seemed to be associated with poorly differentiated phenotype. Absence of p14(ARF) expression was seen in only one HCC, with homozygous deletion of the p14(ARF) gene. CONCLUSIONS: Compared with p53 alteration, p14(ARF) alteration does not occur frequently, but may play a role in a subset of Japanese HCCs in the early stage of hepatocarcinogenesis. On the other hand, overexpression of p14(ARF) was frequently observed in HCC, especially in poorly differentiated tumors, probably reflecting oncogenic stimuli in these tumors.The INK4a/ARF locus encodes p16(INK4a) and p14(ARF), both of which are crucial for two tumor suppressor pathways, retinoblastoma (RB)/p16(INK4a) and p53/ARF. Inactivation of RB/p16(INK4a) was frequently reported, but alterations of the p14(ARF) gene in hepatocellular carcinoma (HCC) in the Japanese population have been insufficiently analyzed.
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3.86Impact points
Comprehensive allelotyping of well-differentiated human hepatocellular carcinoma with semiquantitative determination of chromosomal gain or loss.
Genes, chromosomes & cancer. 01/2003; 35(4):329-39.
Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in human hepatocellular carcinoma (HCC), but the impact of AI on the early stage of hepatocarcinogenesis has not been fully clarified. Moreover, no previous allelotype studies have identified the differe... [more] Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in human hepatocellular carcinoma (HCC), but the impact of AI on the early stage of hepatocarcinogenesis has not been fully clarified. Moreover, no previous allelotype studies have identified the difference in chromosomal gain and loss that results in AI. To resolve these problems, we examined 18 well-differentiated HCCs with comprehensive allelotyping by using 400 microsatellite markers with semiquantitative assessment of chromosomal gain or loss. To detect allelic gain effectively, the cutoff value of the allelic imbalance index was set at 0.70. Each allele showing imbalance was subjected to multiplex PCR with use of a retained allele as an internal control to determine whether the imbalance was the result of chromosomal gain or loss. High frequencies of chromosomal gains were detected at 1q (D1S196-D1S2785, 56%), 5q (D5S647-D5S2027, 44%), 6p (6pter-D6S309, 33%), 7 (7pter-D7S657, 22%), and 8q (D8S514-qter, 44%), whereas chromosomal losses were frequently observed at 1p (1pter-D1S234, 22%), 8p (8pter-D8S549, 44%), and 17p (17pter-D17S921, 28%). The extent of overall chromosomal aberration was closely related to the maximum tumor diameter (P = 0.002) and the presence of hepatitis B surface antigen (P = 0.03). Recurrent chromosomal losses at 1p and 8p and gains at 1q and 8q, even in HCCs with a minimal extent of aberrant chromosomes, indicate that these alterations were critical in the early stage of hepatocarcinogenesis. On the other hand, deletions of 13q and 16q were infrequent and were seen only in the most aberrant cases, which suggested that these were late events.
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2.95Impact points
Benign hepatic nodules in Budd-Chiari syndrome: radiologic-pathologic correlation with emphasis on the central scar.
AJR. American journal of roentgenology. 04/2002; 178(4):869-75.
OBJECTIVE: The purpose of this study was to determine the imaging features of benign hepatic nodules in patients with Budd-Chiari syndrome and to correlate them with pathologic findings, with special attention placed on the presence of a central scar. MATERIALS AND METHODS: Imaging findings of 59 be... [more] OBJECTIVE: The purpose of this study was to determine the imaging features of benign hepatic nodules in patients with Budd-Chiari syndrome and to correlate them with pathologic findings, with special attention placed on the presence of a central scar. MATERIALS AND METHODS: Imaging findings of 59 benign hepatic nodules in four patients with chronic Budd-Chiari syndrome were analyzed retrospectively, and radiologic- pathologic correlation was performed in three patients with 50 hepatic nodules who underwent liver transplantation. All patients underwent multiphasic helical CT. In three patients with 29 lesions, MR imaging, including a multiphasic dynamic study, was performed. The CT and MR imaging findings in these patients were compared with those of 103 small hepatocellular carcinomas in 56 other patients (54 of them displayed chronic hepatitis or liver cirrhosis associated with viral hepatitis but none had Budd-Chiari syndrome). Image analysis was performed by two radiologists with no knowledge of the diagnosis. RESULTS: All patients with Budd-Chiari syndrome exhibited multiple benign nodules up to 3 cm in diameter, and 42 of 59 lesions were hypervascular. Microscopically, 15 of 32 nodules demonstrated a central scar; moreover, some nodules closely resembled focal nodular hyperplasia. Frequencies of hyperintensity on T1-weighted images (14/29 vs 25/103), hypointensity on T2-weighted images (7/29 vs 1/103), and the presence of a central scar (6/59 vs 1/103) were significantly higher in benign nodules than in hepatocellular carcinomas (p < 0.05; Fisher's exact test). Moreover, for lesions larger than 1 cm, imaging studies revealed a central scar in six of 15 benign lesions. CONCLUSION: Benign hepatic nodules in patients with in Budd-Chiari syndrome are usually small, multiple, and hypervascular. The presence of a central scar is a characteristic feature in those larger than 1 cm in diameter.
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2.11Impact points
Prognostic impact of multiple allelic losses on metastatic recurrence in hepatocellular carcinoma after curative resection.
Oncology. 02/2002; 62(2):141-8.
Loss of heterozygosity (LOH) on chromosomes 13q, 16q and 17p has been associated with the progression of hepatocellular carcinoma (HCC). To investigate the prognostic impact of such LOH, we examined the metastasis-free survival of curatively resected HCC cases, in whom these LOHs were analyzed. Amon... [more] Loss of heterozygosity (LOH) on chromosomes 13q, 16q and 17p has been associated with the progression of hepatocellular carcinoma (HCC). To investigate the prognostic impact of such LOH, we examined the metastasis-free survival of curatively resected HCC cases, in whom these LOHs were analyzed. Among the 49 HCC patients examined, the frequency of LOHs was 28% on 13q, 33% on 16q and 40% on 17p. The patients were followed up for metastatic recurrence after surgery and for analysis of the relationship between chromosomal changes and patients' metastasis-free survival. Univariate survival analysis showed the presence of LOH on 16q, 17p and the number of chromosomes with LOH were significantly and negatively associated with metastasis-free survival, indicating that patients with LOH on multiple chromosomes had a poorer prognosis after surgery than those with LOH on a single chromosome or no LOH. Multivariate Cox survival analysis identified the presence of LOH on 16q and the number of chromosomes with LOH as the most significant independent negatively predictive factors for metastasis-free survival. These findings indicate that accumulation of chromosomal changes is associated with metastatic behavior, and that LOH on 16q was the most useful prognostic indicator for metastasis after curative resection of HCC.
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1.95Impact points
Transcatheter arterial embolization for tumor seeding in the chest wall after radiofrequency ablation for hepatocellular carcinoma.
Cardiovascular and interventional radiology. 29(3):479-81.
Tumor seeding in the chest wall was depicted at follow-up CT obtained 9 months after radiofrequency ablation for hepatocellular carcinoma. Transcatheter arterial embolization was successfully performed, injecting emulsion of 10 mg of epirubicin and 1 ml of iodized oil followed by gelatin sponge part... [more] Tumor seeding in the chest wall was depicted at follow-up CT obtained 9 months after radiofrequency ablation for hepatocellular carcinoma. Transcatheter arterial embolization was successfully performed, injecting emulsion of 10 mg of epirubicin and 1 ml of iodized oil followed by gelatin sponge particles via the microcatheter placed in the right eleventh intercostal artery. The patient died of tumor growth in the liver one year after the embolization, but no progression of the tumor seeding was noted during the follow-up period. We conclude that transcatheter arterial embolization was effective for the control of tumor seeding after radiofrequency ablation for hepatocellular carcinoma.
Following (2)
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Minoru Koi
Baylor Health Care System -
Takaki Sakurai
Saitama Medical School
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