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Papers - KANAI Yae

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Comprehensive Exploration of Novel Chimeric Transcripts in Clear Cell Renal Cell Carcinomas Using Whole Transcriptome Analysis

Gotoh, Masahiro, Ichikawa, Hitoshi, Arai, Eri, Chiku, Suenori, Sakamoto, Hiromi, Fujimoto, Hiroyuki, Hiramoto, Masaki, Nammo, Takao, Yasuda, Kazuki, Yoshida, Teruhiko, Kanai, Yae

GENES CHROMOSOMES & CANCER (WILEY-BLACKWELL) 53 ( 12 ) 1018 - 1032 2014.12

Research paper (scientific journal), ISSN 1045-2257

The aim of this study was to clarify the participation of expression of chimeric transcripts in renal carcinogenesis. Whole transcriptome analysis (RNA sequencing) and exploration of candidate chimeric transcripts using the deFuse program were performed on 68 specimens of cancerous tissue (T) and 11 specimens of non-cancerous renal cortex tissue (N) obtained from 68 patients with clear cell renal cell carcinomas (RCCs) in an initial cohort. As positive controls, two RCCs associated with Xp11.2 translocation were analyzed. After verification by reverse transcription (RT)-PCR and Sanger sequencing, 26 novel chimeric transcripts were identified in 17 (25%) of the 68 clear cell RCCs. Genomic breakpoints were determined in five of the chimeric transcripts. Quantitative RT-PCR analysis revealed that the mRNA expression levels for the MMACHC, PTER, EPC2, ATXN7, FHIT, KIFAP3, CPEB1, MINPP1, TEX264, FAM107A, UPF3A, CDC16, MCCC1, CPSF3, and ASAP2 genes, being partner genes involved in the chimeric transcripts in the initial cohort, were significantly reduced in 26 T samples relative to the corresponding 26 N samples in the second cohort. Moreover, the mRNA expression levels for the above partner genes in T samples were significantly correlated with tumor aggressiveness and poorer patient outcome, indicating that reduced expression of these genes may participate in malignant progression of RCCs. As is the case when their levels of expression are reduced, these partner genes also may not fully function when involved in chimeric transcripts. These data suggest that generation of chimeric transcripts may participate in renal carcinogenesis by inducing dysfunction of tumor-related genes. (c) 2014 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes

Tian, Ying, Arai, Eri, Gotoh, Masahiro, Komiyama, Motokiyo, Fujimoto, Hiroyuki, Kanai, Yae

BMC CANCER (BIOMED CENTRAL LTD) 14 ( 1 ) 64 - 72 2014.10

Research paper (scientific journal), ISSN 1471-2407

Background: The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes.
Methods: DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP-negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort.
Results: Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP-marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP-negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 x 10(-5) and 2.43 x 10(-13), respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 x 10(-4)) than those with CIMP-negative ccRCCs.
Conclusions: The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs.

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Histopathological characteristics of hypervascular cholangiocellular carcinoma as an early stage of cholangiocellular carcinoma

Sato, Yuya, Ojima, Hidenori, Onaya, Hiroaki, Mori, Taisuke, Hiraoka, Nobuyoshi, Kishi, Yoji, Nara, Satoshi, Esaki, Minoru, Shimada, Kazuaki, Kosuge, Tomoo, Sugihara, Kenich, Kanai, Yae

HEPATOLOGY RESEARCH (WILEY-BLACKWELL) 44 ( 11 ) 1119 - 1129 2014.10

Research paper (scientific journal), ISSN 1386-6346

AimPrognosis of hypervascular cholangiocellular carcinoma (h-CCC) is reportedly better than that of ordinary hypovascular CCC (o-CCC). The aim of this study is to clarify the histopathological characteristics of h-CCC.
MethodsOn the basis of the findings in the arterial phase of contrast-enhanced computed tomography, 16 cases of mass-forming-type CCC were divided into two groups (h-CCC, n=8; o-CCC, n=8). Areas of high (Area H-a) and low (Area H-b) attenuation in h-CCC cases and areas of low attenuation in o-CCC cases (Area O) were delineated. These areas were then evaluated histopathologically to determine the proportion of tumor cells, fibrous stroma, arterial vessel density, and immunohistochemical expression of Vascular endothelial growth factor; angiopoietin-2; cytokeratin 7, CK19, SOX9 and SOX17 genes; epithelial cell adhesion molecule; and the Bmi-1, Ki-67, epithelial membrane antigen and polyclonal carcinoembryonic antigen.
ResultsThe areal ratio of tumor cells decreased and that of fibrous stroma increased in the following order: Area H-a, Area H-b and Area O. Values for AVD and neural cell adhesion molecule positivity rate were significantly higher in Area H-a than in Areas H-b or O. Expressions of vascular endothelial growth factor and angiopoietin-2 were significantly higher in Areas H-a and H-b than in Area O. The Ki-67 labeling index increased in the following order: Area H-a, Area H-b and Area O.
ConclusionA high areal ratio of tumor cells and AVD as well as a high expression of stem cells and angiogenic markers were observed in cases of h-CCC, whereas the areal ratio of fibrous stroma and malignant potential were low. These results suggest that h-CCC may represent the early stage of CCC.

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Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis

Takaki, Yoko, Saito, Yoshimasa, Takasugi, Azusa, Toshimitsu, Kohta, Yamada, Shoji, Muramatsu, Toshihide, Kimura, Masaki, Sugiyama, Kazuo, Suzuki, Hiromu, Arai, Eri, Ojima, Hidenori, Kanai, Yae, Saito, Hidetsugu

CANCER SCIENCE (WILEY-BLACKWELL) 105 ( 10 ) 1254 - 1260 2014.10

Research paper (scientific journal), ISSN 1347-9032

Non-alcoholic steatohepatitis (NASH) has emerged as a common cause of chronic liver disease and virus-independent hepatocellular carcinoma (HCC) in patients with obesity, diabetes, and metabolic syndrome. To reveal the molecular mechanism underlying hepatocarcinogenesis from NASH, microRNA (miRNA) expression profiles were analyzed in STAM mice, a NASH-HCC animal model. MicroRNA expression was also examined in 42 clinical samples of HCC tissue. Histopathological images of the liver of STAM mice at the ages of 6, 8, 12, and 18weeks showed findings compatible with fatty liver, NASH, liver cirrhosis (LC), and HCC, respectively. Expression of miR-122 in non-tumor LC at the age of 18weeks was significantly lower than that in LC at the age of 12weeks. Expression of miR-122 was further decreased in HCCs relative to non-tumor LC at the age of 18weeks. Expression of miR-122 was also decreased in clinical samples of liver tissue showing macrovesicular steatosis and HCC, being consistent with the findings in the NASH model mice. DNA methylation analysis revealed that silencing of miR-122 was not mediated by DNA hypermethylation of the promoter region. These results suggest that silencing of miR-122 is an early event during hepatocarcinogenesis from NASH, and that miR-122 could be a novel molecular marker for evaluating the risk of HCC in patients with NASH.

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Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome

Arai, Eri, Sakamoto, Hiromi, Ichikawa, Hitoshi, Totsuka, Hirohiko, Chiku, Suenori, Gotoh, Masahiro, Mori, Taisuke, Nakatani, Tamao, Ohnami, Sumiko, Nakagawa, Tohru, Fujimoto, Hiroyuki, Wang, Linghua, Aburatani, Hiroyuki, Yoshida, Teruhiko, Kanai, Yae

INTERNATIONAL JOURNAL OF CANCER (WILEY-BLACKWELL) 135 ( 6 ) 1330 - 1342 2014.09

Research paper (scientific journal), ISSN 0020-7136

The aim of this study was to identify pathways that have a significant impact during renal carcinogenesis. Sixty-seven paired samples of both noncancerous renal cortex tissue and cancerous tissue from patients with clear cell renal cell carcinomas (RCCs) were subjected to whole-exome, methylome and transcriptome analyses using Agilent SureSelect All Exon capture followed by sequencing on an Illumina HiSeq 2000 platform, Illumina Infinium HumanMethylation27 BeadArray and Agilent Sure-Print Human Gene Expression microarray, respectively. Sanger sequencing and quantitative reverse transcription-PCR were performed for technical verification. MetaCore software was used for pathway analysis. Somatic nonsynonymous single-nucleotide mutations, insertions/deletions and intragenic breaks of 2,153, 359 and 8 genes were detected, respectively. Mutations of GCN1L1, MED12 and CCNC, which are members of CDK8 mediator complex directly regulating beta-catenin-driven transcription, were identified in 16% of the RCCs. Mutations of MACF1, which functions in the Wnt/beta-catenin signaling pathway, were identified in 4% of the RCCs. A combination of methylome and transcriptome analyses further highlighted the significant role of the Wnt/beta-catenin signaling pathway in renal carcinogenesis. Genetic aberrations and reduced expression of ERC2 and ABCA13 were frequent in RCCs, and MTOR mutations were identified as one of the major disrupters of cell signaling during renal carcinogenesis. Our results confirm that multilayer-omics analysis can be a powerful tool for revealing pathways that play a significant role in carcinogenesis.

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Epigenetic clustering of lung adenocarcinomas based on DNA methylation profiles in adjacent lung tissue: Its correlation with smoking history and chronic obstructive pulmonary disease

Sato, Takashi, Arai, Eri, Kohno, Takashi, Takahashi, Yoriko, Miyata, Sayaka, Tsuta, Koji, Watanabe, Shun-ichi, Soejima, Kenzo, Betsuyaku, Tomoko, Kanai, Yae

INTERNATIONAL JOURNAL OF CANCER (WILEY-BLACKWELL) 135 ( 2 ) 319 - 334 2014.07

Research paper (scientific journal), ISSN 0020-7136

The aim of this study was to clarify the significance of DNA methylation alterations during lung carcinogenesis. Infinium assay was performed using 139 paired samples of non-cancerous lung tissue (N) and tumorous tissue (T) from a learning cohort of patients with lung adenocarcinomas (LADCs). Fifty paired N and T samples from a validation cohort were also analyzed. DNA methylation alterations on 1,928 probes occurred in N samples relative to normal lung tissue from patients without primary lung tumors, and were inherited by, or strengthened in, T samples. Unsupervised hierarchical clustering using DNA methylation levels in N samples on all 26,447 probes subclustered patients into Cluster I (n = 32), Cluster II (n = 35) and Cluster III (n = 72). LADCs in Cluster I developed from the inflammatory background in chronic obstructive pulmonary disease (COPD) in heavy smokers and were locally invasive. Most patients in Cluster II were non-smokers and had a favorable outcome. LADCs in Cluster III developed in light smokers were most aggressive (frequently showing lymphatic and blood vessel invasion, lymph node metastasis and an advanced pathological stage), and had a poor outcome. DNA methylation levels of hallmark genes for each cluster, such as IRX2, HOXD8, SPARCL1, RGS5 and EI24, were again correlated with clinicopathological characteristics in the validation cohort. DNA methylation profiles reflecting carcinogenetic factors such as smoking and COPD appear to be established in non-cancerous lung tissue from patients with LADCs and may determine the aggressiveness of tumors developing in individual patients, and thus patient outcome.
What's new? While genetic abnormalities are well studied in human cancers, epigenetic changes, especially in the early stages of carcinogenesis, remain largely unknown. Here, the authors perform a genome-wide analysis focusing on DNA methylation profiles in normal lung tissue adjacent to lung adenocarcinomas. Using single-CpG-resolution Infinium assays, they identify distinct DNA methylation profiles clustering with specific risk factors such as cigarette smoking, inflammation and chronic obstructive pulmonary disease. The authors speculate that these epigenetic profiles detected in the neighboring cells may influence the aggressiveness of tumors developing in individual patients and may thus help predict disease outcome.

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Early venous return in hepatic angiomyolipoma due to an intratumoral structure resembling an arteriovenous fistula

Iwao, Yasuhito, Ojima, Hidenori, Onaya, Hiroaki, Sakamoto, Yoshihiro, Kishi, Yoji, Nara, Satoshi, Esaki, Minoru, Mizuguchi, Yasunori, Ushigome, Masahiko, Asahina, Daisuke, Hiraoka, Nobuyoshi, Shimada, Kazuaki, Kosuge, Tomoo, Kanai, Yae

HEPATOLOGY RESEARCH (WILEY-BLACKWELL) 44 ( 6 ) 700 - 706 2014.06

Research paper (scientific journal), ISSN 1386-6346

Early venous return (EVR) is an important radiological feature of hepatic angiomyolipoma (HAML) that can aid in differential diagnosis, but the pathogenic mechanisms of EVR have yet to be elucidated. We present the first HAML case for which a probable mechanism for EVR is described. The patient was a 46-year-old woman, who had a growing 6-cm tumor with EVR in segment 3 of the liver as revealed by dynamic contrast-enhanced computed tomography. Left hepatic lobectomy was performed to prevent tumor rupture. Histopathological and immunohistochemical analyses of the excised tumor indicated HAML. Successive microsections of the tumor were stained with hematoxylin-eosin and Victoria blue to visualize the vascular structure within and around the tumor. These analyses led to three major findings. First, many well-defined thick-walled vessels, such as arteries, were found entering the tumor. Second, many thick-walled vessels within the tumor were connected directly to thin-walled vessels, resembling arteriovenous fistulae. Finally, thin-walled intratumoral vessels were connected directly to the hepatic vein. These histological findings suggested that the rich arterial flow into the tumor was being rapidly drained into the hepatic vein through intratumoral arteriovenous connections. We also detected these same anomalous circulatory pathways in tissue sections from three of four additional HAML cases with EVR. Aberrant arteriovenous fistulae within the tumor may account for many cases of EVR in HAML patients.

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PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors

Ohki, Rieko, Saito, Kozue, Chen, Yu, Kawase, Tatsuya, Hiraoka, Nobuyoshi, Saigawa, Raira, Minegishi, Maiko, Aita, Yukie, Yanai, Goichi, Shimizu, Hiroko, Yachida, Shinichi, Sakata, Naoaki, Doi, Ryuichiro, Kosuge, Tomoo, Shimada, Kazuaki, Tycko, Benjamin, Tsukada, Toshihiko, Kanai, Yae, Sumi, Shoichiro, Namiki, Hideo, Taya, Yoichi, Shibata, Tatsuhiro, Nakagama, Hitoshi

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (NATL ACAD SCIENCES) 111 ( 23 ) E2404 - E2413 2014.06

Research paper (scientific journal), ISSN 0027-8424

The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.

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Frequent Lack of GNAS Mutations in Colorectal Adenocarcinoma Associated with GNAS-Mutated Villous Adenoma

Sekine, Shigeki, Ogawa, Reiko, Oshiro, Taihei, Kanemitsu, Yukihide, Taniguchi, Hirokazu, Kushima, Ryoji, Kanai, Yae

GENES CHROMOSOMES & CANCER (WILEY-BLACKWELL) 53 ( 4 ) 366 - 372 2014.04

Research paper (scientific journal), ISSN 1045-2257

Colorectal villous adenoma is thought to be associated with a high risk of progression to adenocarcinoma. To better characterize the genetic alterations involved in colorectal carcinogenesis related to villous adenoma, we analyzed mutations in APC, BRAF, KRAS, TP53, and GNAS in 12 colorectal adenocarcinomas associated with villous adenomas. APC, KRAS, and BRAF mutations were identified in five, 11, and one lesion, respectively, and most of these mutations were shared between the villous adenoma and the adenocarcinoma components in the respective lesions, except in one lesion with APC mutations and in two lesions with KRAS mutations. TP53 mutations were observed exclusively in four adenocarcinoma components, consistent with their role in the progression from adenoma to adenocarcinoma. Activating GNAS mutations were found in nine villous adenomas; however, unexpectedly, these mutations were shared only in three associated adenocarcinomas. Notably, all six adenocarcinomas with discordant GNAS mutation statuses were nonmucinous type, whereas all the other adenocarcinomas, including three adenocarcinomas associated with GNAS wild-type villous adenomas, were mucinous type. The current study suggests that GNAS-mutated villous adenomas may not necessarily be direct precursors of associated adenocarcinomas. At the same time, our observations support the role of activating GNAS mutations in increased mucin production in colorectal neoplasms. © 2014 Wiley Periodicals, Inc.

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Lobular Endocervical Glandular Hyperplasia Is a Neoplastic Entity With Frequent Activating GNAS Mutations

Matsubara, Akiko, Sekine, Shigeki, Ogawa, Reiko, Yoshida, Masayuki, Kasamatsu, Takahiro, Tsuda, Hitoshi, Kanai, Yae

AMERICAN JOURNAL OF SURGICAL PATHOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 3 ) 370 - 376 2014.03

Research paper (scientific journal), ISSN 0147-5185

To clarify the significance of GNAS mutations in cervical tumorigenesis, we performed mutational analyses in a total of 154 lesions and in 22 normal tissues of the uterine cervix. Activating GNAS mutations were found in 8 of the 19 lobular endocervical glandular hyperplasias (LEGH; 42%) and 4 of the 79 endocervical-type mucinous adenocarcinomas (5%) but were never seen in the normal endocervical tissue, minimal deviation adenocarcinomas, endometrioid adenocarcinomas, or squamous cell carcinomas. We further examined the presence of human papillomavirus (HPV) DNA and p16 expression to probe the relationship between GNAS mutations and HPV infection in LEGHs and carcinomas. All the GNAS-mutated LEGHs were negative for HPV DNA and p16 expression, whereas all the GNAS-mutated adenocarcinomas were positive for HPV DNA and/or p16 expression, implicating GNAS mutations in the development of LEGH and a minor subset of HPV-related cervical adenocarcinomas. Additional mutational analyses of LEGH identified KRAS and STK11 mutations in 1 and 2 cases, respectively. The GNAS, KRAS, and STK11 mutations were mutually exclusive; thus, a total of 11 LEGHs (58%) had 1 of these genetic alterations. Although LEGH has been regarded as a metaplastic lesion, the frequent presence of genetic alterations suggests a neoplastic nature.

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Association of Pancreatic Fatty Infiltration With Pancreatic Ductal Adenocarcinoma

Hori, Mika, Takahashi, Mami, Hiraoka, Nobuyoshi, Yamaji, Taiki, Mutoh, Michihiro, Ishigamori, Rikako, Furuta, Koh, Okusaka, Takuji, Shimada, Kazuaki, Kosuge, Tomoo, Kanai, Yae, Nakagama, Hitoshi

CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY (NATURE PUBLISHING GROUP) 5 2304 - 2315 2014.03

Research paper (scientific journal), ISSN 2155-384X

OBJECTIVES: Fatty infiltration (FI) in the pancreas is positively correlated with high body mass index (BMI) or obesity, and the prevalence of diabetes mellitus (DM), which are well-known risk factors of pancreatic cancer. However, the association of FI in the pancreas with pancreatic cancer is unclear. Recently, we have shown that Syrian golden hamsters feature FI of the pancreas, the severity of which increases along with the progression of carcinogenesis induced by a chemical carcinogen. To translate the results to a clinical setting, we investigated whether FI in the pancreas is associated with pancreatic cancer in a series of patients who had undergone pancreatoduodenectomy.
METHODS: In the series, we identified 102 cases with pancreatic ductal adenocarcinoma (PDAC) and 85 controls with cancers except for PDAC. The degree of FI was evaluated histopathologically from the area occupied by adipocytes in pancreas sections, and was compared between the cases and controls.
RESULTS: The degree of FI in the pancreas was significantly higher in cases than in controls (median 26 vs. 15%, P<0.001) and positively associated with PDAC, even after adjustment for BMI, prevalence of DM and other confounding factors (odds ratio (OR), 6.1; P<0.001). BMI was identified as the most significantly associated factor with FI in the pancreas.
CONCLUSIONS: There is a positive correlation between FI in the pancreas and pancreatic cancer.

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Multilayer-omics analyses of human cancers: exploration of bionnarkers and drug targets based on the activities of the International Human Epigenome Consortium

Kanai, Yae, Arai, Eri

FRONTIERS IN GENETICS 5 1330 - 1342 2014.02

Research paper (scientific journal), ISSN 1664-8021

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Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

Nakahata, Shingo, Ichikawa, Tomonaga, Maneesaay, Phudit, Saito, Yusuke, Nagai, Kentaro, Tamura, Tomohiro, Manachai, Nawin, Yamakawa, Norio, Hamasaki, Makoto, Kitabayashi, Issay, Arai, Yasuhito, Kanai, Yae, Taki, Tomohiko, Abe, Takaya, Kiyonari, Hiroshi, Shimoda, Kazuya, Ohshima, Koichi, Horii, Akira, Shima, Hiroshi, Taniwaki, Masafumi, Yamaguchi, Ryoji, Morishita, Kazuhiro

NATURE COMMUNICATIONS (NATURE PUBLISHING GROUP) 5 91 - 93 2014.02

Research paper (scientific journal), ISSN 2041-1723

Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.

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Intraductal dissemination of papillary adenocarcinoma of the ampulla of Vater in the pancreatic duct

Matsubara, Akiko, Nara, Satoshi, Sekine, Shigeki, Ojima, Hidenori, Kosuge, Tomoo, Shimada, Kazuaki, Kushima, Ryoji, Kanai, Yae, Hiraoka, Nobuyoshi

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL) 64 ( 1 ) 39 - 44 2014.01

Research paper (scientific journal), ISSN 1320-5463

It has been speculated that intraductal dissemination, via the pancreatic duct, bile duct, or mammary duct, is a unique form of cancer cell spread. However, clinical evidence to confirm this form of dissemination has been lacking. Here we report a case of papillary adenocarcinoma of the ampulla of Vater in which retrograde dissemination to the pancreatic duct was strongly suggested. A 79-year-old woman underwent pancreatoduodenectomy for a 22 mm microinvasive papillary adenocarcinoma of the ampulla. Multiple carcinomas in situ were found in the pancreatic duct distant from the ampulla. Seven months later, she underwent a second operation for a recurrent papillary adenocarcinoma at the pancreato-jejunal anastomosis showing exophytic and expansive growth into the jejunal lumen that connected to an intraductal adenocarcinoma in the pancreatic body. None of these tumors showed invasive growth, or vascular or neural invasion, being separate from each other but sharing identical histological, immunohistochemical, and molecular features; papillary growth, a pancreatobiliary phenotype, the same pattern of genomic loss of heterozygosity, and no mutation of the KRAS, TP53, and GNAS genes. These results imply that this papillary adenocarcinoma of the ampulla of Vater had disseminated to the pancreatic duct in a retrograde manner and recurred in the remnant pancreas.

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Clinicopathological characterization of so-called "cholangiocarcinoma with intraductal papillary growth" with respect to "intraductal papillary neoplasm of bile duct (IPNB)"

Kanai Yae

INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY (E-CENTURY PUBLISHING CORP) 7 ( 6 ) 3112 - 3122 2014

Research paper (scientific journal), ISSN 1936-2625

Cholangiocarcinoma (CC) of the biliary tract occasionally presents a predominant intraductal papillary growth in the bile ducts, called as biliary tract carcinoma (BTC) of papillary growth (PG) and intrahepatic CC (ICC) of intraductal growth (IG) type. Recently, intraductal papillary neoplasm of bile duct (IPNB) has been proposed as a pre- invasive biliary neoplasm. This study was performed to characterize pathologically BTC of PG type and ICC of IG type with respect to IPNB. It was found that 126 of such 154 CCs (81.8%) fulfilled the criteria of IPNB, while the remaining 28 cases showed different histologies, such as tubular adenocarcinoma and carcinosarcoma. These IPNBs occurred in old aged patients with a male predominance, and the left lobe was rather frequently affected in the liver. A majority of these cases were high grade IPNB (43 cases) and invasive IPNB (77 cases), while low grade IPNB was rare (6 cases). Pancreatobiliary type was predominant (48 cases) followed by gastric (30 cases), intestinal (29 cases) and oncocytic (19 cases) types. Mucus hypersecretion was found in 45 cases, and this was frequent in IPNB at the intrahepatic large bile duct and hilar bile ducts but rare at the extrahepatic bile ducts. Interestingly, 36 cases of high grade and invasive IPNBs contained foci of moderately differentiated adenocacinoma within the intraductal papillary tumor. In conclusion, a majority of ICC of IG type and BTC of PG type could be regarded as a IPNB lineage, and clinically detectable IPNBs were already a malignant papillary lesion.

Potential biomarker for human uterine leiomyosarcoma.

Hayashi T, Horiuchi A, Aburatani H, Ishiko O, Yaegashi N, Kanai Y, Zharhary D, Shiozawa T, Tonegawa S, Konishi I.

J Clin Med Res 6 392 - 394 2014

Accepted

Pathological diagnosis of flat epithelial lesions of the biliary tract with emphasis on biliary intraepithelial neoplasia.

Sato Y, Sasaki M, Harada K, Aishima S, Fukusato T, Ojima H, Kanai Y, Kage M, Nakanuma Y, Tsubouchi H; Hepatolithiasis Subdivision of Intractable Hepatobiliary Diseases Study Group of Japan (Chairman, Hirohito Tsubouchi).

J Gastroenterol (SPRINGER JAPAN KK) 49 ( 1 ) 64 - 72 2014

Accepted, ISSN 09441174

Flat epithelial lesions of the biliary tract cannot be detected by the image analysis, and the diagnosis entirely depends on pathological examination. The biliary tract is often affected by inflammatory conditions, and the resultant changes of the biliary epithelium make it difficult to differentiate them from neoplasia. Thus, the pathological diagnosis of biliary flat epithelial lesions can be challenging. In the biliary tract, there are several forms of intraepithelial neoplasia of the flat type, and biliary intraepithelial neoplasia (BilIN) is known as one of such lesions that represent the multistep cholangiocarcinogenesis. In this article, the diagnostic criteria and the differential diagnosis of biliary flat epithelial lesions, particularly focusing on BilIN, were presented and discussed to provide help to advance clinical and research applications of the BilIN system.

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Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis

Yamazaki, Hiroshi, Mori, Taisuke, Yazawa, Masaki, Maeshima, Akiko M., Matsumoto, Fumihiko, Yoshi-moto, Seiichi, Ota, Yoshihide, Kaneko, Akihiro, Tsuda, Hitoshi, Kanai, Yae

LABORATORY INVESTIGATION (NATURE PUBLISHING GROUP) 93 ( 12 ) 1331 - 1338 2013.12

Research paper (scientific journal), ISSN 0023-6837

Head and neck squamous cell carcinoma (HNSCC) includes both morphological and functional cellular heterogeneity, as would be expected if it arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell; however, stemness molecule expression levels and distribution in HNSCC remain unclear. To clarify this, stemness molecule expressions were determined in HNSCC, as well as their properties and prognosis. Two protooncogenic chromatin regulators, Bmi-1 and high-mobility-group A2 (Hmga2), were identified in 12 pair cases of HNSCC tumor regions by comparison with their non-cancerous background tissues using cDNA microarray. Both Bmi-1 and Hmga2 are known to promote stem cell self-renewal by negatively regulating the expressions of Ink4a and Arf tumor suppressors. Despite similar targets, Bmi-1 protein was expressed in an early cancerous region and HMGA2 protein was expressed in a region showing more progression. Similarly, Bmi1 expression had no significance with regard to overall survival (P = 0.67), whereas HMGA2 expression was associated with decreased overall survival (P = 0.05). Quantitative real-time reverse transcription polymerase chain reaction analyses also correlated with protein levels. These findings suggest that Bmi-1 is an early detection marker to distinguish cancerous from non-cancerous regions, whereas HMGA2 is presumed to be a tumor prognosis marker. Among our HNSCC analyses, these stemness molecules expressed fewer primitive rare cells in the tumor than all other cells in the tumor. HNSCC cells with high expression of stemness molecules partly behave like stem cells.

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Bile Acids Increase Levels of MicroRNAs 221 and 222, Leading to Degradation of CDX2 During Esophageal Carcinogenesis

Matsuzaki, Juntaro, Suzuki, Hidekazu, Tsugawa, Hitoshi, Watanabe, Mitsuhiro, Hossain, Sharif, Arai, Eri, Saito, Yoshimasa, Sekine, Shigeki, Akaike, Toshihiro, Kanai, Yae, Mukaisho, Ken-Ichi, Auwerx, Johan, Hibi, Toshifumi

GASTROENTEROLOGY (Gastroenterology) 145 ( 6 ) 1300 - 1311 2013.12

Research paper (scientific journal), ISSN 0016-5085

Background &amp
Aims Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3′-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2
levels of CDX2 have been reported to decrease during progression of BE to EAC. Methods We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγnull mice. Results Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2
this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγnull mice. Conclusions We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC. © 2013 by the AGA Institute.

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Ability of preoperative 3.0-Tesla magnetic resonance imaging to predict the absence of side-specific extracapsular extension of prostate cancer

Hara, Tomohiko, Nakanishi, Hiroyuki, Nakagawa, Tohru, Komiyama, Motokiyo, Kawahara, Takashi, Manabe, Tomoko, Miyake, Mototaka, Arai, Eri, Kanai, Yae, Fujimoto, Hiroyuki

INTERNATIONAL JOURNAL OF UROLOGY (WILEY-BLACKWELL) 20 ( 10 ) 993 - 999 2013.10

Research paper (scientific journal), ISSN 0919-8172

ObjectiveRecent studies have shown an improvement in prostate cancer diagnosis with the use of 3.0-Tesla magnetic resonance imaging. We retrospectively assessed the ability of this imaging technique to predict side-specific extracapsular extension of prostate cancer.
MethodsFrom October 2007 to August 2011, prostatectomy was carried out in 396 patients after preoperative 3.0-Tesla magnetic resonance imaging. Among these, 132 (primary sample) and 134 patients (validation sample) underwent 12-core prostate biopsy at the National Cancer Center Hospital of Tokyo, Japan, and at other institutions, respectively. In the primary dataset, univariate and multivariate analyses were carried out to predict side-specific extracapsular extension using variables determined preoperatively, including 3.0-Tesla magnetic resonance imaging findings (T2-weighted and diffusion-weighted imaging). A prediction model was then constructed and applied to the validation study sample.
ResultsMultivariate analysis identified four significant independent predictors (P<0.05), including a biopsy Gleason score of 8, positive 3.0-Tesla diffusion-weighted magnetic resonance imaging findings, 2 positive biopsy cores on each side and a maximum percentage of positive cores 31% on each side. The negative predictive value was 93.9% in the combination model with these four predictors, meanwhile the positive predictive value was 33.8%. Good reproducibility of these four significant predictors and the combination model was observed in the validation study sample.
ConclusionsThe side-specific extracapsular extension prediction by the biopsy Gleason score and factors associated with tumor location, including a positive 3.0-Tesla diffusion-weighted magnetic resonance imaging finding, have a high negative predictive value, but a low positive predictive value.

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