bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 517: MiR-29b is a novel potential prognostic marker and inhibits cell proliferation in colorectal cancer
Authors: Inoue Akira , Yamamoto Hirofumi , Uemura Mamoru , Nishimura Junichi , Hata Taishi , Takemasa Ichiro , Mizushima Tsunekazu , Doki Yuichiro , Mori Masaki 
Published: May 2015

Abstract
Introduction Accumulating evidence indicates that microRNAs (miRNAs) are aberrantly expressed in human cancers and contribute to the tumorigenesis. Recent studies have suggested that microRNA-29 (miR-29) family members in human may play an important role in many types of cancer by regulating cell proliferation, differentiation, apoptosis, migration and invasion. MiR-29 is considered good candidate for miRNA-based therapeutics. In colorectal cancer (CRC), however, few studies have shown the clinical significance and biological function of miR-29. The aim of the present study was to examine the prognostic impact of miR-29b and the biological significance of miR-29b in CRC.
Materials and methods Expression of miR-29b was quantified by quantitative real-time PCR in 127 CRC patients who underwent curative resection. The impact of miR-29b expression on disease free survival (DFS) and overall survival (OS) was assessed in these 127 CRC patients. To investigate the functional role of miR-29b in vitro, tumor suppressive activity of miR-29b was assessed by proliferation assay, TUNEL assay and Ki-67 staining in CRC-derived cell lines (DLD1, HT29 and SW480).
Results MiR-29b expression was significantly decreased in tumor tissues compared to corresponding normal tissue (P = 0.014). The DFS and OS were significantly longer in the high miR-29b expression group compared to those in the low miR-29b expression group (P &lt; 0.05). Univariate and multivariate analyses indicated that expression of miR-29b was an independent prognostic factor for OS (P = 0.003), together with lymph node metastasis (P = 0.009), and serosal invasion (P = 0.002). In vitro assays revealed that forced expression of miR-29b was associated with a reduction of proliferative activity. TUNEL assay and Ki-67 staining revealed that miR-29b could induce apoptosis and cell cycle arrest in CRC cell lines.
Conclusions Our findings suggested that miR-29b is a useful prognostic marker for CRC, and could be a promising therapeutic target against CRC.
Citation Format: Akira Inoue, Hirofumi Yamamoto, Mamoru Uemura, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori. MiR-29b is a novel potential prognostic marker and inhibits cell proliferation in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 517. doi:10.1158/1538-7445.AM2014-517
Abstract 5171: An integrated analysis of copy number alteration and global gene expression reveals potential oncogenes underlying stomach cancer
Authors: Song Kyoung , Kim Ryong Nam , Jeon Sinyoung , Kim Hae I. , Choi Yoon-La , Shin Young Kee 
Published: May 2015

Abstract
Although several studies had been carried out to elucidate causative copy number alteration (CNA) underlying stomach carcinogenesis, deeper understanding of CNA accumulations in stomach cancer genome in association with age and histo-pathological subtypes remains still mysterious. Here, we report an integrated analysis of genome-wide copy number alteration and global mRNA expression of 40 stomach cancer tissues from 19 old and 21 young patients using aCGH and microarray. We identified that stomach cancer genomes showed recurrent amplifications at 17q12 (ERBB2 amplicon) and 7q31.1-7q31.31 (MET amplicon), and homozygous deletions at 9p21.3 and 17p12 regions harboring tumor suppressor genes. The most frequent gained regions were 3q26.2 (45%), 7p21.1 (&gt;50%), 7p12.2 (∼50%), 8q21.11-8q21.12 (45%), 8q22.3 (45%), 8q24.21 (45%), 8q24.22 (45%), 8q24.3 (45%), 20q12 (45%) and 20q13.2 (45%). The most frequent deleted regions were 21p11.1 (∼50%), 19p13.2 (45%), 19p13.3 (45%), 4q12 (40%), 3p21.31 (40%) and 1p35.3 (40%). Whereas young stomach cancer genomes showed more frequent gains at 7q21-7q31 than old cancer genomes, old stomach cancer genomes exhibited more recurrent gains at 8q12-8q24 and 1p12-1q42 than young cancer genomes, providing a clue about evolution of CNA accumulation in stomach cancer genome. Hierarchical expression clustering of 506 (in amplified regions) and 60 (in regions showing homozygous deletion) genes across the 40 stomach cancer samples reclassified pathological and histological subtypes based on expression pattern. Our integrated analysis of aCGH and microarray gene expression identified a pool of potential candidate stomach oncogenes and tumor suppressor genes. SiRNA-based interference of genes in MET amplicon and ERBB2 amplicon in stomach cancer cell lines significantly suppressed cell proliferation and migration, suggesting that they could be novel potential oncogenes in stomach cancer. Taken together, this study improves our understanding of stomach cancer genome evolution during CNA accumulation process and provides a new gene set of novel potential oncogenes and tumor suppressor genes that are essential for developing novel diagnostic biomarker and therapeutics for stomach cancer.
Citation Format: Kyoung Song, Ryong Nam Kim, Sinyoung Jeon, Hae In Kim, Yoon-La Choi, Young Kee Shin. An integrated analysis of copy number alteration and global gene expression reveals potential oncogenes underlying stomach cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5171. doi:10.1158/1538-7445.AM2014-5171
Abstract 5174: Toward understanding the genomic alterations in human gastric cancer
Authors: Cui Juan , Xu Ying 
Published: May 2015

Abstract
Gastric cancer is one of the most prevalent and aggressive cancers worldwide, and its molecular mechanism remains largely elusive. Although recent genome sequencing studies have uncovered rich information on cancer evolutions of many types, little is known about the genetic basis of gastric cancer due to its complexity. Here we report genomic mutations in primary gastric adenocarcinoma of human, based on the whole genome sequences of five pairs of cancer and matching normal samples. In total, 407 non-synonymous somatic point mutations have been identified in these genomes and the most recurrent mutations were harbored by genes such as Mucins (MUC3A and MUC12) and transcription factors (ZNF717, ZNF595 and TP53). 679 genomic rearrangements were detected which affect 355 protein-coding genes; and 76 genes show copy number changes. The focus of the functional analysis is to validate the biological relevance of each variant to cancer formation and progression, particularly to explore the to-be-determined causal relationships between the observed mutations in cancer genomes and cancer development. Additionally, we have attempted to investigate the mechanism of how these variants form in each tumor and discuss about multiple possible factors that may affect the susceptibility to each specific chromosomal changes. For examples, structural correlation between two boundaries of most rearrangements was observed based on the Hi-C data analysis, which indicate these rearrangements may happen among DNA fragments in close spatial proximity, especially when two endpoints stay in a similar replication phase. Sequence analysis on the flacking region of those rearrangements also showed clear evidences that about half of these genomic changes may be involved in the mechanism of microhomology-mediated break induced replication (MMBIR). Furthermore, DNA integrations from Helicobacter pylori have been detected for the first time, for instance, in the gene region of PREX2, which may reflect a new mechanism about how H. pylori induce cancer development. Overall, the in-depth analyses on these sequenced genomes lead to the detection of a myriad of novel genomic variations in gastric cancer, which in turn bring new insights in our understanding of the genetic basis and indicate new molecular mechanism of the gastric tumorigenesis.
Citation Format: Juan Cui, Ying Xu. Toward understanding the genomic alterations in human gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2014-5174
Abstract 5176: Implications of clonality relationship and CD133 expression between cancer synchronous/preceding adenomas and their colorectal adenocarcinoma pairs
Authors: Yang Chih-Yung , Tseng Ju-Yu , Lin Chi-Hung 
Published: May 2015

Abstract
Background:
It is thought that each cell only generates a unifocal lineage that is independent from one another in colorectal adenoma-carcinoma progression. This study compared the genome-wide copy number aberration profiles of adenoma and primary colorectal carcinomas (CRCs) derived from the same patient to trace their clonality relationship. The CD133 positive cells, putative colorectal cancer stem cells, are capable of tumor initiation and metastasis. Therefore, we also investigated the use of CD133 expression as a potential marker for prediction of subsequent risk of colorectal cancer.
Methods:
Microarray-based comparative genomic hybridization (aCGH) experiments were performed on 18 cancer-synchronous polyps (CSP) and 9 cancer-preceding polyps (CPP), together with their corresponding cancers, and 16 cases of incidental polyps (IP). Genome-wide copy number imbalances revealed by aCGH were analyzed to determine the clonal relationship between the paired adenomas and carcinomas. CD133 expression in cancerous tissue was evaluated by immunohistochemistry (IHC) staining.
Results:
There were more CGH lesions in CRC than CSP/CPP, and least in IP. Clonal relationship determined by tissues' aCGH profiles showed that 50 percent of CSP and 67 percent of CPP were clonally related to the concurrent or subsequent cancers, respectively. The expression level of stem cell marker CD133 was significantly higher in CSP/CPP than in IP (P&lt;0.0001), and even higher CD133 staining were observed in CSP/CPP that were clonally related to the corresponding carcinomas than CSP/CPP that were unrelated (P&lt;0.05).
Conclusions:
In the present study more than half of the polyp-carcinoma pairs share highly similar pattern of numerical chromosomal aberrations implying that the pairs might descent from the same monoclonal cell origin. The high expression of stem cell marker CD133 in colorectal adenomas is predictive of high cancer risk for polyp-bearing patients.
Citation Format: Chih-Yung Yang, Ju-Yu Tseng, Chi-Hung Lin. Implications of clonality relationship and CD133 expression between cancer synchronous/preceding adenomas and their colorectal adenocarcinoma pairs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5176. doi:10.1158/1538-7445.AM2014-5176
Abstract 5177: Genome-wide profiling of somatic mutations in liver cancers revealed significantly mutated genes and non-coding regions in liver cancers
Authors: Furuta Mayuko , Fuimoto Akihiro , Shiraishi Yuichi , Miyano Satoru , Tsunoda Tatsuhiko , Nakagawa Hidewaki 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Previously we have reported genomic aberrations detected by the whole genome sequencing (WGS) of 27 HCCs and frequently and recurrently mutated genes in this tumor (Nat Genet, 2012). Consistent with recent reports of WGS on human cancers from other groups, large parts of somatic point mutations (98.4%) were detected in non-coding genomic regions in our HCC samples. However, the consequence and significance of somatic mutations in non-coding regions are largely unknown. Here we analyzed 107 hepatitis C virus- (HCV-) associated HCCs by WGS analysis and calculated the somatic mutation rate of all single nucleotide variations (SNVs) and insertion-deletions (indels) within each 500-base bins on entire human genome. Among the whole genomic regions, 67 bins were significantly selected. After removing mutations in self-chained regions or simple repeat regions, which is expected to be false positives due to mapping errors, the bin containing exon 3 of CTNNB1 and multiple bins contains exons of TP53, which are known as driver mutations in HCCs, were highly ranked. In addition, entire coding region of the ALB gene showed high mutation rate compared with surrounding region distinctively. Interestingly, a recurrent short deletion on chromosome 18 was observed in the similar frequency as alterations of CTNNB1 or TP53. This short deletion was somatically detected in 35 of 321 liver cancers (10.9%) by Sanger sequencing. Significant accumulation of somatic mutations on exons of genes such as CTNNB1 and TP53 within entire genome through comparative analyses indicates their importance in hepatocarcinogenesis. Moreover, these results also suggest that novel mutations on non-coding regions, which are somatically and recurrently detected in higher rate in liver cancers, are involved in liver cancer development. These comprehensive approaches using WGS data will help the understanding of functions and alterations in non-coding regions occurred in cancer genome.
Citation Format: Mayuko Furuta, Akihiro Fuimoto, Yuichi Shiraishi, Satoru Miyano, Tatsuhiko Tsunoda, Hidewaki Nakagawa. Genome-wide profiling of somatic mutations in liver cancers revealed significantly mutated genes and non-coding regions in liver cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5177. doi:10.1158/1538-7445.AM2014-5177
Abstract 5183: Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome
Authors: Parpart Sonya T. , Roessler Stephanie , Dong Fei , Rao Vinay , Ji Junfang , Qin Lun–Xiu , Ye Qing–Hai , Tang Zhao–You , Jia Hu–Liang , Wang Xin Wei 
Published: May 2015

Abstract
Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Using microarray-based global microRNA profiling in 223 HCC patients, we found that members of the miR-29 family were the most significantly (p&lt;0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (p&lt;0.001) between miR-29 and DNMT3A gene expression suggesting that they might be functionally antagonistic. Moreover, global DNA methylation array profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Interestingly, miR-29 family physiological expression is low in mouse embryonic livers but gradually increases after birth. This is in contrary to AFP expression, which dramatically decreases after birth. Experimentally, we demonstrated that increased AFP expression, or conditioned media from AFP expressing HCC cells, inhibits miR-29a expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus and this effect is mediated through c-MYC binding to the miR-29a/b-1 promoter. Our findings indicate that tumor biology differs considerably between AFP+ HCC and AFP- HCC and that AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.
Citation Format: Sonya T. Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Junfang Ji, Lun–Xiu Qin, Qing–Hai Ye, Zhao–You Tang, Hu–Liang Jia, Xin Wei Wang. Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5183. doi:10.1158/1538-7445.AM2014-5183
Abstract 5186: Reduced expression of BRM in hepatocellular carcinoma
Authors: Yasui Kohichiroh , Gen Yasuyuki , Tomie Akira , Kitaichi Tomoko , Itoh Yoshito 
Published: May 2015

Abstract
Background: Hepatocellular carcinoma (HCC) is the fifth most common malignancy in men and the eighth most common in women worldwide. The eukaryotic genome is organized into highly ordered chromatin structures in the nucleus. Chromatin creates a barrier to nuclear processes, such as transcription, by obstructing the access of the transcriptional machinery and gene-specific regulators to recognition sequences within target promoters. The SWI/SNF protein complex, an ATPase-dependent chromatin remodeling enzyme, mobilizes nucleosomes and functions as a master regulator of gene expression and chromatin dynamics. SWI/SNF is a large multiprotein complex that contains either BRG1 or brahma (BRM) as the catalytic ATPase. Each SWI/SNF complex thus incorporates one of two possible ATPases, BRG1 or BRM.
Aims: To examine alterations of BRG1 and BRM in HCC.
Methods: We investigated DNA copy number aberrations in human HCC cell lines using a high-density oligonucleotide microarray. We determined DNA copy numbers and expression levels of BRG1 and BRM genes in primary HCC tumors, and conducted further searches for mutations in BRG1 and BRM genes.
Results: Homozygous deletion of the BRG1 gene was found in HCC cell line SNU398. Copy number losses of BRG1 and BRM genes were observed in 14 (26%) and 7 (13%) of 54 primary HCC tumors respectively. We found four somatic missense mutations in the BRG1 gene in two of 36 primary HCC tumors, but no mutations in BRM gene. Expression of BRM mRNA, but not BRG1 mRNA, was significantly reduced in primary HCC tumors, compared to non-tumor tissue counterparts. Immunohistochemical analyses of non-tumour liver tissues showed that BRM protein was expressed in hepatocytes and bile-duct epithelial cells, whereas BRG1 protein was expressed in bile-duct epithelial cells, but not in hepatocytes. BRM protein expression was lost in nine (22.5%) of 40 HCC tumours. Loss of BRM protein expression was significantly associated with poor overall survival.
Conclusion: Reduced expression of BRM may contribute to the carcinogenesis of HCC. Although deletions and mutations in BRG1 gene were identified, the role of BRG1 in HCC tumourigenesis remains unclear.
Citation Format: Kohichiroh Yasui, Yasuyuki Gen, Akira Tomie, Tomoko Kitaichi, Yoshito Itoh. Reduced expression of BRM in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2014-5186
Abstract 5188: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs
Authors: Hiyama Eiso , Kurihara Sho , Onitake Yoshiyuki , Morihara Nagisa , Ikeda Kyoko , Hiyama Keiko 
Published: May 2015

Abstract
Background: Hepatobastoma (HBL) accounts for more than 80% of childhood hepatic malignant tumors. The outcome of the HBL cases mainly depends on the biological characteristics and disease stagings, but the candidate genes correlated with HBL progression have not been identified. Sequence capture enrichment strategies and massively parallel next generation sequencing (NGS) were used for such gene discovery.Methods: Out of approximately 300 HBL case treated according to the JPLT (Japanese study group for Pediatric Liver Tumor)-2 protocol, 48 samples cases were analyzed by a method for whole-exome sequencing coupling Ilumina Nextera whole-exome capture to the Illumina DNA-sequencing platform. In these cases, 10 had lung metastatic cases and 13 of the remaining 38 cases had vascular invasion or multifocal lesions at admission. Consequently, 14 cases had a relapse and 10 cases died of disease. Using conventional technology, we investigated CNNB1 point-mutations and deletions in these cases.Results: Among these 48 HBL cases, mutation and deletion in CNNB1 exon 3 was identified in 40 cases, which had been already detected by conventional techniques. The remaining 8 cases showed the mutation of Wnt signal genes including AXIN1 and FAP genes. Among the cases with metastatic lesion and/or consequently dead cases, stemness-associated and cancer-associated genes showed homozygous deletion (e. g. CDKN2A), a homozygous inversion in the genes including NF1, and an unbalanced translocation. The response rates in the 35 cases that underwent neo-adjuvant chemotherapy revealed that existence of the mutations in several genes associated with proliferation was significantly correlated with chemo-resistance. Therefore, we are now constructing next clinical trial for HBL based on the whole-exome era.Conclusions: Whole-exome sequencing using NGS in hepatoblastoma revealed several candidates mutated or deleted genes except for CNNB1 in Wnt-signaling pathway. NGS can be also used in research and diagnostic settings to screen for mutations and deletion/insertion of the genes associated with malignant grade and chemo-resistance. Further NGS analysis provided important candidates of indicators for diagnostic and therapeutic targets for HBL clinical trials.
Note: This abstract was not presented at the meeting.
Citation Format: Eiso Hiyama, Sho Kurihara, Yoshiyuki Onitake, Nagisa Morihara, Kyoko Ikeda, Keiko Hiyama. Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5188. doi:10.1158/1538-7445.AM2014-5188