| 1. |
Chie Kikutake, Mikita Suyama, Pan-cancer analysis of whole-genome doubling and its association with patient prognosis., BMC cancer, 10.1186/s12885-023-11132-6, 23, 1, 619-619, 2023.07, BACKGROUND: Whole-genome doubling (WGD) is a common mutation in cancer. Various studies have suggested that WGD is associated with a poor prognosis in cancer. However, the detailed association between WGD occurrence and prognosis remains unclear. In this study, we aimed to elucidate the mechanism by which WGD affects prognosis using sequencing data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) and The Cancer Genome Atlas. METHODS: Whole-genome sequencing data of 23 cancer types were downloaded from PCAWG project. We defined the WGD event in each sample using the WGD status annotated using PCAWG. We used MutationTimeR to predict the relative timings of mutations and loss of heterozygosity (LOH) in WGD, thus evaluating their association with WGD. We also analyzed the association between WGD-associated factors and patient prognosis. RESULTS: WGD was associated with several factors, e.g., length of LOH regions. Survival analysis using WGD-associated factors revealed that longer LOH regions and LOH in chr17 were associated with poor prognosis in samples with WGD (WGD samples) and samples without WGD (nWGD samples). In addition to these two factors, nWGD samples showed that the number of mutations in tumor suppressor genes was associated with prognosis. Moreover, we explored the genes associated with prognosis in both samples separately. CONCLUSION: The prognosis-related factors in WGD samples differed significantly compared with those in nWGD samples. This study emphasizes the need for different treatment strategies for WGD and nWGD samples.. |
| 2. |
Chie Kikutake, Mikita Suyama, Possible involvement of silent mutations in cancer pathogenesis and evolution., Scientific reports, 10.1038/s41598-023-34452-w, 13, 1, 7593-7593, 2023.05, Recent studies have shown that some silent mutations can be harmful to various processes. In this study, we performed a comprehensive in silico analysis to elucidate the effects of silent mutations on cancer pathogenesis using exome sequencing data derived from the Cancer Genome Atlas. We focused on the codon optimality scores of silent mutations, which were defined as the difference between the optimality of synonymous codons, calculated using the codon usage table. The relationship between cancer evolution and silent mutations showed that the codon optimality score of the mutations that occurred later in carcinogenesis was significantly higher than of those that occurred earlier. In addition, mutations with higher scores were enriched in genes involved in the cell cycle and cell division, while those with lower scores were enriched in genes involved in apoptosis and cellular senescence. Our results demonstrate that some silent mutations can be involved in cancer pathogenesis.. |
| 3. |
Ryusei Kaneko, Ako Matsui, Mahiro Watanabe, Yoshihiro Harada, Mitsuhiro Kanamori, Natsumi Awata, Mio Kawazoe, Tomoaki Takao, Yutaro Kobayashi, Chie Kikutake, Mikita Suyama, Takashi Saito, Takaomi C Saido, Minako Ito, Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease., Inflammation and regeneration, 10.1186/s41232-023-00257-7, 43, 1, 20-20, 2023.03, BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis. METHODS: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry. RESULTS: An increase in aggregated Aβ was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation. CONCLUSION: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.. |
| 4. |
Toru Masuda, Shojiro Haji, Yasuhiro Nakashima, Mariko Tsuda, Daisaku Kimura, Akiko Takamatsu, Norifusa Iwahashi, Hironobu Umakoshi, Motoaki Shiratsuchi, Chie Kikutake, Mikita Suyama, Yasuyuki Ohkawa, Yoshihiro Ogawa, Identification of a drug-response gene in multiple myeloma through longitudinal single-cell transcriptome sequencing., iScience, 10.1016/j.isci.2022.104781, 25, 8, 104781-104781, 2022.08, Despite recent therapeutic advances for multiple myeloma (MM), relapse is very common. Here, we conducted longitudinal single-cell transcriptome sequencing (scRNA-seq) of MM cells from a patient with relapsed MM, treated with multiple anti-myeloma drugs. We observed five subclusters of MM cells, which appeared and/or disappeared in response to the therapeutic pressure, and identified cluster 3 which emerged during lenalidomide treatment and disappeared after proteasome inhibitor (PI) treatment. Among the differentially expressed genes in cluster 3, we found a candidate drug-response gene; pellino E3 ubiquitin-protein ligase family member 2 (PELI2), which is responsible for PI-induced cell death in in vitro assay. Kaplan-Meier survival analysis of database revealed that higher expression of PELI2 is associated with a better prognosis. Our integrated strategy combining longitudinal scRNA-seq analysis, in vitro functional assay, and database analysis would facilitate the understanding of clonal dynamics of MM in response to anti-myeloma drugs and identification of drug-response genes.. |
| 5. |
Norio Kobayashi, Hiroaki Okae, Hitoshi Hiura, Naoto Kubota, Eri H Kobayashi, Shun Shibata, Akira Oike, Takeshi Hori, Chie Kikutake, Hirotaka Hamada, Hirokazu Kaji, Mikita Suyama, Marie-Line Bortolin-Cavaillé, Jérôme Cavaillé, Takahiro Arima, The microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells., Nature communications, 10.1038/s41467-022-30775-w, 13, 1, 3071-3071, 2022.06, The first cell fate commitment during mammalian development is the specification of the inner cell mass and trophectoderm. This irreversible cell fate commitment should be epigenetically regulated, but the precise mechanism is largely unknown in humans. Here, we show that naïve human embryonic stem (hES) cells can transdifferentiate into trophoblast stem (hTS) cells, but primed hES cells cannot. Our transcriptome and methylome analyses reveal that a primate-specific miRNA cluster on chromosome 19 (C19MC) is active in naïve hES cells but epigenetically silenced in primed ones. Moreover, genome and epigenome editing using CRISPR/Cas systems demonstrate that C19MC is essential for hTS cell maintenance and C19MC-reactivated primed hES cells can give rise to hTS cells. Thus, we reveal that C19MC activation confers differentiation potential into trophoblast lineages on hES cells. Our findings are fundamental to understanding the epigenetic regulation of human early development and pluripotency.. |
| 6. |
Chie Kikutake, Mikita Suyama, Pan-cancer analysis of mutations in open chromatin regions and their possible association with cancer pathogenesis., Cancer medicine, 10.1002/cam4.4749, 2022.04, BACKGROUND: Open chromatin is associated with gene transcription. Previous studies have shown that the density of mutations in open chromatin regions is lower than that in flanking regions because of the higher accessibility of DNA repair machinery. However, in several cancer types, open chromatin regions show an increased local density of mutations in activated regulatory regions. Although the mutation distribution within open chromatin regions in cancer cells has been investigated, only few studies have focused on their functional implications in cancer. To reveal the impact of highly mutated open chromatin regions on cancer, we investigated the association between mutations in open chromatin regions and their possible functions. METHODS: Whole-genome sequencing data of 18 cancer types were downloaded from the PanCancer Analysis of Whole Genomes and Catalog of Somatic Mutations in Cancer. We quantified the mutations located in open chromatin regions defined by The Cancer Genome Atlas and classified open chromatin regions into three categories based on the number of mutations. Then, we investigated the chromatin state, amplification, and possible target genes of the open chromatin regions with a high number of mutations. We also analyzed the association between the number of mutations in open chromatin regions and patient prognosis. RESULTS: In some cancer types, the proportion of promoter or enhancer chromatin state in open chromatin regions with a high number of mutations was significantly higher than that in the regions with a low number of mutations. The possible target genes of open chromatin regions with a high number of mutations were more strongly associated with cancer than those of other open chromatin regions. Moreover, a high number of mutations in open chromatin regions was significantly associated with a poor prognosis in some cancer types. CONCLUSIONS: These results suggest that highly mutated open chromatin regions play an important role in cancer pathogenesis and can be effectively used to predict patient prognosis.. |
| 7. |
Zhuo Qu, Narumi Sakaguchi, Chie Kikutake, Mikita Suyama, Genome-wide identification of exon extension/shrinkage events induced by splice-site-creating mutations., RNA biology, 10.1080/15476286.2022.2139111, 19, 1, 1143-1152, 2022.01, Mutations that affect phenotypes have been identified primarily as those that directly alter amino acid sequences or disrupt splice sites. However, some mutations not located in functionally important sites can also affect phenotypes, such as splice-site-creating mutations (SCMs). To investigate how frequent exon extension/shrinkage events induced by SCMs occur in normal individuals, we used personal genome sequencing data and transcriptome data of the corresponding individuals and identified 371 exon extension/shrinkage events in normal individuals. This number was about three times higher than the number of pseudo-exon activation events identified in the previous study. The average numbers of exon extension and exon shrinkage events in each sample were 3.3 and 11.2, respectively. We also evaluated the impact of exon extension/shrinkage events on the resulting transcripts and their protein products and found that 40.2% of the identified events may have possible functional impacts by either generating premature termination codons in transcripts or affecting protein domains. Our results indicated that a certain fraction of SCMs identified in this study can be pathogenic mutations by creating novel splice sites.. |
| 8. |
Naoki Haratake, Qingjiang Hu, Tatsuro Okamoto, Tomoko Jogo, Gouji Toyokawa, Fumihiko Kinoshita, Tomoyoshi Takenaka, Tetsuzo Tagawa, Norifumi Iseda, Shinji Itoh, Yuichi Yamada, Yoshinao Oda, Mototsugu Shimokawa, Chie Kikutake, Mikita Suyama, Motoko Unoki, Hiroyuki Sasaki, Masaki Mori, Identification of SLC38A7 as a Prognostic Marker and Potential Therapeutic Target of Lung Squamous Cell Carcinoma., Annals of surgery, 10.1097/SLA.0000000000005001, 2021.06, BACKGROUND: No effective molecular targeted therapy has been established for squamous cell lung cancer (SCC). We conducted a comprehensive study of SCC patients using RNA-sequencing and The Cancer Genome Atlas (TCGA) dataset in order to clarify the driver oncogene of SCC. METHOD: Forty-six samples of 23 patients were totally analyzed with RNA-sequencing. We then searched for candidate-oncogenes of SCC using the TCGA database. To identify candidate oncogenes, we used the following two criteria: 1) the genes of interest were overexpressed in tumor tissues of SCC patients in comparison to normal tissues; and 2) using an integrated mRNA expression and DNA copy number profiling analysis using the TCGA dataset, the DNA copy number of the genes was positively correlated with the mRNA expression. RESULT: We identified 188 candidate-oncogenes. Among those, the high expression of SLC38A7 was a strong prognostic marker that was significantly associated with a poor prognosis in terms of both overall survival (OS) and recurrence-free survival in the TCGA dataset (p |
| 9. |
Chie Kikutake, Minako Yoshihara, Mikita Suyama, Pan-cancer analysis of non-coding recurrent mutations and their possible involvement in cancer pathogenesis., NAR cancer, 10.1093/narcan/zcab008, 3, 1, zcab008, 2021.03, Cancer-related mutations have been mainly identified in protein-coding regions. Recent studies have demonstrated that mutations in non-coding regions of the genome could also be a risk factor for cancer. However, the non-coding regions comprise 98% of the total length of the human genome and contain a huge number of mutations, making it difficult to interpret their impacts on pathogenesis of cancer. To comprehensively identify cancer-related non-coding mutations, we focused on recurrent mutations in non-coding regions using somatic mutation data from COSMIC and whole-genome sequencing data from The Cancer Genome Atlas (TCGA). We identified 21 574 recurrent mutations in non-coding regions that were shared by at least two different samples from both COSMIC and TCGA databases. Among them, 580 candidate cancer-related non-coding recurrent mutations were identified based on epigenomic and chromatin structure datasets. One of such mutation was located in RREB1 binding site that is thought to interact with TEAD1 promoter. Our results suggest that mutations may disrupt the binding of RREB1 to the candidate enhancer region and increase TEAD1 expression levels. Our findings demonstrate that non-coding recurrent mutations and coding mutations may contribute to the pathogenesis of cancer.. |
| 10. |
Ryota Matsuda, Yoshihiro Miyasaka, Yoshihiro Ohishi, Takeo Yamamoto, Kiyoshi Saeki, Naoki Mochidome, Atsushi Abe, Keigo Ozono, Koji Shindo, Takao Ohtsuka, Chie Kikutake, Masafumi Nakamura, Yoshinao Oda, Concomitant Intraductal Papillary Mucinous Neoplasm in Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas, Annals of surgery, 10.1097/SLA.0000000000003060, 271, 5, 941-948, 2020.05, OBJECTIVE: To determine the factors predicting the subsequent development of pancreatic ductal adenocarcinoma in remnant pancreas (PDAC-RP) after partial pancreatectomy for PDAC. SUMMARY BACKGROUND DATA: PDAC-RP after partial pancreatectomy for PDAC is currently not so rare because of improved prognosis of PDAC patients due to recent advances in surgical techniques and adjuvant therapy. However, the predictive factors related to PDAC-RP remain unknown. METHODS: We retrospectively reviewed the clinicopathological data of a consecutive series of 379 patients with PDAC treated by partial pancreatectomy between 1992 and 2015; 14 patients (3.69%) had PDAC-RP. Clinicopathological variables were compared between PDAC-RP and non-PDAC-RP. RESULTS: In univariate analysis, concomitant intraductal papillary mucinous neoplasm (IPMN) (P = 0.0005), cancer location (body/tail) (P = 0.0060), and lower T factor in UICC (P = 0.0039) were correlated with PDAC-RP development. Multivariate analysis revealed concomitant IPMN (P = 0.0135) to be an independent predictive factor for PDAC-RP. PDAC concomitant with IPMN had higher cumulative incidence of PDAC-RP (47.5%/10 yrs) than PDAC without IPMN (9.96%/10 yrs) (P = 0.0071). Moreover, the density of pancreatic intraepithelial neoplasia lesions in the background pancreas of cases of PDAC concomitant with IPMN (1.86/cm) was higher than that of cases of PDAC without IPMN (0.91/cm) (P = 0.0007). CONCLUSIONS: Concomitant IPMN in PDAC is an independent predictive factor for the development of new PDAC in remnant pancreas. Cancer susceptibility of remnant pancreas after resection for PDAC concomitant with IPMN is probably due to an increased density of pancreatic intraepithelial neoplasia lesions.. |
| 11. |
A Prediction Model for Detrusor Underactivity Based on Symptoms and Noninvasive Test Parameters in Men with Lower Urinary Tract Symptoms: An Analysis from a Large Group of Patients Undergoing Pressure Flow Studies.. |
| 12. |
Chie Kikutake, Minako Yoshihara, Tetsuya Sato, Daisuke Saito, Mikita Suyama, Pan-cancer analysis of intratumor heterogeneity associated with patient prognosis using multidimensional measures, Oncotarget, 10.18632/oncotarget.26485, 9, 102, 37689-37699, 2018.12, Human cancers accumulate various mutations during development and consist of highly heterogeneous cell populations. This phenomenon is called intratumor heterogeneity (ITH). ITH is known to be involved in tumor growth, progression, invasion, and metastasis, presenting obstacles to accurate diagnoses and effective treatments. Numerous studies have explored the dynamics of ITH, including constructions of phylogenetic trees in cancer samples using multiregional ultradeep sequencing and simulations of evolution using statistical models. Although ITH is associated with prognosis, it is still challenging to use the characteristics of ITH as prognostic factors because of difficulties in quantifying ITH precisely. In this study, we analyzed the relationship between patient prognosis and the distribution of variant allele frequencies (VAFs) in cancer samples (n = 6,064) across 16 cancer types registered in The Cancer Genome Atlas. To measure VAF distributions multidimensionally, we adopted parameters that define the shape of VAF distributions and evaluated the relationships between these parameters and prognosis. In seven cancer types, we found significant relationships between prognosis and VAF distributions. Moreover, we observed that samples with a larger amount of mutations were not necessarily linked to worse prognosis. By evaluating the ITH from multidimensional viewpoints, it will be possible to provide a more accurate prediction of cancer prognosis.. |
| 13. |
Concomitant Intraductal Papillary Mucinous Neoplasm in Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas.. |
| 14. |
Chie Kikutake, Minako Yoshihara, Tetsuya Sato, Daisuke Saito, Mikita Suyama, Intratumor heterogeneity of HMCN1 mutant alleles associated with poor prognosis in patients with breast cancer, Oncotarget, 10.18632/oncotarget.26071, 9, 70, 33337-33347, 2018.09, Human breast cancers comprise a complex and highly heterogeneous population of tumor cells. Intratumor heterogeneity is an underlying cause of resistance to effective therapies and disease recurrence. To explore prognostic factors based on intratumor heterogeneity, we analyzed genomic mutations in breast cancer patients registered in The Cancer Genome Atlas. We calculated the variant allele frequency (VAF) at each mutation site and evaluated the associations of VAFs with the prognosis of breast cancer. VAFs of HMCN1 correlated with the prognosis and lymph node status. Although the detailed function of HMCN1 remains unknown, it is located in extracellular matrix and the mutation in the gene might be associated with cancer cell invasion and metastasis. This finding suggests that HMCN1 is a potential metastatic factor and can be a candidate gene for targeted breast cancer therapy.. |
| 15. |
Koji Yahara, Yoshikazu Furuta, Shinpei Morimoto, Chie Kikutake, Sho Komukai, Dorota Matelska, Stanislaw Dunin-Horkawicz, Janusz M. Bujnicki, Ikuo Uchiyama, Ichizo Kobayashi, Genome-wide survey of codons under diversifying selection in a highly recombining bacterial species, Helicobacter pylori, DNA RESEARCH, 10.1093/dnares/dsw003, 23, 2, 135-143, 2016.04, Selection has been a central issue in biology in eukaryotes as well as prokaryotes. Inference of selection in recombining bacterial species, compared with clonal ones, has been a challenge. It is not known how codons under diversifying selection are distributed along the chromosome or among functional categories or how frequently such codons are subject to mutual homologous recombination. Here, we explored these questions by analysing genes present in > 90% among 29 genomes of Helicobacter pylori, one of the bacterial species with the highest mutation and recombination rates. By a method for recombining sequences, we identified codons under diversifying selection (dN/dS > 1), which were widely distributed and accounted for similar to 0.2% of all the codons of the genome. The codons were enriched in genes of host interaction/cell surface and genome maintenance (DNA replication, recombination, repair, and restriction modification system). The encoded amino acid residues were sometimes found adjacent to critical catalytic/binding residues in protein structures. Furthermore, by estimating the intensity of homologous recombination at a single nucleotide level, we found that these codons appear to be more frequently subject to recombination. We expect that the present study provides a new approach to population genomics of selection in recombining prokaryotes.. |
| 16. |
Chie Kikutake, Koji Yahara, Identification of Epigenetic Biomarkers of Lung Adenocarcinoma through Multi-Omics Data Analysis, PLOS ONE, 10.1371/journal.pone.0152918, 11, 4, e0152918, 2016.04, Epigenetic mechanisms such as DNA methylation or histone modifications are essential for the regulation of gene expression and development of tissues. Alteration of epigenetic modifications can be used as an epigenetic biomarker for diagnosis and as promising targets for epigenetic therapy. A recent study explored cancer-cell specific epigenetic biomarkers by examining different types of epigenetic modifications simultaneously. However, it was based on microarrays and reported biomarkers that were also present in normal cells at a low frequency. Here, we first analyzed multi-omics data (including ChIP-Seq data of six types of histone modifications: H3K27ac, H3K4me1, H3K9me3, H3K36me3, H3K27me3, and H3K4me3) obtained from 26 lung adenocarcinoma cell lines and a normal cell line. We identified six genes with both H3K27ac and H3K4me3 histone modifications in their promoter regions, which were not present in the normal cell line, but present in >= 85% (22 out of 26) and |
| 17. |
Chie Kikutake, Masaaki Shinohara, Hisanori Takagi, Takashi Nakashima, Makoto Kimura, The C-terminal portion of an archaeal toxin, aRelE, plays a crucial role in protein synthesis inhibition, Bioscience, Biotechnology and Biochemistry, 10.1271/bbb.90485, 73, 12, 2766-2768, 2009.12, Mutations of amino acids in the C-terminal region of an archaeal toxin, aRelE, from Pyrococcus horikoshii were characterized with respect to protein synthesis inhibitory activity and 70S ribosome-binding activity. The results suggest that basic residues at the C-terminal region in aRelE play a crucial role both in 70S ribosome binding and in protein synthesis inhibition activities.. |
