5731 results for "canc*"

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• Homologous recombination DNA repair deficiency and activity of PARP inhibition in primary triple negative breast cancer

  Study EGAS00001004190

• Single-cell RNA sequencing data using the BDRhapsody platform of human B-cell lymphoma. The data comprises both immune and stromal cells of 19 individuals (6 healthy control and 13 cancer patients)

  Study EGAS00001006986

• Genomic and transcriptomic analysis of thymic epithelial tumors

  Study EGAS00001004227

• Multi-Layered Molecular Profiling Informs the Diagnosis and Targeted Therapy of Desmoplastic Small Round Cell Tumor

  Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft tissue sarcoma with dismal prognosis and limited therapeutic options. Here, we identified individual therapeutic targets in a cohort of 30 DSRCT patients by use of multilayered molecular profiling (genomic, transcriptomic, and (phospho-)proteomic analyses) within the DKFZ NCT DKTK MASTER program. 28 of the 30 patients received at least one personalized treatment recommendation. In line with the observation that DSRCTs are an entity with a low mutational load, most of the treatment recommendations were based on target gene or -protein expression. 13 patients received a recommended therapy, resulting in four partial responses, four stable diseases, and five progressive diseases. Eight of 13 patients received the multi tyrosine kinase inhibitor pazopanib, with mixed response. Based on high ERBB2 expression levels, two patients received the antibody drug conjugate trastuzumab deruxtecan (T-DXd), showed exceptional, long-lasting responses and are currently (8/2024) still on treatment and progression-free. We detected high ERBB2 protein expression in all DSRCT samples with proteome data (n = 9), which suggests that ERBB2 may be a particularly useful therapeutic target for DSRCT patients. For one of the two exceptional responders we did not detect a substantial ERBB2/HER2 overexpression, which may indicate that T-DXd could also be efficacious in DSRCT patients with low levels of HER2, as also described for breast cancer patients. In conclusion, multi-omic molecular profiling revealed personalized therapeutic targets in patients with DSRCT with HER2 targeting, with T-DXd as a promising therapeutic option for this ultra-rare and difficult-to-treat tumor entity.

  Study EGAS00001007934

• Leveraging intratumor heterogeneity in locally advanced prostate cancer to identify molecular processes driving metastasis

  Study EGAS00001006715

• Target sequencing of 27 cancer-predisposing genes in Japanese colorectal cancer patients

  Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

  Study JGAS000346

• Identification of biomarkers for prediction of efficacy of microtubule inhibitors and antifolates in non-small cell lung cancer

  Identification of predictive markers based on transcriptome modules for microtubule inhibitors of lung adenocarcinoma patients

  Study JGAS000267

• Proteogenomic discovery of a novel class of cancer antigens by HLA ligandome analysis of colon cancer tissues

  CD8+ T cells recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Recent advances in proteogenomic analysis of HLA ligandomes have demonstrated that cells present a subset of cryptic peptides derived from non-coding regions of the genome; however, the roles of cryptic HLA ligands in tumor immunity remain unknown. In the present study, we comprehensively and quantitatively investigated the HLA class I ligandome of a set of human colorectal cancer (CRC) and matched normal tissues, showing that cryptic translation products account for a small fraction of the HLA class I ligandome and serve as antigens for patient T cell surveillance against colon cancer.

  Study JGAS000280

• Comprehensive analyses of clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma

  Combined hepatocellular and cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer. We performed whole exome sequencing to clarify the relationship between genetic mutations and clinicopathological features in cHCC-CCA.

  Study JGAS000599

• Whole exome sequencing of patients with esophageal squamous cell carcinoma receiving chemoradiotherapy

  We performed multi-region whole exome sequencing (WES) of pre-treatment and recurrent esophageal cancer receiving chemoradiotherapy in order to characterize clonal evolution of treatment resistant clones. Furthermore, additional solitary pre-treatment tumor samples were subjected to WES to detect biomarkers predicting clinical outcome.

  Study JGAS000227

• Ten colorectal cancer patients with locally advanced primary tumors who underwent primary tumor resection following neoadjuvant chemotherapy (NAC).

  Background We aim to investigate the utility of serial gene mutation tracking for locally advanced CRC in those who underwent curative resection following neoadjuvant chemotherapy. Methods We prospectively collected 10 locally advanced CRC cases for which curative resection was performed following preoperative neoadjuvant chemotherapy. Tissues from the primary tumour, distant metastatic tumours, and blood plasma were obtained during serial treatment. Comprehensive mutation analysis of 47 cancer-associated genes was performed using a pre-designed gene panel and next-generation sequencing. Results All cases showed a partial response to neoadjuvant chemotherapy, and pathological R0 resection was accomplished. In primary tumours, non-synonymous mutations were detected at between 1 and 14 sites before chemotherapy and at between 1 and 2 sites after. Founder mutations were precisely detected in blood plasma and metastatic tumours during longitudinal treatment. Conclusions Serial mutational analysis indicated that subclonal selection occurs during chemotherapy and that plasma can substitute for tumourous tissue in mutational analysis for drug selection and treatment decisions.

  Study JGAS000222

• Development of Novel Chondrosarcoma Organoid Models for Drug Discovery

  Chondrosarcoma is a rare and aggressive malignant bone tumor characterized by resistance to conventional chemotherapy and radiotherapy. Its pathogenesis remains poorly understood, although recurrent mutations such as IDH1 have been implicated in tumor development. We treated patients with chondrosarcoma at the Osaka International Cancer Institute and established two organoid cultures from resected tumor specimens using a modified air-liquid interface method. After serial passaging, the organoids were successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoids retained key histological features and genetic characteristics of the original tumors. These organoid models provide a novel and reliable platform for studying the biology of chondrosarcoma and may facilitate the development of effective therapeutic strategies for this treatment-resistant tumor.

  Study JGAS000834

• PanCancer genome analysis in 5143 Japanese cancer patients

  This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called ���High-tech Omics-based Patient Evaluation��� or ���Project HOPE��� conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling.

  Study JGAS000274

• Comprehensive molecular profiling of subsequent solid cancers after allogenic hematopoietic cell transplantation

  Subsequent solid cancers after allogenic hematopoietic cell transplantation may have unique genomic profiles compared with de novo cancers. In order to identify such profiles, we applied whole exome sequencing (WES) of subsequent solid cancers after allogeneic hematopoietic cell transplantation as well as de novo cancers.

  Study JGAS000377

• Genomic subtypes and cellular phenotypes of high-grade endometrial carcinoma

  Based on the mechanism of carcinogenesis, endometrial cancer (EC) is classified into two major types, Type I and Type II. Type I EC is characterized by G1/G2 histology, accounting for about 80% of all uterine carcinomas. On the other hand, Type II EC, which often develops after menopause, is estrogen-independent and consists of serous and clear cell carcinomas. G3 EC is often classified as a Type II EC, but the pathogenesis is thought to be a mixture of estrogen-dependent and estrogen-independent carcinogenesis. We will conduct an integrative genomic analysis to clarify the pathogenesis of Type II EC and redefine its classification by combining genomic status with cell phenotypes reflected in gene expression profiles.

  Study JGAS000753

• Molecular Characterization of Large Cell Neuroendocrine Carcinoma of the Lung by Multilayered Omics Analysis

  Large cell neuroendocrine carcinoma (LCNEC) is a rare lung cancer type with a very poor prognosis. The underlying molecular features remain unclear. Here, we conducted a multi-omics analysis of 27 LCNEC cases along with 7 small cell lung carcinoma and aimed to propose new classification by extracting genomic and transcriptomic features in LCNEC, leading to the elucidation of the therapeutic approaches.

  Study JGAS000832

• Target bisulfite sequencing of endometrial cancer

  This study aims to investigate epigenetic alterations in the HLA-A locus in endometrial cancer. Targeted bisulfite sequencing was performed to evaluate DNA methylation status of the HLA-A region in a cohort of endometrial cancer samples. The resulting data were used to assess the association between HLA-A methylation and tumor immune microenvironment. These findings contribute to understanding the role of epigenetic regulation of antigen presentation in endometrial cancer.

  Study JGAS000897

• Development of Novel Histiocytic Sarcoma Organoid Model for Drug Discovery

  Histiocytic sarcoma is an extremely rare and aggressive hematopoietic malignancy. Its pathogenesis remains poorly understood and effective treatments are lacking. We treated a patient with histiocytic sarcoma of soft tissue in Osaka International Cancer Institute and established an organoid culture from a resected tumor specimen using a modified air���liquid interface method. After serial passaging, the organoid was successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoid retained key histological features and genetic characteristics of the original tumor. This organoid model offers a novel and reliable platform for studying the biology of histiocytic sarcoma and may contribute to the development of future therapeutic strategies.

  Study JGAS000807

• Identification and phenotypic characterization of neoantigen-specific cytotoxic CD4+ T cells in endometrial cancer

  Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in anti-tumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II (HLA-II)-positive endometrial cancer with inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte (TIL) responses. We experimentally demonstrate that neoantigen-specific CD4+ TILs lyse target cells in an HLA-II-dependent manner. Single cell analysis of the TME coupled with T cell receptor (TCR) sequencing revealed the presence of CD4+ T cell clusters characterized by CXCL13 expression. The CXCL13+ clusters contained two subclusters with distinct cytotoxic gene expression patterns. The identified neoantigen-specific CD4+ T cells were found exclusively in one of the CXCL13-positive subclusters characterized by GZMB and CCL5 expression. These results demonstrate the involvement of tumor reactive CD4+ T cells with cytotoxic function in immune surveillance of endometrial cancer and reveal their transcriptomic signature.

  Study JGAS000766

• Target bisulfite sequencing of uterine cervical cancer

  We performed targeted bisulfite sequencing of the HLA-A promoter region in cervical tissue samples to investigate DNA methylation patterns that regulate immune recognition and antigen presentation, which may influence viral immune surveillance and malignant transformation in cervical pathology.

  Study JGAS000825

• Metabolomic and transcriptomic analyses identify metabolic alterations and immune suppression in ovarian cancer

  The objective of this study is to identify metabolic alterations and related phenotypes specific to ovarian cancer by performing metabolomic analysis of plasma and tissue samples. In addition, transcriptomic analysis is conducted to investigate the relationship between metabolic status and immune-related gene expression. By integrating metabolomic and transcriptomic data, this study aims to clarify how metabolic reprogramming contributes to tumor progression and immune suppression, particularly the reduction of natural killer (NK) cell activity, in ovarian cancer.

  Study JGAS000831

• Whole exome sequencing of uterine cervical cancer

  We conducted whole-exome sequencing of cervical tissue samples to evaluate HLA loss of heterozygosity (LOH) and B2M gene mutations, which are key mechanisms of immune evasion that allow cancer cells to escape T-cell recognition and antigen presentation.

  Study JGAS000824

• "Elucidation of Immune Status and Its Clinical Significance in Patients with Solid Tumors, Including Gastrointestinal Cancers": A Phase II Clinical Trial of Lenvatinib Plus Pembrolizumab in Patients with Advanced Gastric Cancer

  The objective is to analyze tumor and normal cell exome sequencing of gastric cancer patients participating in the EPOC1706 trial before treatment and RNA sequencing specimens of tumor biopsy specimens at two points before treatment and after the combination therapy of Lenvatinib plus pembrolizumab, in order to search for biomarkers to predict treatment response. Exome sequencing from 10 gastric cancer patients participating in the EPOC1706 trial, and RNA sequencing of tumor biopsy specimens at two time points before treatment (9 patients) and after the combination therapy (8 patients) were obtained.

  Study JGAS000894

• Development of New Diagnostics, Therapeutics, and Prevention Methods for Personalized Medicine Based on Comprehensive Cancer-Related Gene Exome Analysis and Information Analysis Using Cancer Specimens Stored in TMDU Biobank.

  Biobanked tumor samples are a valuable resource in real-world solid tumor research. Panel-based genomic profiling enables the identification of clinically significant alterations that inform personalized diagnostic and treatment decisions. This study aimed to characterize the genomic landscape of solid tumors collected through the TMDU Biobank by summarizing mutational, copy number, and gene fusion alterations in a large and diverse patient cohort. This dataset contains summary-level genomic information from 1,996 tumor samples analyzed by ACT Genomics and ACT med using the ACTOnco Comprehensive 440-Gene Cancer Panel. Data provided includes (1) gene-level mutation counts, (2) a summary of copy number alterations, and (3) a summary of detected fusion events. Clinical attributes such as ICD-10 codes, age group, sex, tumor mutational burden (TMB), and microsatellite instability (MSI) status were included at the aggregate level. Summary statistics were generated from three source tables (gene, sample, and copy number data) using standardized processing rules. Due to contractual and ethical considerations, individual-level mutation locations and raw sequence data are not included; only summary-level information is provided. This dataset will support future research in tumor-type-specific genomic patterns, molecular characterization of solid malignancies, and precision oncology.

  Study JGAS000863

• Construction of endoscopic biopsy banking for understanding the intestinal environment in colorectal diseases and exploratory studies using these banking systems.

  Colorectal cancer is the most common type of cancer in Japan. Although some colorectal cancers have a genetic background, most colorectal cancers are sporadic. Known risk factors for colorectal cancer include smoking, obesity, lack of exercise, and red and processed meat. Furthermore, although it has been suggested that changes in the intestinal environment due to changes in diet and lifestyle may be involved in the increased incidence of colorectal cancer in Japan, the molecular mechanism has not yet been fully elucidated. The main objective of this study is to elucidate the changes in the intestinal environment that cause colorectal tumors, and also to contribute to the establishment of colorectal mucosal tissue banking in Japan.

  Study JGAS000655

• Microbiomic and immunogenic biomarkers of adjuvant chemotherapy efficacy in stage III colorectal cancer

  The standard treatment for stage III colorectal cancer (CRC) is surgery, followed by adjuvant chemotherapy (AC). However, the efficacy of AC is limited, and approximately 30% of patients experience recurrence. Therefore, easily assessable molecular biomarkers that can predict response to AC are needed. Here, we aimed to identify predictive biomarkers of response to AC using tumor transcriptomic data. Tumor specimens from 253 patients who underwent surgery for stage III CRC between 1997 and 2019 were analyzed using RNA sequencing. Transcriptional subtyping and analyses of gut microbiome, immune cell fractions, and T-cell receptor (TCR) were performed to identify factors associated with recurrence-free survival (RFS) in patients treated with or without AC. Of 253 patients, 118 (46.6%) received AC. Twenty phyla and 799 species of the microbiomes were identified, among which Fusobacteria were identified in 247 patients (97.6%). Multivariable Cox proportional hazards regression analysis of patients who received AC showed that intratumoral Fusobacterium and M1 macrophage abundance and diversity of TCR alpha and delta (TRAD) were independently associated with RFS. Fusobacterium and M1 macrophage abundance, and TRAD diversity were associated with the response to AC, suggesting that these factors could serve as biomarkers for personalized treatment in stage III CRC.

  Study JGAS000875

• Whole-exome sequencing of uterine carcinosarcoma in a young woman with HBOC (tumor-normal pair)

  This study deposits controlled-access human genomic data (tumor-normal whole-exome sequencing) from a patient with uterine carcinosarcoma and hereditary breast and ovarian cancer (HBOC) syndrome, to support reproducibility of reported genomic findings.

  Study JGAS000883

• Analytical study of protein function and RNA expression involved in predicting treatment efficacy and adverse event development in lung cancer radiotherapy.

  The purpose of this study is to elucidate the functions of DNA repair proteins and RNA expression that are involved in the therapeutic efficacy and adverse events of radiotherapy for lung cancer at our hospital. In particular, this is an exploratory study to identify proteins and RNAs involved in the expression of proteins that are likely to be involved in the prediction of radiotherapy response and adverse events.

  Study JGAS000545

• Whole-exome sequencing of Helicobacter pylori-uninfected normal gastric gland

  Recent studies showed that somatic mutations accumulate in normal tissues with age; however, mutation accumulation in the Helicobacter pylori-uninfected normal gastric mucosa has not been reported. A total of 18 biopsied gastric mucosa were obtained from nine subjects without Helicobacter pylori-infection or gastric cancer. Gastric epithelia were manually dissociated from the lamina propria. Subsequently, single glands were picked up under a stereomicroscope. Genomic DNA isolated from each gland was subjected to whole-exome sequencing.

  Study JGAS000313

• Single cell RNA seq of breast cancer stem cells

  RNA sequences of breast cancer have been investigated for many patients. Recently it has been shown that there are intra-heterogeneity in tumor tissues. When the tumor cells were sequenced in bulk condition, only the major populations' mRNA will be detected. With respect to breast cancer, it has been also reported that cancer cells can sub-gropued into cancer stem cells and non-cancer stem cells. Although the mRNA expressions' difference between this two groups has been profoundly investigated, whether each group is composed by unique cell or not is yet to be elucidated. Since cancer stem cells are the thought to be the major contributor of metastasis and/or recurrence, we focused on cancer stem cells in this study. We separated cancer cells into cancer stem cells and non-cancer stem cells exploiting cancer stem cell specific surface markers. Thereafter, we sequenced mRNA of cancer stem cells in single cell resolution. From this result, we examined whether these cells can be sub-grouped or not.

  Study JGAS000305

• Identification and Characterization of Cancer Mutations in Japanese LungAdenocarcinoma without Sequencing of Normal Tissue Counterparts

  We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinomapatients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may beused for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normaltissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.

  Study JGAS000001

• Identifying aberrant splicing isoforms and potential neoantigens in non-small cell lung cancer

  To identify aberrant splicing isoforms and potential neoantigens, we performed full-length cDNA sequencing of seven non-small cell lung cancer specimens using a long-read sequencer MinION. We detected aberrant splicing isoforms using our bioinformatics pipeline and constructed a comprehensive catalogue.

  Study JGAS000245

• Integrated Exome and RNA Sequencing of Dedifferentiated Liposarcoma

  Multiomics analysis of rare cancers to identify genetic alterations related with pathogenesis and prognosis. To identification of genetics alterations of Dedifferentiated liposarcoma, DNAs and RNAs were extracted from dedifferentiated liposarcoma and paired non-cancer (normal) tissues. NGS libaraies were prepared by using Agilent SureSelect XT Human All Exon V5 + IncRNA kit for whole exome sequencing (WES) and TruSeq Stranded mRNA Prep kit or TruSeq RNA Access Library Prep kit (RNA seq). Sequencing was perfomred by Illumina HiSeq 2500.

  Study JGAS000177

• BHD-associated kidney cancer

  Background Birt-Hogg-Dub? (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene, FLCN is a tumor suppressor for kidney cancer which plays an important role for energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, how FLCN-deficiency leads to renal tumorigenesis is unclear. Results Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations (CNV) of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. Somatic mutation analysis revealed BHD-associated kidney cancer has quite few common mutations in specific genes; however, chromatin remodeling genes in total were frequently mutated in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis revealed that glycolysis, pentose phosphate pathway and lipid metabolism were upregulated whereas the rate of beta oxydation and TCA cycle is decreased in BHD-associated kidney cancer compared to normal adjacent kidney. Conclusions BHD-associated kidney cancer displays a unique molecular characteristics which is totally different from that of sporadic kidney cancer, providing the mechanistic insight into tumorigenesis under FLCN deficiency as well as the foundation for the development of novel therapeutics for kidney cancer.

  Study JGAS000115

• Whole exome sequence and transcliptomic analysis of tumor tissues with hepatocellular carcinoma and metastatic liver cancer

  We used our pipeline to select neoepitopes with high immunogenicity from the tumor tissues of 46 patients with hepatocellular carcinoma or metastasis of colorectal carcinoma by whole exome sequence and transcriptomic analysis with tumor tissue.

  Study JGAS000507

• Genome and gene analysis of gastrointestinal cancer and elucidation of its clinicopathological significance

  Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we molecularly compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLLs, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC, regardless of CTNNB1 mutation status, because ?-catenin did not translocate into the nucleus due to the E-Cadherin/?-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in the target genes. Similarly, cell cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC with TP53 and/or RB1 gene mutations associated with chromosomal deletion of 4q and/or 16q. Differing from the expression profile, HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Taken together, additional molecular events besides driver gene mutations cooperatively contribute to transcriptional activation of downstream targets as HCC progresses, according to the methylation status of the associated genes.

  Study JGAS000233

• Identification of driver oncogenes in scirrhous-type gastric cancer cell lines

  Scirrhous type gastric cancer (SGC) is one of the most intractable cancer subtypes in human, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next generation sequencers has been hampered by low tumor contents by the markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources to search for novel oncogenes in. Here we have conducted whole exome sequencing and RNA sequencing on two SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and the tyrosine-kinase domains of IGF1R. Further, both of CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. On the other hand, OCUM-9 seems to possess multiple oncogenic events in its genome. The MET gene is highly amplified, and the treatment of OCUM-9 with crizotinib, a MET inhibitor, results in cell death. Further, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.

  Study JGAS000179

• Whole genome sequence analysis in patients with primary central nervous system lymphomas

  We performed target amplicon sequencing analysis in 28 patients with primary central nervous system lymphomas using target capture technology (NGS) on Cancer Panel to explore molecular targets.

  Study JGAS000258

• WGS analysis of Japanese liver cancer

  Liver cancer is prevalent worldwide, mainly associated with virus infection, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 Japanese liver cancers. Our comprehensive analysis elucidated point mutations in non-coding regions, structural variants (SVs), and virus integrations, in addition to coding mutations, and demonstrated new mutational signatures related with liver carcinogenesis, novel recurrently mutated coding and non-coding regions such as lincRNA NEAT1/MALAT1, promoters, CTCF binding sites, and regulatory regions. SV analysis found a significant association with replication timing, and revealed that known cancer genes (CDKN2A, CCND1, APC, and TERT) and new cancer genes (ASH1L, NCOR1, MACROD2) were recurrently affected by SVs, leading to altered expression of nearby genes. These results emphasize the value of whole genome sequencing analysis to discover cancer driver mutations and to understand comprehensive molecular profiles of liver cancer, especially for SVs and non-coding mutations.

  Study JGAS000151

• Immuno-genomic Profiling of Biopsy Specimens Predicts Neoadjuvant Chemotherapy Response in Esophageal Squamous Cell Carcinoma

  Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is primarily treated with platinum-based neoadjuvant chemotherapy (NAC). Some ESCCs respond well to NAC. However, biomarkers to predict NAC sensitivity and their response mechanism in ESCC remain unclear. We introduce a model by machine learning and validated its potential to predict the NAC response in ESCC. To create this model, we performed whole genome sequencing and RNA-seq analysis on totally 141 ESCC biopsy specimens before NAC treatment and analyzed their immuno-genomic features and association with NAC response. Neutrophils infiltration could play an important role in ESCC response to NAC. We also demonstrated that specific copy number alterations and copy number signatures in the ESCC genome were significantly associated with NAC response. The interactions between the tumor genome and immune features of ESCC are likely to be a new indicator of therapeutic capability and a new therapeutic target for ESCC, and machine learning prediction for NAC response is useful.

  Study JGAS000535

• Identification of therapeutic target molecules for prostate cancer by using next generation sequencer

  Comprehensive transcriptional characterization of cancer tissues can reveal important molecular signatures associated with the disease progression. Long non-coding RNA (LncRNA) has a diversity of functions such as transcription, epigenetic and gene regulation in cancer cells including prostate cancer cells. Here, we performed directional RNA-sequence (RNA-seq) on clinical samples obtained from prostate cancer (PC) and lethal castration-resistant PC (CRPC) patients to identify novel molecular signatures including protein coding genes and non-coding RNAs induced in CRPC tissues.

  Study JGAS000198

• Geriatric Oncology Database of genotypes and methylation, gene expression, clinical data, and survey results on psychosocial and physical conditions in Japanese elderly cancer patients to establish truly effective treatment strategy

  Owing to the advent of super-aged society, cancer mortality in Japan is forecasted to become an all-time high. The management of elderly patients with cancer is a serious health issue and the need for specific care guidelines for this population is critical in Japan. The significant individual differences in comorbidity, physical and mental functioning, and social problems among aging individuals are obstacles to the progress. The response to cancer treatment varies significantly among patients, even in the same stage of the same type of cancer. Older aged patients are still less likely to be offered participation in clinical trials, thus the number of clinical evidences is limited. The molecular mechanisms regulating the physiological process of ageing and senescence, and cancer are far from understood. To establish a truly effective treatment algorithm, we attempted to develop a geriatric oncology database for genotypes and methylation, gene expression, clinical data, and survey results on psychosocial and physical conditions in Japanese elderly cancer patients in this retrospective study. The genomic analysis was performed in 62, 106, and 173 cases, respectively for gastric, colon and lung cancers. The clinical data and survey results on psychosocial and physical conditions were collected from 166, 313, and 344 patients respectively for gastric, colon and lung cancers, and also collected from 357, 49, and 300 benign cases respectively for cardiovascular disorder, respiratory dysfunction, diabetes and nephropathy as the analysis control.

  Study JGAS000061

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000229

• Exploration of predictive biomarkers for postoperative recurrence of stage II/III colorectal cancer using genomic sequencing

  To identify biomarkers that can predict treatment outcomes, we compared the mutational profiles of surgically resected specimens from patients with recurrent cancer with those from patients with non-recurrent cancer. Target sequencing, whole-exome sequencing (WES), or whole-genome sequencing (WGS) was perfomed.

  Study JGAS000335

• Project for Development of Innovative Research on Cancer Therapeutics;Shuttle system between petient-derived xenograft and ex vivo culture for innovative platform of evaluating drug sensitivity.

  We developed CTOS (cancer tissue-originated spheroid) panel covering diversity among patients for colorectal cancer, lung cancer and cervical small cell carcinoma. We then carried out exome sequence analysis of tumor tissues, cell lines and CTOS derived from patients to validate qualitative changes in preparation, culture, cell line, transplantation and passage of CTOS pathologically, biochemically, molecular biologically.

  Study JGAS000089

• Mutational anysis of breast cancer stem cells

  Exome sequences of breast cancer have been investigated for many patients. Recently it has been shown that there are intra-heterogeneity in tumor tissues. When the tumor cells were sequenced in bulk condition, only the major populations��� (clones���) mutations will be detected. Based on cancer stem theory, each populations��� cells are derived from each cancer stem cells, which their numbers are not so different among different clones. Here, we separated cancer cells into cancer stem cells and non-cancer stem cells exploiting cancer stem cell specific surface markers. By comping two groups��� mutation, we identified mutations, which were only detected in stem cell population. These mutations could be the mutations in cells of small size populations, and maybe the important mutations to understand the heterogeneity of tumor tissues, progression, and/or prediction for the outcome to therapies.

  Study JGAS000304

• Analysis of genes related to the oncogenesis, progression or effectiveness of drug therapies of urological tumors .

  To clarify the oncogenesis and the progression mechanism of urological tumors, we continuously collect tumor samples of our patients with high quality. Then we used them to comprehensive analyses such as genome sequencing or epi-genome sequencing. Through these analyses, we aim for elucidating the oncogenesis or for developing newly treatment strategies of each cancer.

  Study JGAS000303

• Treg cell subset-specific gene expression patterns in human head and neck cancer

  Backgrand: The occurrence of head and neck cancer has been increased all over the world. Although the prognosis has been improved by using several treatment modalities including immunotherapy, it is still unsatisfying. It is still unclear why the immunotherapy is effective only for partial amount of patients. To resolve this problem and to make a new treatment strategy based on human immune system, further investigation of antitumor immunity is required. Regulatory T (Treg) cells play critical roles in human immune responses including antitumor immunity. Therefore, the research to elucidate Treg function is strongly urged to clarify the mechanisms of antitumor immunity. Methods: We performed RNA-seuencing analysis of regulatory T cells infiltrating head and neck cancer. We devided into four populations, DP, CD25+, CTLA4+, DN and analyzed gene expressions. Results: The gene expression patterns of Treg-related genes were different between CD25+ cells and CD25- cells. Furthermore, DP cells had unique gene expression pattern compared to other populations. Conclusions: We found Treg cells infiltrating head and neck cancer had high expression levels of Treg-related genes and DP cells had unique gene expression pattern that may become a target of new treatment strategy. Regulatory T (Treg) cells play critical roles in human immune responses including antitumor immunity. Therefore, the research to elucidate Treg function is strongly urged to clarify the mechanisms of antitumor immunity.

  Study JGAS000135

• Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens

  Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

  Study JGAS000164

• Comprehensive gene analysis of colorectal cancer cases

  Colorectal cancer is the third most common morbidity and the fourth leading cause of cancer death in the world.To characterize the mutation profiles of colorectal cancer with liver metastasis,we performed both whole-exosome sequencing and RNA sequencing for 12 cases of colorectal cancer with liver metastasis (group A) and 16 cases of colorectal cancer without liver metastasis (group B). As a result of driver mutation search by Mutsig pipeline, PTEN was identified as a significant mutant gene in group A alone.ADAMTS10,NELL1 and RXFP3 were identified as candidate genes for metastasis by MuTect,SID and VarScan pipeline.Furthermore, in all samples, the copy number of chromosomes 1p,4,7,8,13,15, 17p,18,20 and 22q were significantly abnormal. Chromosomes 1p,4,15,18,17p,22q were deleted and chromosomes 7, 8,13 and 20 were amplified by CNV.Pathway analysed revealed Wnt/Ca2+ and PCP pathway was involved in metastasis of cl cancer.9 kinds of fusion genes were identified in deFuse pipeline. Among them, ADAP1 fusion genes were identified in 2 samples, and ADAP1 fusion genes were further identified in 3 samples by our in-house algorithm. It is suggested that new fusion genes present in such multiple samples may be involved in the development of colorectal cancer.

  Study JGAS000128