5707 results for "canc*"

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• Discovering novel mechanisms of taxane resistance in human breast cancer by whole-exome sequencing

  Taxanes are key drugs in the treatment of breast cancer, but some breast cancers are resistant to taxanes. Obtaining extensive genomic information in a short time has recently become possible. We used whole exome-sequencing (WES) to investigate mechanisms of taxane resistance in human breast cancer. We selected six patients with breast cancer whose tumors responded well to anthracycline treatment but grew rapidly during neoadjuvant taxane-based chemotherapy. We then performed WES of these samples and identified somatic mutations of candidate genes that are thought to affect taxane resistance.

  Study JGAS000370

• High-coverage whole-genome sequencing reveals structural variations in triple-negative breast cancer

  Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors or human epidermal growth factor receptor 2 (HER2). Currently, apart from poly ADP-ribose polymerase (PARP) inhibitors, there are few effective therapeutic options for this cancer type. Here, we present a comprehensive characterization of genetic alterations in TNBC via high-coverage whole-genome sequencing along with transcriptomic and whole-exome sequencing. Silencing of BRCA1 gene impaired the homologous recombination (HR) pathway in a subset of TNBC, which exhibited similar phenotypes with tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were the early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2 or NOTCH3 and impacted tumor suppressor genes including RB1, PTEN and KMT2C. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblast cells, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC that had important clinical implications.

  Study JGAS000095

• Identification of the genes associated with EGFR-mutant lung cancer

  To gain an insight into the genetic factors underlying the carcinogenesis of EGFR-mutant lung adenocarcinoma, we sequenced the exomes in peripheral-blood DNA from the patients.

  Study JGAS000129

• Research for biological features by gene expression analysis and biomarkers at diagnosis/therapeutics in lung cancer

  WGS, WES, ATAC-seq and methylation analysis with DNA harvested from lung cancer organoids established from surgery, biopsy, pleural effusion, sputum and blood samples of patients. RNA-seq analysis with RNA harvested from lung cancer organoids established from surgery, biopsy, pleural effusion, sputum and blood samples of patients.

  Study JGAS000609

• Target sequencing of 8 hereditary prostate cancer genes in Japanese

  We performed a case control association study for variants in coding regions of 8 hereditary prostate cancer genes in 7,636 male unselected prostate cancer patients, 12,366 male controls of Japanese ancestry. The 8 genes were ATM, BRCA1, BRCA2, BRIP1, CHEK2, HOXB13, NBN, and PALB2.

  Study JGAS000203

• 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

• Comprehensive genomic analysis of colorectal cancer with microsatellite instability

  Microsatellite instability-high (MSI-H) colorectal cancers (CRCs) account for 10?15% of all CRCs. MSI-H CRC is characterized by a large number of somatic insertions/deletions (indels) resulting from either mutations within or the silencing of genes involved in the DNA mismatch repair (MMR) system. A subset of MSI-H CRCs is associated with Lynch syndrome (LS), which is caused by germline MMR gene mutations, leading to hereditary cancer predisposition. Other than frequent somatic mutations in BRAF, the transformation mechanisms underlying MSI-H CRC are largely unknown. Here, genomic DNA from 149 MSI-H CRC specimens was analyzed using whole-exome sequencing, and 93 of these samples were subjected to genome-wide DNA methylation analysis. Furthermore, transcriptome sequencing was conducted on 111 samples. Genomic/epigenomic analyses identified three subgroups within our cohort: (1) MSI-H CRCs with silenced MLH1 that share frequent indels, a specific mutation/copy number alteration profile and promoter DNA methylation; (2) LS-associated MSI-H CRCs with MMR genes containing germline mutations; and (3) the remaining MSI-H CRCs with frequent somatic disruptive mutations of MLH1 or MSH2. Unexpectedly, only the first group was found to frequently carry fusion-type protein kinases (15% of this group and 9.9% of all MSI-H CRCs) that are promising therapeutic targets. Thus, MSI-H CRCs can be classified into three subgroups with distinctive genomic as well as epigenomic statuses, probably reflecting the oncogenic processes of these cancers. Fusion-type kinases are enriched in MSI-H CRCs, shedding new light on potential treatment strategies.

  Study JGAS000113

• CRISPR-screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer

  Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated NSCLC and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 �� TNO155, alone or combined with the PI3K�� inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition.

  Study JGAS000643

• exploration of biomarkers discriminating squamous cell carcinoma from other lung cancers

  Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed. To achieve this goal, we initially performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD). We furhter expanded the transcriptome profiling to cover additional 48 malignant neoplasm of bronchus and lung, including mesothelioma and metastatic lung cancers derived from other tissues.

  Study JGAS000488

• Comprehensive analyses of genetic aberrations in cholangiolocarcinoma

  The nature of CLC is still unclear and its pathological classification still remains controversial. To clarify the positioning of CLC among primary liver cancers, and to find characteristics that could distinguish CLC from other liver cancers.

  Study JGAS000597

• Molecular Profiling and Sequential Somatic Mutation Shift in Hypermutator Tumors Harboring POLE Mutations

  Defective DNA polymerase ? (POLE) proofreading leads to extensive somatic mutations that exhibits biased mutational properties; however, the characteristics of POLE-mutated tumors remain unclear. In present study, we described a molecular profile using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumors that obtained from 2,42 Japanese patients. The bias of accumulated variations in this mutant was quantified to follow a pattern of somatic mutations, thereby classifying the sequential mutation shift into three periods. During the period prior to occurrence of the aberrant POLE, no accumulation of mutations in cancer-related genes was observed, whereas PTEN was highly mutated in conjunction with or subsequent to the event, suggesting that POLE and PTEN mutations were responsible for the development of POLE-mutated tumors. Furthermore, homologous recombination was restored after occurring PTEN mutations. Our strategy for estimation of the footprint of somatic mutations may provide new insight toward the understanding of mutation-driven tumorigenesis.

  Study JGAS000130

• 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

• Target sequencing of 11 hereditary breast cancer genes in Japanese

  We performed a case control association study for variants in coding regions of 11 hereditary breast cancer genes in 7,051 female unselected breast cancer patients, 11,241 female controls, 53 male patients, and 12,490 male controls of Japanese ancestry. The 11 genes were ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11, and TP53.

  Study JGAS000140

• Development of actionable molecular targets and/or biomarkers for prognostication and patient stratification in gynecological cancer based on whole-exome sequencing and epigenomic analysis

  We collected 187 samples of normal and primary tumor tissues in 69 cases of endometrial carcinoma. The purpose of this study is to develop actionable molecular targets and/or biomarkers for prognostication and patient stratification.

  Study JGAS000174

• Whole exome sequencing and RNA sequencing of patient-derived pancreas neoplasm organoids

  Pancreatic cancers arise from two different precursors; intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasm (PanIN), while biological differences in cancers originated from them remain obscure. Here, we analyzed their genomic and transcriptomic landscapes using patient-derived organoids.

  Study JGAS000263

• 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

• The RNA, ChIP and whole exome sequencing analysis of human colorectal cancer organoids and normal colon organoids treated with (+)-JQ1

  To reveal the mechanism of anti-tumor effect of (+)-JQ1, we performed RNA, ChIP and whole exome sequencing using human colorectal cancer and normal colon organoids.

  Study JGAS000378

• 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 JGAS000228

• Analysis of mutational and proteomic heterogeneity of gastric cancer to monitor post-treatment tumor burden using circulating tumor DNA

  It remains unclear whether complete spectrum of tumor heterogeneity is reflected in circulating tumor DNA (ctDNA). Here, we performed multi-regional target sequencing of primary tumors from 10 patients who underwent surgical resection for gastric cancer. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were likely mutations that occurred early in tumor development (i.e., present in all three regions) and were designated founder mutations. Among those validated with highly sensitive digital PCR (dPCR), 93% of non-founder mutations were found in all three regions. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis demonstrated that five of eight tumors (62.5%, excluding two hypermutator) had at least one identifiable truncal/founder mutation. These findings led us to prioritize founder mutations for ctDNA detection with individually-designed primer/probe sets for dPCR. Marked proteomic diversity was present across the tumor regions both within and between patients independent of mutational status. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Our present data demonstrated that high VAF mutations in the tumor likely represent founder or truncal mutations. However, mutation patterns alone appear insufficient to predict protein heterogeneity. These results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be useful for ctDNA monitoring but are inadequate to fully predict proteomic heterogeneity of the tumor.

  Study JGAS000231

• CAGE analysis for endometrial carcinoma

  For endometrial cancer patients, lymphadenectomy is recommended to exclude rarely metastasized cancer cells. This procedure is performed even in patients with low risk of recurrence despite the risk of complications such as lymphedema. A method to accurately identify cases with no lymph node metastases (LN-) before lymphadenectomy is therefore highly required. We approached this clinical problem by examining primary lesions of endometrial cancers with CAGE (Cap Analysis Gene Expression), which quantifies promoter-level expression across the genome. Fourteen profiles delineated distinct transcriptional networks between LN?+?and LN- cases, within those classified as having the low or intermediate risk of recurrence.

  Study JGAS000124

• Whole exome sequencing of colorectal cancer

  To elucidate immune status of solid tumors including gastrointenstinal cancer, we performed whole exome sequencing of colorectal cancer 7 patients.

  Study JGAS000279

• Development of blood-based biomarkers for precision medicine in castration-resistant prostate cancer

  Cell-free DNA (cfDNA) testing is emerging as a tool for cancer precision medicine. However, little is known about the clinical significance of low-frequency variants detected in circulating cell-free tumor DNA (ctDNA) from castration-resistant prostate cancer (CRPC) patients. We conducted targeted sequencing of cfDNA and paired leukocyte DNA from CRPC patients using molecular barcodes, and ctDNA variants with a variant allele frequency ??? 0.1% were detected using an in-house pipeline.

  Study JGAS000330

• Development of the prevention and therapy of CRC using patient derived culture tissues.

  Tumor tissues consist of functionally heterogeneous cells including those with high clonogenic potential called cancer stem cells (CSCs) which produce differentiated non-tumorigenic progenies. Transplantation assays have been performed to identify cell surface markers in solid tumors including colorectal cancers, which identified several CSC markers such as CD133 and CD44. In addition to the transplantation, the lineage tracing of genetically labelling cells in animal models of cancer qhas been employed to explore the cellular heterogeneity of tumors by identifying the CSCs and its progenies. This approach is particularly useful to investigate solid tumors, where cellular proliferation and differentiation are controlled by niche factors and cell-cell contact with adjacent cells. Lineage tracing of mouse model of cancer unravel the mode of growth of autochthonous tumor in their native environment. In this study, we used patient derived organoids (PDO) established from surgically resected CRC patients to identify the CSC. Single cell RNA-seq analysis identified potential CRC markers, which may exhibit self-renewal activity and produce progenitors

  Study JGAS000139

• Targeted sequencing of cell free DNA samples from oligometastatic colorectal cancer patients

  In order to discover specific mutations that correlate with prognosis, target sequencing was performed using cell-free DNA samples from oligometastatic colorectal cancer patients.

  Study JGAS000196

• 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

• 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

• Identification of responsible genes and development of standardized medicine for familial breast cancer by genetic analysis with NGS technology

  Aims: To clarify risk of germline variants of known causal genes for Hereditary Breast Ovarian Cancer Syndrome in Japan by combinatorial analysis of somatic and germline variants in the breast cancer tissue. Methods: Target caputure analysis by using Illumina HiSeq 2000; the panel genes are 119 genes including 30 HBOC known causal genes. Participants/Materials: 108 whole blood and 124 primary tumor samples from familial breast cancer patients.

  Study JGAS000224

• Sequencing cancer mutations in various types of lung cancer using the long-read, portable sequencer

  In this study, we used a long-read and portable sequencer MinION to identify cancer mutations in lung adenocarcinoma cells. We performed cDNA amplicon sequencing for various types of mutations such as point mutations in EGFR and KRAS and oncogenic fusion transcripts in ALK and RET. Using the long reads of MinION, we also conducted mutation phasing of EGFR TKI-sensitive and resistant mutations, which would provide useful information to next thrapeutic approaches for cancers. We applied this method to identify mutation genotypes of eight clinical samples from Japanese lung adenocarcinomas. This method could provide new sequencing-based diagnostic approaches for lung cancers. Additinally we also performed cancer mutation identification of risk-dependent unique samples. Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP.We performed whole exome sequencing of lung adenocarcinoma with usual interstitial pneumonia.

  Study JGAS000065

• Whole exome sequencing and RNA sequencing of cervical cancer

  We designed this study to identify molecular markers involved in the development and prognosis of cervical adenocarcinoma. In this study, we would like to elucidate the molecular biological characteristics of cervical adenocarcinoma in relation to the carcinogenesis of other cervical cancers (squamous cell carcinoma), vaginal and vulvar cancers. In addition, some squamous cell carcinomas of the cervix develop at a young age and have a poor prognosis. Furthermore, small cell carcinoma of the cervix also progresses rapidly and has a poor prognosis, making the establishment of diagnostic and therapeutic methods an urgent task.

  Study JGAS000586

• Establishment of xenogfafts and cultured cell lines from clinical samples

  The purpose of the present study was to clarify the presence or absence of alterations in the molecular properties of patient-derived xenografts (PDXs) with up to eight passages in endometrial carcinomas. Alterations in the proportion of immunohistochemically positive/negative cells for PAX8, estrogen receptor, PAX2, and PTEN were observed in established PDXs of endometrioid carcinomas and carcinosarcomas, whereas proportions of cells with AE1/AE3, TP53, ARID1A PMS2, and MSH6 were maintained. Variants of cancer-associated genes in PDX compared to those in the parental tumors were examined in two cases, a frameshift deletion in BRCA1 was observed in the parental tumor tissue, and additional genomic alterations were found in the PDXs of this case. Genomic and phenotypic alterations in endometrial carcinoma PDXs relative to the parental tumors were observed and were partly associated with endometrial cancer-specific characteristics in cellular differentiation and gene mutations.

  Study JGAS000585

• Project for Development of Innovative Research on Cancer Therapeutics; Identifiying the predictive factors for response to chemoherapy in ovarian cancer

  To identify novel predictive biomarkers of response to chemotherapy for clear cell carcinoma of the ovary

  Study JGAS000076

• Research for biological features by gene expression analysis and biomarkers at diagnosis/therapeutics in lung cancer

  WGS, WES, ATAC-seq and methylation analysis with DNA harvested from lung cancer organoids established from surgery, biopsy, pleural effusion, sputum and blood samples of patients. RNA-seq analysis with RNA harvested from lung cancer organoids established from surgery, biopsy, pleural effusion, sputum and blood samples of patients.

  Study JGAS000557

• ATAC-seq and ChIP-seq analysis of patient-derived normal pancreas and pancreas neoplasm organoids

  Pancreatic cancers arise from two different precursors; intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasm (PanIN), while biological differences in cancers originated from them remain obscure. Here, we analyzed their epigenomic landscape by ATAC-seq and ChIP-seq using patient-derived organoids.

  Study JGAS000264

• The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer

  Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8��� Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.

  Study JGAS000454

• BHD-associated kidney cancer

  BackgroundBirt-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.ResultsWhole-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

• CAGE analysis for non-small cell lung carcinoma

  Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed.To achieve this goal, we performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD). The result was followed up by by immunohistochemical analysis (IHC) in an independent group.

  Study JGAS000070

• Frequent post-treatment monitoring of colorectal cancer using individualized ctDNA validated by multi-regional molecular profiling

  Purpose: Circulating tumor DNA (ctDNA) analysis has been proposed as an approach for prediction of post-treatment patient outcomes. However, whether a single platform will provide optimal information in all patients or alternatively a patient-specific monitoring approach based on assessment of mutations in the primary tumor from that patient remains an urgent question. Experimental Design: We conducted multiregional sequencing of 42 specimens of 14 colorectal tumors (Stage III and more) from 12 patients, including two double cancer cases, to identify the full spectrum of mutational heterogeneity and identify aberrations that could be used to develop personalized ctDNA assays. Results: ?Founder? mutations that occur in all regions of the sample were identified in 12/14 (85.7%) tumors. Subsequent phylogenetic analysis of each tumor showed that 12/14 tumors (85.7%) carried at least one ?truncal? mutation. Most founder and truncal mutations exhibited higher variant allele frequency (VAF) than ?non-founder? and ?branch? mutations. In addition, both founder and truncal mutations were more likely to be detected as ctDNA than non-founder and branch mutations. Synchronized ctDNA dynamics of multiple mutations suggested those mutations from the same clonal origin. For 10/12 patients (83.3%) with nearly 1,000 days of post-operative observation, the validity of frequent personalized ctDNA monitoring was confirmed in terms of early relapse prediction, treatment efficacy, and non-relapse corroboration. Conclusions: Personalized ctDNA monitoring based on aberrations with a high VAF in the primary tumor site should be explored in larger prospective clinical trials to determine the full clinical validity.

  Study JGAS000243

• Whole exome sequencing of uterine adenomyosis

  Uterine adenomyosis, defined by proliferation of the ectopic endometrial glands in myometrium, is a common benign uterine disorder that significantly impairs the quality of life of the women it affects. Adenomyosis lesions have chronic inflammatory reactions as well as cancer-like features such as invasive capacity into the normal myometrium. In contrast to endometriosis and leiomyoma, the genomic characterization of adenomyosis has yet to be reported. We conducted high-coverage whole exome sequencing analyses of freshly frozen adenomyosis samples, as well as co-occurring leiomyoma. Our WES analyses showed that adenomyosis is a clonal disorder with somatic mutations.

  Study JGAS000169

• 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

• Immunohistochemical and molecular pathological search in gastrointestinal tumors

  Purpose: RSPO fusions are recently identified recurrent genetic alterations in colorectal cancer (CRC), which lead to WNT pathway activation and are potential therapeutic targets. We aimed to investigate the clinicopathological and molecular features of RSPO fusion-positive CRCs.Experimental Design: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription polymerase chain reaction. RSPO fusion-positive tumors were characterized for their clinicopathological features and subjected to whole exome sequencing (WES).Results: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of 5 with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 females and 12 males with the median age of 64 years. Thirteen tumors were located in the right colon, 8 were in the left colon, and 8 were in the rectum. Histologically, most of the tumors (24/29, 83%) were classified as adenocarcinomas, not otherwise specified. However, about half of the tumors (13/29, 45%) had a focal or extensive mucinous component, which is significantly more frequent compared with RSPO fusion-negative tumors (13%; p = 8.1 �� 10-7). Four tumors (14%) were mismatch repair-deficient, three of which were associated with MLH1 promoter methylation. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 cases (93%). In contrast, pathogenic mutations in major WNT pathway genes other than RSPO fusions were virtually absent. The presence of an RSPO fusion tended to show shorter overall and recurrence-free survivals in stage II and III patients although the differences were not significant.Conclusions: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features. The mutual exclusivity with other WNT pathway gene alterations supports RSPO fusions as valid therapeutic targets in CRC.

  Study JGAS000538

• 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

• Genomic Profiling Reveals Heterogeneous Populations of Ductal Carcinoma In Situ

  Whole Exome Sequencing(WES) and copy number variation(CNV) analysis were performed using breast samples collected from non-invasive breast cancer patients in order to analysis of somatic mutations related to breast tumor phenotypes.

  Study JGAS000202

• Development of molecular targeted therapy for small cell lung cancer by comprehensive genome analysis

  Aims: Identifying new therapeutic targets of small cell lung cancer (SCLC), genome-wide mutation analysis has been performed.Methods: Genomic DNA was extracted from formalin-fixed or methanol-fixed tissue samples. 71 Mb of DNA fragments containing whole coding exons were concentrated using SureSelect Human All Exon V4+UTRs Kit (Agilent Technologies) followed by 100-bp paired end sequencing by HiSeq 2000 (Illumina).Participants/Materials: 51 of 1042 cases of pathologically diagnosed small seen lung cancer that were registered to National Cancer Hospital East Lung Cancer Database in 1992-2012, and which surgically resected or biopsy samples were suitable for DNA extraction for further analyses.

  Study JGAS000037

• 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

• Whole genome analysis of liver cancer by long-read sequencing

  Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture

  Study JGAS000361

• High-coverage whole exome sequence in non-TRU-type lung adenocarcinomas

  In order to elucidate the key genetic events in non-TRU-type lung cancer, we selected 43 non-TRU-type lung adenocarcinomas and performed a whole exome sequence and RNA-seq analysis using a next-generation sequencer. The results of the analysis identified mutations in TP53, KRAS and NKX2-1 as the top three significantly mutated genes, while the EGFR mutation was rare in this cohort. Eight NKX2-1 mutations (5 frameshift, 2 nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1 mutations (missense and frameshift). All NKX2-1 mutants were transcriptionally inactive in reporter assays. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1 mutations (5 cases), while 1 enteric and 1 acinar adenocarcinoma harbored the NKX2-1 mutation.

  Study JGAS000105