16865 results for "sec+and+unspecified+malignant+neoplasm"

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• WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

  A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations.

  Study JGAS000123

• 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

• Loss of presentation of estimated neoantigens from mutated genes in ctDNA was essential for fostering primary to recurrent tumors in postoperative colorectal cancer cases

  Specific parameters regarding mutations at primary sites for the detection of postoperative recurrence using circulating tumor (ct)DNA liquid biopsy are lacking. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes between primary and recurrent tumors showed abundant and significant expression with no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.

  Study JGAS000549

• Direct genetic transformation bypasses tumor-associated DNA methylation alterations

  Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models.

  Study EGAS50000000902

• High-grade B-cell lymphoma, not otherwise specified: an LLMPP study

  Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. These tumors were profiled using whole-genome sequencing (WGS) or whole-exome sequencing (WES) to identify somatic mutations, WGS or low-pass WGS to detect copy number alterations, targeted capture sequencing to assess MYC and BCL2 structural variants, and RNA sequencing. The genetic features of HGBCL-NOS were compared to those of diffuse large B-cell lymphoma (DLBCL-NOS) and EBV-negative adult Burkitt lymphoma (BL). DLBCL-NOS tumors underwent targeted capture sequencing using a panel of 125 genes recurrently mutated in aggressive B-cell lymphomas. BL biopsies were drawn from the Burkitt Lymphoma Genome Sequencing Project and had available WGS (dbGaP Study Accession: phs000527.v18.p6).

  Study EGAS50000000932

• Initial leukemic epigenomic state determines hypomethylating agent response

  Hypomethylating agents (HMAs) are a mainstay of therapy for myeloid cancers, but genetic biomarkers do not predict who will respond to treatment. Using a variety of single-cell sequencing approaches to define the epigenomic state of responder and nonresponder leukemic cells, we aim to demonstrate that leukemic stem cells (LSC) exist in at least two different epigenomic states: a hematopoietic stem cell (HSC)-or multipotent progenitor (MPP)-like state that is sensitive to HMAs, independent of genetic mutations, or a lymphoid-primed MPP (LMPP)-like nonresponder state. Additionally, we aim to demonstrate that hypomethylation and chromatin accessibility at ZNF143- and CTCF-binding sites result in activation of HOXB4, which defines the HSC/MPP-like state and HMA-sensitivity. Our study aims to provide evidence that the epigenomic state of the LSC is a major determinant of response to HMAs, and demonstrates that a routine clinical assay can identify patients who will respond.

  Study EGAS50000000936

• Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: CheckMate 649 biomarker analyses

  First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) versus chemotherapy for advanced gastroesophageal adenocarcinoma (CheckMate 649). Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein Bar Virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T-cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

  Study EGAS50000000747

• ROCHE PD 92 Multiome dataset

  This dataset contains 10X Multiome data generated on post-mortem brain from 92 individuals (70 PD, 22 controls). For the Roche_PD dataset, nuclei were isolated using Nuclei Pure Prep Nuclei Isolation Kit (Sigma Aldrich) with the following modifications. The tissue was lysed in Nuclei Pure Lysis Solution with 0.1% Triton X, 1mM DTT and 0.4U/ul SUPERase-In™ RNase Inhibitor (ThermoFisher Scientific) freshly added before use and homogenized with the help first of a 23G and then of a 29G syringe. Cold 1.8M Sucrose Cushion Solution, prepared immediately before use with the addition of1mM DTT and 0.4U/ul RNase Inhibitor, was added to the suspensions before they were filtered through a 30μm strainer. The lysates were then carefully and slowly layered on top of 1.8M Sucrose Cushion Solution previously added in new Eppendorf tubes. Samples were centrifuged for 45 minutes at 16000xg at 4°C. Pellets were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, transferred in new Eppendorf tubes and centrifuged twice for 5 minutes at 500xg at 4°C. Finally purified nuclei were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, stained with trypan blue and counted using Countess II (Life technology). After count, nuclei permeabilization was carried out following the demonstrated protocol for single cell multiome ATAC + Gene Expression sequencing from 10x Genomics. A total of 12,000 estimated nuclei from each sample was used for the transposition step and then loaded on the Chromium Next GEM Single Cell Chip J. ATAC library and gene expression library construction was performed using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit according to the manufacturer’s instructions. Libraries were sequenced using Illumina NovaSeq 6000 System and NovaSeq 6000 S2 Reagent Kit v1.5 (100 cycles), aiming at a minimum sequencing depth of 30K reads/nucleus. Genotype was generated as previously described (Bryois et al, Nature Neuroscience, 2022).

  Dataset EGAD50000000964

• Cellular Dynamics Upon Immune Checkpoint Inhibition

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet most patients experience limited or no clinical benefit. To elucidate the mechanisms of response and resistance, we analyzed single-cell RNA-sequencing data from 141 patients across multiple cancer types and ICI treatment modalities, with longitudinally paired samples. Using a robust, integration-free deep phenotyping framework, we annotated 876,410 cells into 80 granular states. We identified consistent compositional changes in 17 cell subtypes following ICI treatment, including enhanced adaptive immune responses and reduced interferon-responsive cells. Co-regulated cell communities within the tumor microenvironment (TME) highlighted coordinated interplay between immune and non-immune components. Importantly, we discovered two distinct patient groups with divergent TME dynamics post-treatment: responders showed expansion of naive lymphocytes, while non-responders exhibited increased immune-experienced/suppressive cells. This dichotomy offers a potential predictive biomarker for patient stratification. Our comprehensive analysis of TME dynamics during ICI treatment advances understanding of response mechanisms and personalized cancer immunotherapy.

  Study EGAS50000000459

• CLL Genome

  The Chronic Lymphocytic Leukemia (CLL) Genome Project aims to identify genetic alterations involved in the development and progression of the CLL, which are still unknown, with the objective of generating a comprehensive catalogue of genetic alterations in 500 independent tumours. The CLL Genome Project, as a contributing member of the International Cancer Genome Consortium (ICGC), has the purposes of creating diagnostic tools, discovering therapeutic targets and developing new strategies that will allow a customized therapy for CLL in order to make it more precise and effective. This study consists of two datasets. EGAD00001000023 described in the Nature paper (2011), Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia, and the dataset EGA00001000044 & & EGAD00001000083 described in the Nature (2011) paper, Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.Additional data generated within the ICGC-CLL genome project can be found in studies EGAS00001000374 and EGAS00001001306

  Study EGAS00000000092