16758 results for "sec+and+unspecified+malignant+neoplasm"

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• Comprehensive molecular and clinicopathological profiling of glioma

  Various molecular profiles are needed to classify malignant brain tumors, including gliomas, based on the latest classification criteria of the World Health Organization, and their poor prognosis necessitates new therapeutic targets. The Todai OncoPanel 2 RNA Panel (TOP2-RNA) is a custom-target RNA-sequencing (RNA-seq) using the junction capture method to maximize the sensitivity of detecting 455 fusion gene transcripts and analyze the expression profiles of 1,390 genes. This study aimed to classify gliomas and identify their molecular targets using TOP2-RNA. A total of 124 frozen samples of malignant gliomas were subjected to TOP2-RNA for classification based on their molecular profiles and the identification of molecular targets.

  Study JGAS000671

• Fetal origins of malignant germ cell tumours

  Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells (PGCs). They are uniquely able to generate embryonic and extraembryonic tissues, which in malignant GCTs carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we studied the phylogenetic and transcriptional diversity of 15 malignant gonadal GCTs and four normal testis biopsies by sequencing 131 whole genomes and 416 transcriptomes from 14 gonadal histologies, excised by laser capture microdissection. Our findings demonstrate that tumours were initiated by whole genome duplication likely in embryogenesis, within ~5-8 cell divisions post-PGC specification, followed by chromosome 12p gains associated with invasive disease. Of note, 12p imbalances were not only generated through GCT-typical isochromosomes, but also through non-isochromosomic configurations. Whilst tumours developed along homogenous phylogenetic pathways, they spawned manifold tissues independent of genetic subclonal diversification. A key feature of GCT tissues was the expression of fetal-specific genes. The transcriptional diversity notwithstanding, we found universal transcriptional elements correlated with hallmark 12p gains. Overall, our study reveals stereotyped phylogenies and transcriptomes underpinning the development of GCT that originate in fetal life and may lend themselves to therapeutic manipulation.

  Dataset EGAD00001007038

• Somatic mutations of non-malignant T cells

  Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in non-malignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected in lymphoid neoplasia. Single-cell sequencing revealed cytotoxic Temra phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.

  Study EGAS50000000237

• Integrated genomic characterization of IDH1 mutant Glioma malignant progression

  Gliomas represent approximately 30% of all central nervous system tumors, and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade Isocitrate Dehydrogenase 1 (IDH1) mutant gliomas, we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing, copy number, gene expression and DNA methylation profiling, demonstrated non-linear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways, up-regulation of the FOXM1- and E2F2-mediated cell cycle transition genes, as well as epigenetic silencing of developmental transcriptional factors bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extra-terminal (BET) family as a potential therapeutic approach.

  Study EGAS00001001588

• The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumorinfiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

  Study EGAS00001002839

• Clonal Evolution and Blastic Plasmacytoid Dendritic Cell Neoplasm - Two Cases

  Here we present two case studies of sequential whole exome sequencing (WES) in patients, who both developed BPDCN throughout their medical history but primarily presented with lymphoid cancers (clonally related ALK-negative anaplastic large-cell lymphoma (ALCL) and T-lymphoblastic lymphoma (T-LBL)) and whose bone marrow at remission exhibited a CMML phenotype, from which in both cases BPDCN clones arose that subsequently became treatment refractory.

  Study EGAS50000000214

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799

• Single Cell RNA-Seq Reveals Malignant and Stromal Programs Associated with Metastasis in Head and Neck Cancer

  This study of head and neck cancer aimed to profile individual malignant, stromal, and immune cells in treatment-naive oral cavity squamous cell carcinoma, with or without matched metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. Biopsy specimens were processed for single cell RNA-seq (scRNA-seq) and/or whole exome sequencing (WES). A total of ~6,000 single cells from 18 participants were included in the final dataset. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). One of the top scoring genes in this program was TGFβ-induced (TGFBI), implicating the classic EMT regulator TGFβ. Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined Head and Neck Squamous Cell Carcinoma (HNSCC) subtypes by their malignant and stromal composition, and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

  Study phs001474

• Integrative multi-omic analyses of malignant pleural mesothelioma

  Multi-omic data (whole-genome sequencing, RNA-seq, EPIC 850K methylation arrays) for 123 samples from the MESOMICS project, the French project of molecular characterization of malignant pleural mesothelioma

  Study EGAS00001004812

• Single-Cell ATAC and RNA Sequencing of Human Breast Cancer Reveals Salient Cancer-Specific Enhancers

  Matched single-cell chromatin accessibility sequencing (scATAC-seq) and single-cell transcriptomic sequencing (scRNA-seq) were performed for 12 human breast tumor samples, 4 normal human mammary reduction samples, and 4 human breast cancer cell lines (HCC1143, SUM149PT, MCF7, and T47D). Both scATAC-seq and scRNA-seq assays resolved the underlying cellular heterogeneity in chromatin accessibility and transcriptional output for each patient sample. In this work, we quantitatively linked variation in chromatin accessibility to gene expression across malignant and non-malignant cell types from patient samples. We then showed that our findings were recapitulated in the breast cancer cell line samples. These data will serve as an important resource for the single-cell genomics and breast cancer research communities.

  Study phs003253