14311 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

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• Integrative molecular analysis of pediatric Anaplastic large cell lymphoma reveals subtypes with distinct immune suppression signatures.

  Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma accounting for 10–15% of all childhood lymphomas. While more than 90% of the ALCL cases contain ALK-rearrangement, these tumors possess significant inter-tumor molecular heterogeneity that contributes to distinct morphologic differences and clinical impact. To gain insight into the molecular heterogeneity within ALK+ ALCL, we performed whole-exome sequencing, RNA-sequencing, and methylome analysis of 42 primary pediatric ALK+ ALCL patients. Our data showed that ALK+ALCLs was subclassified into two subtypes based on ALK gene expression, methylation profiles, and somatic mutation patterns. ALK-low samples had more highly methylated gene regions while enriched with immune infiltration. ALK-high samples were enriched with somatic copy number alteration and high expression of MYC and PD-L1. These data indicate that ALK expression, somatic mutations, and aneuploidy status are negatively associated with immune infiltration, stipulating that ALK expression status might be associated with resistance to immune checkpoint inhibitors.

  Study EGAS00001004189

• Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

  Study EGAS00001004235

• Whole genome sequencing data for 10 hepatocellular carcinomas (HCC) and matched non-tumor liver tissues + optical mapping data for 4 HCC and 3 matched non-tumor liver tissues.

  Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole genome sequencing to explore in-depth the nature of structural variants (SVs) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC display frequent intra- and inter-chromosomal templated insertion cycles (TIC) likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are close in the 3D genome organization. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induces continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics and consequences of SV accumulation in tumors with oncogene-induced replication stress.

  Study EGAS00001005629

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

  COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

  Study EGAS00001005634

• Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

  Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.

  Study EGAS00001005769

• Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma (arrays set)

  Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood of virtually all MM cases and are prognostic, but their applicability for non-invasive screening has been poorly investigated. Here, we used next-generation flow cytometry to isolate matched CTCs and BM tumor cells from 42 patients and compare their genetic profile. In 8 cases, tumor cells from extramedullary plasmacytomas were also sorted and whole-exome sequencing performed in the three spatially-distributed clones. Noteworthy, ≥84% mutations present in BM and extramedullary clones were detectable in CTCs. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy-number alterations (≥94%) though not for translocations (43%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Altogether, these results support CTCs for non-invasive risk-stratification of MM patients based on their numbers and genetic profile.

  Study EGAS00001004314

• A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  Control of the intracellular parasites that cause malaria and visceral leishmaniasis (VL) is dependent on the generation of pro-inflammatory, IFNγ+ Tbet+ CD4+ T (Th1) cells by infected hosts. Immunoregulatory IL-10 produced by Th1 cells serves to mitigate subsequent inflammation and related disease pathology. However, these IL-10-producing Th1 (Tr1) cells can also not only promote parasite persistence, but may impair immunity to re-infection and potential vaccine efficacy. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in both experimental VL, caused by infection of C57BL/6 mice with the human parasite Leishmania donovani, and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. Such characterisations allow for the better understanding of Tr1 cell development and function in the context of these parasitic diseases, and for the identification of targets for immune modulation to improve anti-parasitic immunity.

  Study EGAS00001004454

• Combined clinical and gene expression score identifies high-risk individuals among follicular lymphoma patients on immunotherapy

  Follicular lymphoma (FL) is usually an indolent malignant B-cell lymphoma, but at least 30% of the patients experience transformation to Diffuse Large B-cell Lymphoma (DLBCL) with inferior survival. Early identification of patients with poor prognosis is essential for tailoring treatment. Here, we describe a network-based integrative analysis of 168 FL-biopsies from 127 patients with long clinical follow-up and transformation status. A distinct shift in expression towards a DLBCL expression phenotype is observed in BTK associated genes in cases with transformation. This shift is present years prior to transformation. An integrated score combining the BTK score and a clinical index is proposed, termed the BTK-FLIPI score. It identifies patients (16%) with very poor prognosis, with median time to progression 21.7 months (95% CI: 14.3-42.6) versus 70.9 months (95% CI: 41.5-95.0) for the remainder. The results suggest BTK as a potential target for treatment of high-risk FL-patients.

  Study EGAS00001002566

• The evolution of hematopoietic cells under cancer therapy

  Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs showed the mutational footprint of these drugs, indicating that non-malignant blood cells received chemotherapy mutations. No trace of 5-fluorouracil (5FU) mutational signature was found in AML secondary to exposure to 5FU, suggesting that cells establishing the AML were quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determined that secondary AMLs began their clonal expansion after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with a clonal expansion that predates the exposure to the cytotoxic agent.

  Study EGAS00001005234

• Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation

  The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic PIK3CA transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including a-smooth muscle actin (a-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200high and CD200low progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200low and CD200high phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with shp53 and mutant PIK3CA. Upon transplantation, CD200low MEP progenitors distinguish from CD200high by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.

  Study EGAS00001005933