Pre-neoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma
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PROVIDER: PRJNA767837 | ENA |
REPOSITORIES: ENA
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Project description:Pre-neoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma [WES]
| PRJNA767843 | ENA
Project description:Pre-neoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma [scRNA-seq]
| PRJNA767844 | ENA
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. We sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88. We observed similar accumulation of random mutations in B-lineages from both cohorts and, unexpectedly, found MYD88L265P in normal precursor and mature B-lymphocytes from lymphoma patients. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B-cell precursors and BCL2 overexpression. Thus, MYD88L265P is a pre-neoplastic event, which challenges current understanding of lymphomagenesis and may have implications for early detection of B-cell lymphomas.
2021-11-04 | GSE185156 | GEO
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. We sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88. We observed similar accumulation of random mutations in B-lineages from both cohorts and, unexpectedly, found MYD88L265P in normal precursor and mature B-lymphocytes from lymphoma patients. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B-cell precursors and BCL2 overexpression. Thus, MYD88L265P is a pre-neoplastic event, which challenges current understanding of lymphomagenesis and may have implications for early detection of B-cell lymphomas.
2021-11-04 | GSE185157 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-11-04 | GSE185158 | GEO
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. In this study, we sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88.
| EGAS00001005656 | EGA
Project description:SUMMARY Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. While pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes critical for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease. ANIMALS Patched heterozygous mice (Goodrich et al., 1997) were obtained from Matthew Scott's lab at Stanford, and maintained by breeding with 129X1/SvJ mice from Jackson Laboratories. Math1-GFP transgenic mice (Lumpkin et al., 2003) were provided by Jane Johnson at UT Southwestern Medical Center. Math1-GFP/patched+/- mice were generated by crossing patched heterozygotes with Math1-GFP mice, and then backcrossing to Math1-GFP mice three times before further analysis. All mice were maintained in the Cancer Center Isolation Facility at Duke University Medical Center. ISOLATION OF CELLS Granule cell precursors (GCPs) were isolated from 7-day-old (P7) patched+/- mice; preneoplastic cells were obtained from 6 week-old patched mutants; and tumor cells were obtained from 10-25-week old patched mutants displaying physical and behavioral signs of medulloblastoma. Cells were isolated from each source using a protocol described in (Wechsler- Reya and Scott, 1999). Briefly, cerebella were digested in solution containing 10 U/ml papain Oliver et al. Pre-Neoplastic Stage of Medulloblastoma - 8 - (Worthington, Lakewood, NJ) and 250 U/ml DNase (Sigma) and triturated to obtain a cell suspension. This suspension was centrifuged through a step gradient of 35% and 65% Percoll (Amersham Biosciences, Piscataway, NJ), and cells were harvested from the 35%-65% interface. Cells were resuspended in serum-free culture medium consisting of Neurobasal containing B27 supplement, sodium pyruvate, L-glutamine, and penicillin/streptomycin (all from Invitrogen, Carlsbad, California) and counted on a hemacytometer. Cells used for RNA isolation were centrifuged and flash frozen in liquid nitrogen. For proliferation assays or immunostaining, cells were plated on poly-D-lysine (PDL)-coated tissue culture vessels and incubated in serum-free culture medium. MICROARRAY HYBRIDIZATION AND ANALYSIS RNA from GCPs, pre-neoplastic cells and tumor cells (isolated as described above, but not FACS-sorted) and from normal adult cerebellum (not dissociated) was converted to cDNA using the Superscript Choice cDNA kit (Invitrogen) and a T7-dT(24) primer (Genset/Proligo, Boulder, CO). cRNA was generated using a T7-transcription/labeling kit from Enzo Life Sciences and hybridized to Affymetrix U74Av2 chips (Affymetrix, Santa Clara, CA). Chips were scanned, and hybridization data were acquired using Affymetrix Suite 5.0 software. Affymetrix CEL files were normalized and quantified using Bioconductor software with the gcRMA model to quantify gene expression levels (Gentleman and Carey, 2002). Unsupervised principal components analysis (PCA) was used to identify the relationships among normal adult cerebellum, GCPs, pre-neoplastic cells and tumor cells based on expression profiles. To identify genes that were differentially expressed among GCPs, pre-neoplastic cells and tumor cells, supervised analysis was carried out. A gene-by-gene ANOVA model with three groups (GCP, pre-neoplastic, tumor) was used to fit the log2-transformed intensities. To correct for multiple comparisons, the nominal p-value was adjusted using the false discovery rate (Benjamini and Hochberg, 1995). Genes were considered to be differentially expressed if they satisfied all of the following criteria: a difference in expression greater than 1.9-fold between any two groups, a maximum absolute intensity difference larger than 32 units, and an adjusted pvalue < 0.01. There were 118 genes that met these criteria. The identities of differentially expressed genes were verified by integrating data from the Affymetrix and Unigene databases. Gene functions were determined using information from Gene Ontology, Unigene, LocusLink and PubMed databases. Clustering was performed with Cluster and Treeview (Eisen et al., 1998). All statistical analysis was performed using R-1.7 software (Dalgaard, 2002). Results were visualized with Spotfire 6.0 (Somerville, MA). CORRESPONDING AUTHOR Robert J. Wechsler-Reya* Dept. of Pharmacology & Cancer Biology, Duke University Medical Center Box 3813, Durham, NC 27710 Phone: 919-613-8754. Fax: 919-668-3556. Email: rw.reya@duke.edu Keywords = medulloblastoma Keywords = brain tumor Keywords = pre-neoplastic Keywords = patched Keywords = hedgehog Keywords = migration Keywords = differentiation
2005-03-22 | GSE2426 | GEO
Project description: Not available
| S-EPMC8769557 | biostudies-literature
Project description:Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis
| PRJNA730582 | ENA
Project description:This was a collaborative study to discover somatic mutations in 188 lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are likely to play a role in carcinogenesis. The observed mutational profiles correlate with clinical features, smoking status, and DNA repair defects. These results are complemented by data integration including SNP array data and gene expression array data (deposited here). Our findings shed further light on several key signaling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
2008-09-05 | GSE12667 | GEO