Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma
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PROVIDER: EGAS00001005617 | EGA |
REPOSITORIES: EGA
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Project description:Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.
| S-EPMC8885412 | biostudies-literature
Project description:Outcome of paediatric B-cell Non-Hodgkin Lymphoma (B-NHL) has significantly improved in the last decades due to risk adapted strategies and the addition of immunotherapy, (survival >90%). However, limited progress has been achieved in relapsed patients, mostly Burkitt lymphoma (<30%). Validation of prognostic biomarkers to identify candidates to novel therapies is imperative. This retrospective study reports on clinical and therapeutic data of 46 children and adolescents with relapsed B-NHL, including integrative molecular data of 16 (35%) cases. TP53 alterations were identified in 10 (60%) patients which were associated with worse outcome. Our data support the focus on TP53 as a potential biomarker.
2025-02-27 | GSE269220 | GEO
Project description:Non-Hodgkin lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV).
2019-07-11 | PXD012087 | Pride
Project description:The adaptor protein LNK (SH2B3) has emerged as an important protein in regulating B cell development B cell leukemia. Loss-of-function mutations in LNK (SH2B3) are found in Philadelphia chromosomeâlike acute lymphoblastic leukemia (Ph-like ALL), but how LNK regulates normal B cell development or promotes leukemogenesis remains unclear. We found that combined loss of Lnk and tumor suppressors Tp53 in mice triggers a highly aggressive and transplantable precursor B-ALL. This study aims to investigate the molecular mechanism by which LNK regulates B-ALL development. We performed expression profiling of bone marrow proB progenitors from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. Results suggest that Tp53-/-Lnk-/- B-ALLs display similar gene expression profiles to human Ph-like B-ALLs, suggesting this model for preclinical and molecular studies. B220+CD19+CD43+AA4.1+IgM-NK1.1-Ly6c- bone marrow proB cells were double sorted from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. RNA was isolated using miRNeasy kit from QIAGEN and processed using the NuGEN Pico kit. The microarray analysis was performed at the PENN Molecular Profiling/Genomics Facility using GeneChip Mouse Gene 2.0ST array (Affymetrix).
2016-04-01 | E-GEOD-76940 | biostudies-arrayexpress
Project description:In order to investigate the potential role of TP53 in regulating translation, HCT116 wild type and TP53 knockout cells were analyzed using both RNA sequencing, Ribosome sequencing and nascent proteome analysis. The cells were treated with 0.2 µg/ml Neocarcinostatin (NCS) to induce DNA damage and activate TP53.
2022-04-27 | PXD029512 | Pride
Project description:Coxiella burnetii, the agent causing Q fever, has been associated with B-cell non-Hodgkin lymphoma (NHL). To better clarify this link, we analysed the genetic transcriptomic profile of peripheral blood leukocytes from patients with C. burnetii infection to identify possible links to lymphoma. Microarray analyses revealed that 1189 genes were expressed differently (p <.001 and fold change ≥4) in whole blood of patients with C. burnetii infection compared to controls. In addition, 95 genes expressed in patients with non-Hodgkin lymphoma (NHL) and in patients with C. burnetii persistent infection have allowed us to establish the ‘C. burnetii-associated NHL signature’. Among these, 33 genes previously found modulated in C. burnetii-associated -NHL by the microarray analysis were selected and their mRNA expression levels were measured in distinct C. burnetii-induced pathologies, namely, acute Q fever, focalized persistent infection, lymphadenitis and C.burnetii-associated NHL. Specific genes involved in anti-apoptotic process were found highly expressed in leukocytes from patients with C. burnetii associated-NHL: MIR17HG, REL and SP100. This signature differed from that found for NHL-control group. Patients with C. burnetii lymphadenitis presented significant elevated levels of BCL2 and ETS1 mRNAs. Altogether, we identified a specific transcriptionnal signature for NHL during C. burnetii infection reflecting the up-regulation of anti-apoptotic processes and the fact that lymphadenitis might constitute a critical step towards lymphomagenesis.
2019-06-05 | GSE112086 | GEO
Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment
2022-10-24 | GSE216037 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a rare, clinically and genetically heterogeneous inherited cancer syndrome. Most cases are due to mutations in TP53. CHK2 is a minor predisposing locus; we recently mapped a third locus to 1q23. In both TP53 and non-TP53 LFS, there is evidence for risk heterogeneity within and between kindreds, suggesting additional risk modifiers. Using BAC- and SNP-based microarrays, we performed genomic profiling of primary soft tissue sarcomas, osteosarcomas and matching constitutive samples of 10 LFS patients (6 with and 4 without TP53 mutations), to identify genome-wide patterns of copy number changes and loss-of-heterozygosity (LOH). Our complementing global approaches revealed several interesting patterns for TP53 and non-TP53 LFS tumors, including positive (1q/7, 3p/15, 4q/9q, 8q/19p, 9p/10q, 13/14 and 15q/18q) and negative (2q/9q, 3q/14q and 4q/6q) associations between chromosomal regions. The region containing the oncogene TWIST1 (7p21.1) was the most common gain independent of TP53 status and tumor type, while LOH of 8q11.2 with the tumor suppressor ST18 was the only region exclusively associated with non-TP53 soft tissue sarcomas. We resequenced known mutations in BRAF, KRAS and NRAS and identified somatic NRAS mutations in 2 of 10 tumors. TP53 and non-TP53 LFS tumors shared multiple hits in genes of the p53 and overlapping pathways. Although common dogma in cancer genetics holds that multiple hits in the same pathway are redundant and thus unlikely, we show that different combinations of genetic alterations in both TP53 and non-TP53 LFS tumors appear to act together in the p53 network in LFS tumorigenesis Keywords: Comparative genomic hybridization Using the Spectral Genomics dye-swap BAC arrays we studied 10 Li Fraumeni syndrome tumor cases
2008-07-16 | E-GEOD-8798 | biostudies-arrayexpress