Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Case Report: Pathogenesis With a Rare RHOA A161E Mutation in a Patient With Angioimmunoblastic T-Cell Lymphoma

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) genomic abnormalities are highly disease-specific, and the ras homology family member A (RHOA) gene is one of the most recurrent mutated genes, especially for RHOA G17V mutation site. Here, we identified a rare RHOA A161E mutation in an AITL patient through gene sequencing platforms. The patient presented with persistent hypereosinophilia, asymptomatic or symptomatic mildly for over 3 years. At diagnosis, this patient manifested night sweats, weight loss, multiple lymphadenopathies, and enlargement of the liver and spleen. We performed a retrospective genetic mutation analysis by whole-exome sequencing (WES) and droplet digital PCR (ddPCR) on serial gastric, intestinal, and lymph node specimens. The genetic mutation testing result demonstrated that a rare RHOA A161E mutation was found, which was elevated significantly on diagnosis related to AITL pathogenesis. Our case confirms that genetic mutation testing is helpful for diagnostic classification in AITL and dynamic monitoring of gene mutations at multiple time points may facilitate early detection of disease diagnosis.

SUBMITTER: Cao L

PROVIDER: S-EPMC9330045 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.

Project description:Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

| S-EPMC5843900 | biostudies-literature

Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human <i>RHOA</i> with p.Gly17Val mutation.

Project description:A missense mutation in RHOA encoding p.Gly17 Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. Importantly, we provide evidence for expansion of PD-1+ follicular helper T (Tfh) cells which are the neoplastic cells of AITL. In addition, we saw proliferation of B-cells leading to hypergammaglobulinemia and the presence of dominant T cell clonal populations. Transplantation of lymph node cells to immunocompromised mice partly recreated lymphadenopathy after a long latency and with low penetrance suggesting that cells have undergone partial transformation to a premalignant state. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice closely resembles that of AITL patients with the identical RHOA p.Gly17 Val mutation. The murine model should, therefore, be useful in dissecting pathogenesis of AITL at the molecular level particularly for the cases with the RHOA p.Gly17Val mutation.

| S-EPMC7458614 | biostudies-literature

Hemophagocytic lymphohistiocytosis presenting with annular erythema multiforme-like eruptions in a patient with angioimmunoblastic T cell lymphoma: A case report.

Project description:Angioimmunoblastic T cell lymphoma (AITL)-associated hemophagocytic lymphohistiocytosis (HLH) rarely occurs with annular erythema multiforme-like rashes. The present case report describes a patient who was misdiagnosed with erythema multiforme at an early stage of the disease due to annular erythema multiforme-like eruptions. However, antihistamine treatment was ineffective. The patient progressed rapidly with high fever, hepatosplenomegaly and pharyngitis. The number of copies of Epstein-Barr virus DNA continuously increased. Accompanied by the swelling of lymph nodes, the blood cell count decreased. Further bone-marrow examination and biopsy of the lymph nodes were conducted. The patient was eventually diagnosed with AITL-associated HLH, and treated with etoposide together with cyclophosphamide, doxorubicin, vincristine and prednisolone. The patient was successfully treated with several courses of chemotherapy. In view of the fact that AITL-associated HLH with annular erythema multiforme-like rashes is relatively rare worldwide and is associated with a high mortality rate, the data on previous cases were reviewed with the hope of providing clinical bases for early diagnosis and treatment of AITL-associated HLH.

| S-EPMC6122190 | biostudies-literature

Detection of the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and related lymphomas using quantitative allele-specific PCR.

Project description:Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60-70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60-70% of AITL and AITL-like PTCL-NOS.

| S-EPMC4195681 | biostudies-literature

Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

Project description:A missense mutation in RHOA encoding p.Gly17Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. We also provide evidence for presence of dominant T cell clonal populations and expansion of B-cells leading to hypergammaglobulinemia. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice most closely resembles that of AITL patients with the identical p.Gly17Val mutation. The murine model should therefore be useful in dissecting pathogenesis of AITL at the molecular level and in preclinical trials of various therapeutic agents, particularly for the cases with the highly prevalent p.Gly17Val mutation.

2020-06-08 | GSE115510 | GEO

Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling.

Project description:Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.

| S-EPMC5392284 | biostudies-literature

Angioimmunoblastic T-cell lymphoma mimicking drug fever and infectious etiology after a thyroidectomy: A case report.

Project description:IntroductionAngioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of mature peripheral T-cell lymphoma and accounts for approximately 1% to 2% of non-Hodgkin lymphomas. Although the B symptoms with generalized lymphadenopathy are the most frequent manifestations of AITL, its diagnosis remains a challenge as clinical manifestations and pathological features are frequently misleading.Patient concernsWe report herein the case of a 70-year-old man with intermittent fever, pulmonary infection, and skin rash developed for 1 month before admission. Previously, he had undergone thyroidectomy for thyroid papillary carcinoma. Fever occurred on the day of discharge and occurred again during the next month. Symptoms worsened despite treatment with antibiotics and papular rash appeared. The local hospital diagnosed it as drug fever and stopped all antibiotics. Fever and rash were controlled temporarily; however, both relapsed 2 days before admission. On the night of admission, the patient developed fever again. Blood culture showed Staphylococcus epidermidis and Staphylococcus haemolyticus infection.InterventionsTaking into account the recent history of surgery, the patient was diagnosed with septicemia and was treated with anti-infective treatment. On 13th day after admission, the patient developed fever again accompanied by generalized lymphadenopathy. However, multiple blood cultures were negative and bone marrow aspiration cytology, biopsy, immunohistochemistry, and gene rearrangement results were normal.DiagnosisThe patient was finally subjected to cervical lymph node biopsy and was diagnosed with AITL.OutcomesThe patient was transferred to the Department of Hematology for further treatment.ConclusionThis case highlights the complex diagnostic challenges of AITL. AITL accompanied by thyroid carcinoma may not be a mere coincidence and administration of antibiotics may be a rare cause of AITL.

| S-EPMC6716746 | biostudies-literature

Multiple chromoanasynthesis in a rare case of sporadic renal leiomyosarcoma: case report

Project description:Renal leiomyosarcomas (LMS) are extremely rare neoplasms with aggressive behaviour and poor survival prognosis. The most frequent somatic events in leiomyosarcomas are mutations in TP53, RB1, ATRX and PTEN genes, chromosomal instability and chromoanagenesis. By using chromosomal microarray analysis we identified monosomy of chromosomes 3 and 11, gain of Xp (ATRX) arm and three chromoanasynthesis regions (6q21-q27, 7p22.3-p12.1 and 12q13.11-q21.2), with MDM2 and CDK4 oncogenes copy number gains, whereas no CNVs or tumor specific SNVs in TP53, RB1 and PTEN genes were observed.

2020-06-04 | GSE151766 | GEO

CHEK2 mutation in a patient with pancreatic adenocarcinoma-a rare case report.

Project description:Pancreatic cancer (PaCa) is very aggressive malignancy with poor prognosis. Individuals with a family history of PaCa have a higher risk of developing cancer which points to a hereditary component. Here, we report a unique case of CHEK2 mutant PaCa in a patient with no medical but significant family history. A 59-year old female presented with 3-month history of worsening epigastric pain and jaundice. CT abdomen/pelvis with contrast showed pancreatic head mass which was confirmed by endoscopic ultrasound guided biopsy. She was diagnosed with pancreatic adenocarcinoma harboring CHEK2 mutation. She had extensive surgery followed by adjuvant chemotherapy. Follow up imaging in 3 months obtained after surgery and adjuvant chemotherapy showed extensive liver metastasis and patient decided to pursue hospice. Germline testing in all PaCa patients has become essential as mutations in CHEK2 and other DNA repair genes constitute a unique subset of PaCas. Not only does it help in assessment of cancer risk in the individual and family members but also guide anticancer therapy selection. PaCa patients harboring CHEK2 mutations do not usually respond to chemotherapeutic agents such as gemcitabine. However, new treatment strategies such as PARP inhibitors targeting defective DNA repair mechanism are currently being investigated and showed some promise in treating CHEK2 mutant PaCa patients.

| S-EPMC7882266 | biostudies-literature

Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking.

Project description:BackgroundAlthough advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking.MethodsWe generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and two with PTCL-NOS.ResultsClonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH-associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥15% of allele burden conferred higher risk for CHN (p=0.0006, hazard ratio = 14.01, positive predictive value = 88.9%, negative predictive value = 92.1%).ConclusionsWe provided genetic evidence that AITL/PTCL-NOS, CH, and CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients.FundingR01 grant (CA194547) from the National Cancer Institute to WT.

| S-EPMC8480981 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data