Methylation-Based Characterization of a New IDH2 Mutation in Sinonasal Undifferentiated Carcinoma.

Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.

Bilateral periorbital leukemia cutis presenting as suspected cellulitis.

Many conditions present with periorbital edema and erythema, mimicking preseptal cellulitis. We report the unique case of a patient with relapsed monoblastic mutant isocitrate dehydrogenase-2 (IDH2) acute myeloid leukemia (AML) who presented with periorbital edema and erythema, unresponsive to antibiotics. Histopathology from punch biopsy was consistent with leukemia cutis. The patient responded rapidly to the initiation of enasidenib, a novel targeted inhibitor of mutant IDH2 enzymes. Our case highlights the importance of considering leukemia cutis in patients with a history of leukemia presenting with periorbital edema and erythema.

[Venetoclax and azacitidine induced cytogenetic response in an elderly patient with IDH2- and DNMT3A-mutated refractory acute myeloid leukemia].

The optimal regimen for refractory acute myeloid leukemia (AML) in the elderly with good performance status has not been established. A 71-year-old man was admitted to our hospital with pancytopenia and 1.0% blasts in the peripheral blood. The patient was diagnosed with AML with DNMT3A (R882H)- and IDH2 (R172K)-positive myeloblasts. He received a reduced dose of idarubicin and cytarabine therapy. However, induction failure with 20% bone marrow blasts and DNMT3A mutations were observed. A reinduction therapy with venetoclax and azacitidine (VEN+AZA) was administered and led to a sustained complete response with significantly reduced DNMT3A-mutated blasts. Even 9 months after starting VEN+AZA, the patient is still alive and healthy without AML recurrence. Thus, VEN+AZA therapy may be highly effective for treating IDH2- and DNMT3A-mutated AML in elderly patients.

IDH-1 polymorphisms in pilocytic astrocytomas.

As of 2016, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations are part of the definition of an oligodendroglioma and may be seen in a significant subset of grade II-IV fibrillary astrocytomas. Reports of IDH-1 and IDH-2 alterations in pilocytic astrocytomas have been rare. This study reports two cases of pilocytic astrocytomas which harbored IDH-1 polymorphisms (G105G) (c.315C > T) discovered on polymerase chain reaction (PCR) testing and sequencing. The first was encountered in a 21-year-old male with a right orbital frontal pole mass. The second occurred in a 19-year-old female with a right frontal tumor. Neither tumor stained with antibody to IDH-1 (R132H). No BRAF V600E immunostaining, minimal p53 staining (<5%) and no loss of ATRX staining was noted in both cases. The significance of the IDH-1 findings at this juncture is uncertain. Misdiagnosis of the tumor as a fibrillary astrocytoma or oligodendroglioma due to the presence of an IDH alteration should be avoided.

Cerebellar high-grade astrocytoma with IDH mutations in the elderly: A report of two cases.

Cerebellar high-grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH-mutated cerebellar high-grade glioma with unusual histological features and uncommon patient ages. One case was an 83-year-old man, whose tumor was predominantly composed of densely packed round-to-polygonal epithelioid cells. The other was a 75-year-old woman's high-grade astrocytoma characterized by cord-like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH-mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2-mutation. Although the number is limited, IDH-mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.

A novel monoclonal antibody SMab-2 recognizes endogenous IDH2-R172S of chondrosarcoma.

Isocitrate dehydrogenase 2 (IDH2) mutations have been reported in gliomas, osteosarcomas, cartilaginous tumors, giant cell tumors of bone, and acute myeloid leukemias. Although IDH2 catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate (α-KG) in mitochondria, mutated IDH2 proteins possess the ability to change α-KG into the oncometabolite R(-)-2-hydroxyglutarate (2-HG). To date, several monoclonal antibodies (mAbs) specific for IDH2 mutations have been established, such as KMab-1 against IDH2-R172K, MMab-1 against IDH2-R172M, and WMab-1 against IDH2-R172W. Although a multi-specific mAb MsMab-1 reacted with IDH2-R172G and IDH2-R172S, a mono-specific mAb against IDH2-R172S has not been established. In this study, we established a novel mAb SMab-2, which recognizes IDH2-R172S but not with wild type IDH2 in ELISA. Although SMab-2 reacted with both IDH1-R132S and IDH2-R172S expressed in Escherichia coli, it reacted with only IDH2-R172S expressed in U-2 OS osteosarcoma cells. Furthermore, SMab-2 recognized endogenous IDH2-R172S protein expressed in SW1353 chondrosarcoma cells in Western blot and immunocytochemical analyses. SMab-2 is expected to be useful for diagnosis of IDH2-R172S-bearing tumors.

IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome.

We report on a 24-year-old woman who was diagnosed as having Maffucci syndrome with anaplastic astrocytoma. We analyzed the IDH1 and IDH2 mutations of enchondroma, hemangioma and anaplastic astrocytoma tissues and the same somatic mosaic mutation in IDH2 gene was identified in all these tissues. In addition, we identified additional mutation of the TP53 gene in anaplastic astrocytoma tissue but not in other benign tumors. This is the first report of the detection of an identical IDH2 mutation in multiple tissues and TP53 mutation in anaplastic astrocytoma in a patient with Maffucci syndrome. This case is unique and supports the IDH2-dependent genetic pathway and second-hit model for gliomagenesis.

Comparison of venetoclax and ivosidenib/enasidenib for unfit newly diagnosed patients with acute myeloid leukemia and IDH1/2 mutation: a network meta-analysis.

Because of lacking of head-to-head comparison between venetoclax and IDH1/IDH2 inhibitors (ivosidenib/enasidenib) for newly diagnosed unfit patients with acute myeloid leukemia (AML), the optimal option for these patients still remains undefined. We searched relevant published reports. Three RCTs with 180 IDH1 mutant and 165 IDH2 mutant patients were identified. Indirect comparison of OS using fixed effects network meta-analysis (NMA) models indicated venetoclax plus azacitidine (Ven-Aza) significantly improved survival than enasidenib plus azacitidine (Ena-Aza) (HR:0.30, p = 0.005) for those newly diagnosed patients with AML and IDH2 Mutation. And, for those IDH2 mutation patients, Ven-Aza also had the highest probability of 98.3% (OS analysis) and 84.0% (CR/CRi analysis) to be the best intervention among these first-line treatment regimens (Ven-Aza, Ena-Aza and Aza). And, there was a favorable trend towards Ven-Aza in survival analysis (HR:0.69, p = 0.42), when compared to ivosidenib plus azacitidine (Ivo-Aza) for those newly diagnosed patients with AML and IDH1 Mutation. For those IDH1 Mutation, venetoclax plus azacitidine (Ven-Aza) had the highest probability of 65.8% (OS analysis) and 73.0% (CR/CRi analysis) to be the best intervention among these first-line treatment regimens (Ven-Aza, ivosidenib plus azacitidine (Ivo-Aza) and azacitidine (Aza)). In conclusion, venetoclax plus azacitidine could be a good option for unfit newly diagnosed patients with acute myeloid leukemia and IDH1/2 mutation. Considering our limits (only trial data-based network meta-analysis et al.), future trials directly comparing these regimens are warranted.

IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo.

Introduction: IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear. Methods: In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2 R172K transgenic mice. Results: We found that thrombopoietin (TPO)-overexpressed Idh2 R172K (Idh2 R172K + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2-wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2 R172K + TPO group. Furthermore, Idh2 R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations. Conclusion: Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2 R172K + TPO mice.

A comprehensive case study on successful multimodal therapy in philadelphia chromosome-positive acute myeloid leukemia with NPM1 and IDH2 mutations.

A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of mutations, including NPM1 and IDH2 mutations. Novel combination therapy with azacitidine, venetoclax and ponatinib allowed her to successfully achieve a complete response (CR) and undergo an allogeneic hematopoietic stem cell transplant (HSCT). This case report provides an overview of her clinical course, emphasizing the significance of integrated therapy and the challenges associated with balancing treatment for AML. It also underscores the importance of a multidisciplinary approach and careful monitoring of patients with complex hematologic conditions.

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma.

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Venetoclax-Azacitidine Bridging PTCy-haplo-PBSCT for Refractory Acute Myeloid Leukemia with IDH2 Mutations.

Venetoclax and azacitidine combination therapy (VEN+AZA) is a promising novel therapy for elderly or unfit patients with acute myeloid leukemia (AML). Recently, VEN+AZA with subsequent allo-hematopoietic stem cell transplantation has been reported, and human leukocyte antigen-haploidentical peripheral blood stem cell transplantation using posttransplant cyclophosphamide (PTCy-haplo-PBSCT) from related donors appears to be a suitable option. Here, we report two elderly patients with refractory AML harboring an IDH2 mutation, who were successfully treated with VEN+AZA bridged to PTCy-haplo-PBSCT. This report suggests the efficacy and safety of VEN+AZA as a bridging treatment for PTCy-haplo-PBSCT in refractory AML.

A case report of complete remission of acute myeloid leukemia combined with DNMT3A, FLT3-TKD, and IDH2 gene mutations and active pulmonary tuberculosis treated with homeharringtonine + venetoclax + azacytidine.

In March 2022, a 58-year-old man was admitted to the local hospital for nausea and vomiting. His blood routine indicated that he had leukocytosis and anemia. The patient was diagnosed with acute myeloid leukemia (AML)-M5b accompanied by DNMT3A, FLT3-TKD, and IDH2 mutations, chest CT revealed pulmonary tuberculosis (TB). Acid-fast bacillus (AFB) was detected in sputum. The patient then received anti-TB treatment with isoniazid + rifampicin + pyrazinamide + ethambutol. On April 8, he was transferred to our hospital's Hematology Department after three consecutive negative sputum smears. He was administered the VA (Venetoclax + Azacytidine) regimen of anti-leukemia treatment and also received levofloxacin + isohydrazide + pyrazinamide + ethambutol anti-TB treatment. After one course of VA therapy, there was no remission in the bone marrow. Therefore, the patient received the HVA (Homeharringtonine + Venetoclax + Azacytidine) regimen of anti-leukemia treatment. On May 25, the bone marrow smear revealed that the original mononuclear cells were 1%. Moreover, bone marrow flow cytometry revealed the absence of any abnormal cells. mNGS showed DNMT3A (mutation rate 44.7%), but no mutations were detected in FLT3-TKD and IDH2. The patient then received the HVA regimen three consecutive times, resulting in complete remission. Repeated chest CT examinations revealed progressive regression of pulmonary TB foci, no AFB was detected in the sputum. This AML patient with DNMT3A, FLT3-TKD, and IDH2 mutations and active TB is difficult to treat. It is very necessary for him to administer prompt anti-leukemia treatment under the premise of active anti-TB treatment. The HVA regimen is effective for this patient.

Data-driven modeling of core gene regulatory network underlying leukemogenesis in IDH mutant AML.

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of poorly differentiated myeloid cells, with a heterogenous mutational landscape. Mutations in IDH1 and IDH2 are found in 20% of the AML cases. Although much effort has been made to identify genes associated with leukemogenesis, the regulatory mechanism of AML state transition is still not fully understood. To alleviate this issue, here we develop a new computational approach that integrates genomic data from diverse sources, including gene expression and ATAC-seq datasets, curated gene regulatory interaction databases, and mathematical modeling to establish models of context-specific core gene regulatory networks (GRNs) for a mechanistic understanding of tumorigenesis of AML with IDH mutations. The approach adopts a novel optimization procedure to identify the optimal network according to its accuracy in capturing gene expression states and its flexibility to allow sufficient control of state transitions. From GRN modeling, we identify key regulators associated with the function of IDH mutations, such as DNA methyltransferase DNMT1, and network destabilizers, such as E2F1. The constructed core regulatory network and outcomes of in-silico network perturbations are supported by survival data from AML patients. We expect that the combined bioinformatics and systems-biology modeling approach will be generally applicable to elucidate the gene regulation of disease progression.

Laser Interstitial Thermal Therapy in Grade 2/3 IDH1/2 Mutant Gliomas: A Preliminary Report and Literature Review.

Laser interstitial thermal therapy (LITT) has become an increasingly utilized alternative to surgical resection for the treatment of glioma in patients. However, treatment outcomes in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant glioma, specifically, have not been reported. The objective of this study was to characterize a single institution's cohort of IDH1/2 mutant grade 2/3 glioma patients treated with LITT. We collected data on patient presentation, radiographic features, tumor molecular profile, complications, and outcomes. We calculated progression-free survival (PFS) and tested factors for significant association with longer PFS. Overall, 22.7% of our cohort experienced progression at a median follow up of 1.8 years. The three- and five-year estimates of PFS were 72.5% and 54.4%, respectively. This is the first study to characterize outcomes in patients with IDH1/2 mutant glioma after LITT. Our results suggest that LITT is an effective treatment option for IDH1/2 mutant glioma.

Pediatric High Grade Glioma Classification Criteria and Molecular Features of a Case Series.

Pediatric high-grade gliomas (pHGGs) encompass a heterogeneous group of tumors. Three main molecular types (H3.3 mutant, IDH mutant, and H3.3/IDH wild-type) and a number of subtypes have been identified. We provide an overview of pHGGs and present a mono-institutional series. We studied eleven non-related pHGG samples through a combined approach of routine diagnostic tools and a gene panel. TP53 and H3F3A were the most mutated genes (six patients each, 54%). The third most mutated gene was EGFR (three patients, 27%), followed by PDGFRA and PTEN (two patients each, 18%). Variants in the EZHIP, MSH2, IDH1, IDH2, TERT, HRAS, NF1, BRAF, ATRX, and PIK3CA genes were relatively infrequent (one patient each, 9%). In one case, gene panel analysis documented the presence of a pathogenic IDH2 variant (c.419G>A, p.Arg140Gln) never described in gliomas. More than one-third of patients carry a variant in a gene associated with tumor-predisposing syndromes. The absence of constitutional DNA did not allow us to identify their constitutional origin.

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer.

Isocitrate dehydrogenase (IDH) is a key metabolic enzyme catalyzing the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in IDH lead to loss of normal enzymatic activity and gain of neomorphic activity that irreversibly converts α-KG to 2-hydroxyglutarate (2-HG), which can competitively inhibit a-KG-dependent enzymes, subsequently induces cell metabolic reprograming, inhibits cell differentiation, and initiates cell tumorigenesis. Encouragingly, this phenomenon can be reversed by specific small molecule inhibitors of IDH mutation. At present, small molecular inhibitors of IDH1 and IDH2 mutant have been developed, and promising progress has been made in preclinical and clinical development, showing encouraging results in patients with IDH2 mutant cancers. This review will focus on the biological roles of IDH2 mutation in tumorigenesis, and provide a proof-of-principle for the development and application of IDH2 mutant inhibitors for human cancer treatment.

Tall cell carcinoma with reversed polarity: case report with gene sequencing and literature review.

Tall cell carcinoma with reversed polarity (TCCRP) is an extremely rare type of invasive breast cancer with only 17 literatures and 75 cases reported. Knowledge on TCCRP is still scanty. The present study reported 2 cases of TCCRP, analyzed their clinicopathological characteristics, and used whole exome sequencing to perform genetic testing. Both two cases were proved to have typical clinicopathological manifestations (solid and papillary architectures lined by tall columnar cells with nuclei displaying "reverse polarization") and hotspot mutations (IDH2 and PIK3CA mutations) of TCCRP. Furthermore, positive expression of TTF-1 was found in a small number of tumor cells nuclei and normal ductal epithelial cells, while the negative rate of TTF-1 in previous case reports was 100%. Attention should be paid in core needle biopsy to avoid misdiagnosis. In addition, this article also reviewed all previous cases and demonstrated that the positive expression of calretinin might have an indicative significance for TCCRP, which could be used as one of the auxiliary diagnosis tools. The diagnosis of TCCRP requires comprehensive analysis of clinical pathology and genetic testing results. There is no clear treatment standard for TCCRP currently, further research should be reported to characterize and deeply investigate the diagnosis and treatment criteria of TCCRP.

Tall cell carcinoma of the breast with reverse polarity: case report with gene sequencing and literature review.

Tall cell carcinoma of the breast with reverse polarity (TCCRP), described firstly and also known as tall cell variant of papillary breast carcinoma (TCVPBC), is a rare type of breast cancer that mimics papillary thyroid carcinoma (PTC) histopathologically. As the incidence of this type of tumor is very low, awareness of it is crucial to ensuring that unnecessary clinical investigations are avoided. The present study examined a 45-year-old woman in China who was diagnosed with TCCRP. This paper outlines her demographic and clinicopathologic data, and her follow-up and immunohistochemical examination results. Furthermore, this study used the next-generation sequencing (NGS) technique to identify concurrent isocitrate dehydrogenase 2 (IDH2) and phosphatidylinositol 3-kinase catalytic alpha (PIK3CA) hotspot mutations. Notably, the novel results of the study showed that the IDH2 R120 (rather than the IDH2 R172) mutation may also be present in this disease. Additionally, a comprehensive literature review was conducted to elucidate some of the significant clinical and pathological features of this type of disease. This information may provide important insights that can be used in diagnosis and treatment. It is essential both for physicians and pathologists to recognize the existence of TCCRP, with its own specific clinical and pathological characteristics. Further research using molecular biology techniques should be conducted in the future to characterize this unique entity.

A Rare Case of Systemic Mastocytosis With Associated Clonal Hematological Non-Mast Cell Lineage Disease That Transformed to Acute Leukemia With IDH2 Mutation.

An elderly 72-year-old man presented with anemia, thrombocytopenia, monocytosis, splenomegaly and lymphadenopathy. Bone marrow biopsy was consistent with mast cell neoplasm with positive CD117, CD25, CD34 myeloblasts and polymerase chain reaction (PCR) revealed mutation of D816V. He developed bilateral femoral neck fractures and biopsy confirmed that he has systemic mastocytosis (SM). He received cladribine and midostaurin with stable disease for 21 months. His SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD) transformed to acute myelogenous leukemia with isocitrate dehydrogenase 2 (IDH2) mutation. A trial of enasidenib was given for 5 months but without any response. Patient decided to go with home hospice and died afterwards.