Case of B-acute lymphoblastic leukaemia with t(1;19)(q23;p13.3) TCF3::PBX1 and co-occurring CBL mutation in an elderly patient.

The t(1;19) (q23;p13) TCF3::PBX1 is a well-described, recurring chromosomal abnormality in B-acute lymphoblastic leukaemia (B-ALL) that has historically been associated with a worse prognosis in paediatric patients. Gene expression profiling has demonstrated that TCF3::PBX1 results in a distinct subtype of B-ALL, leading to its recognition in the most recent WHO and ICC classifications. Though initially believed to be a poor prognostic sign in the adult population, emerging evidence suggests its presence may instead be intermediate or even favourable in B-ALL. However, adults with TCF3::PBX1 are typically younger and often qualify for treatment with paediatric-inspired regimens. Thus, the prognostic significance in this population remains unclear. This translocation appears to be very rare in older adults with B-ALL and its predictive and prognostic nature in this population is unknown. Herein, we explore a case of this translocation occurring in a patient in her 70s. She initially presented to the emergency department with abdominal pain and thrombocytopenia and was subsequently diagnosed with B-ALL. In addition to t(1;19) (q23;p13), a pathologic mutation in the CBL gene was identified. CBL mutations have been implicated in cancer progression and are mostly described in paediatric B-ALL. She was treated with modified Ph-negative EWALL induction (Vincristine, Idarubicin, dexamethasone) and achieved a complete remission. However, she subsequently experienced an early relapse and was refractory to targeted therapy with blinatumomab. After treatment with inotuzumab ozogamicin, she achieved a second complete remission. Unfortunately, she then suffered a central nervous system (CNS) relapse and passed away from complications of her disease. This case serves as an example of the heterogeneous nature of B-ALL. It demonstrates that patients with ostensibly favourable prognostic factors may experience poor response rates to traditional chemotherapy as well as targeted salvage agents. It also illustrates the challenges of treating B-ALL in the elderly population.

A microdeletion event at 19q13.43 in IDH-mutant astrocytomas is strongly correlated with MYC overexpression.

MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic changes. Our pilot analysis uncovered instances of relative MYC overexpression without alterations in the proximal MYC network (PMN), prompting a deeper investigation into potential novel oncogenic mechanisms. Analysing comprehensive genomics profiles of 236 "IDH-mutant 1p/19q non-co-deleted" lower-grade gliomas from The Cancer Genome Atlas, we identified somatic genomic alterations within the PMN. In tumours without PMN-alterations but with MYC-overexpression, genes correlated with MYC-overexpression were identified. Our analyses yielded that 86/236 of astrocytomas exhibited no PMN-alterations, a subset of 21/86 displaying relative MYC overexpression. Within this subset, we discovered 42 genes inversely correlated with relative MYC expression, all on 19q. Further analysis pinpointed a minimal common region at 19q13.43, encompassing 15 genes. The inverse correlations of these 15 genes with relative MYC overexpression were re-confirmed using independent scRNAseq data. Further, the micro-deleted astrocytoma subset displayed significantly higher genomic instability compared to WT cases, but lower instability compared to PMN-hit cases. This newly identified 19q micro-deletion represents a potential novel mechanism underlying MYC dysregulation in astrocytomas. Given the prominence of 19q loss in IDH-mutant gliomas, our findings bear significant implications for understanding gliomagenesis.

Fluoxetine Successfully Treats Intracranial Enterovirus E18 Infection in a Patient with CD79a Deficiency Arising from Segmental Uniparental Disomy of Chromosome 19.

The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igß respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients.

MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

Germline MYOF1::WNK4 and VPS25::MYOF1 Chimeras Generated by the Constitutional Translocation t(17;19)(q21;p13) in Two Siblings With Myelodysplastic Syndrome.

BACKGROUND/AIM: Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS). MATERIALS AND METHODS: Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing. RESULTS: We identified a balanced t(17;19)(q21;p13) translocation in both siblings' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein. CONCLUSION: The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

Real world outcome of B ALL with t (1; 19) (q23; p13)/TCF3::PBX1 in adolescents and adults treated with intensive regimes.

Significant heterogeneity has been reported in outcome of Acute lymphoblastic leukemia with t(1;19)(q23;p13)/TCF3::PBX1 in adolescents and adults leading to a lack of consensus on precise risk stratification. We evaluated clinical outcome of 17 adult ALL cases (≥15 years) with this genotype treated on intensive regimes.13/17 received COG0232 and 4/17 cases received UK-ALL protocol. All achieved CR (100%) with above treatment. End of induction MRD was evaluated in 14/17 cases of which 11 (78.5%) achieved MRD negativity. Total nine patients relapsed (7 marrows, 2 CNS). Overall survival at 2 years was 53.3%. The 2 year estimated PFS was 42.9%. The 2 years CIR was 54.2%. Adults with this genotype perform poorly despite early favorable response. Incorporation of novel immunotherapies and prompt HSCT should be strongly considered with this genotype. Targeted NGS panels for additional genetic aberrations can further help in risk stratifying and guiding therapy for this genotype.

Relaxation Along a Fictitious Field, continuous wave T1rho, adiabatic T1rho and adiabatic T2rho imaging of human gliomas at 3T: A feasibility study.

In pre-clinical models of brain gliomas, Relaxation Along a Fictitious Field in second rotating frame (TRAFF2), continues wave T1rho (T1ρcw), adiabatic T1rho (T1ρadiab), and adiabatic T2rho (T2ρadiab) relaxation time mappings have demonstrated potential to non-invasively characterize brain gliomas. Our aim was to evaluate the feasibility and potential of 4 different spin lock methods at 3T to characterize primary brain glioma. 22 patients (26-72 years) with suspected primary glioma. T1ρcw was performed using pulse peak amplitude of 500Hz and pulse train durations of 40 and 80 ms while the corresponding values for T1ρadiab, T2ρadiab, TRAFF2 were 500/500/500Hz and 48 and 96, 64 and 112, 45 and 90 ms, respectively. The parametric maps were calculated using a monoexponential model. Molecular profiles were evaluated from tissue specimens obtained during the resection. The lesion regions-of-interest were segmented from high intensity FLAIR using automatic segmentation with manual refinement. Statistical descriptors from the voxel intensity values inside each lesion and radiomic features (Pyrad MRC package) were calculated. From extracted radiomics, mRMRe R package version 2.1.0 was used to select 3 features in each modality for statistical comparisons. Of the 22 patients, 10 were found to have IDH-mutant gliomas and of those 5 patients had 1p/19q codeletion group comparisons. Following correction for effects of age and gender, at least one statistical descriptor was able to differentiate between IDH and 1p/19q codeletion status for all the parametric maps. In the radiomic analysis, corner-edge detector features with Harris-Stephens filtered signal showed significant group differences in IDH and 1p/19q codeletion groups. Spin lock imaging at 3T of human glioma was feasible and various qualitative parameters derived from the parametric maps were found to have potential to differentiate IDH and 1p19q codeletion status. Future larger prospective clinical trials are warranted to evaluate these methods further.

A custom next-generation sequencing panel for 1p/19q codeletion and mutational analysis in gliomas.

The World Health Organization has updated their classification system for the diagnosis of gliomas, combining histological features with molecular data including isocitrate dehydrogenase 1 and codeletion of chromosomal arms 1p and 19q. 1p/19q codeletion analysis is commonly performed by fluorescence in situ hybridization (FISH). In this study, we developed a 57-gene targeted next-generation sequencing (NGS) panel including 1p/19q codeletion detection mainly to assess diagnosis and potential treatment response in melanoma, gastrointestinal stromal tumor, and glioma patients. Loss of heterozygosity analysis was performed using the NGS method on 37 formalin-fixed paraffin-embedded glioma tissues that showed 1p and/or 19q loss determined by FISH. Conventional methods were applied for the validation of some glioma-related gene mutations. In 81.1% (30 of 37) and 94.6% (35 of 37) of cases, 1p and 19q were found to be in agreement whereas concordance for 1p/19q codeletion and no 1p/19q codeletion was found in 94.7% (18 of 19) and 94.4% (17 of 18) of cases, respectively. Overall, comparing NGS results with those of conventional methods showed high concordance. In conclusion, the NGS panel allows reliable analysis of 1p/19q codeletion and mutation at the same time.

Rise of oligodendroglioma hypermutator phenotype from a subclone harboring TP53 mutation after TMZ treatment.

Oligodendrogliomas characterized and defined by 1p/19q co-deletion are slowly growing tumors showing better prognosis than astrocytomas. TP53 mutation is rare in oligodendrogliomas while the vast majority of astrocytomas harbor the mutation, making TP53 mutation mutually exclusive with 1p/19q codeletion in lower grade gliomas virtually. We report a case of 51-year-old woman with a left fronto-temporal oligodendroglioma that contained a small portion with a TP53 mutation, R248Q, at the initial surgery. On a first, slow-growing recurrence 29 months after radiation and nitrosourea-based chemotherapy, the patient underwent TMZ chemotherapy. The recurrent tumor responded well to TMZ but developed a rapid progression after 6 cycles as a malignant hypermutator tumor with a MSH6 mutation. Most of the recurrent tumor lacked typical oligodendroglioma morphology that was observed in the primary tumor, while it retained the IDH1 mutation and 1p/19q co-deletion. The identical TP53 mutation observed in the small portion of the primary tumor was universal in the recurrence. This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.

Exploiting nanopore sequencing for characterization and grading of IDH-mutant gliomas.

The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to codeletion of 1p/19q to characterize IDH-mutant gliomas. Here, we demonstrated the use of a nanopore-based copy-number variation sequencing (nCNV-seq) approach to simultaneously identify deletions of CDKN2A/B and 1p/19q. The nCNV-seq approach was initially evaluated on three distinct glioma cell lines and then applied to 19 IDH-mutant gliomas (8 astrocytomas and 11 oligodendrogliomas) from patients. The whole-arm 1p/19q codeletion was detected in all oligodendrogliomas with high concordance among nCNV-seq, FISH, DNA methylation profiling, and whole-genome sequencing. For the CDKN2A/B deletion, nCNV-seq detected the loss in both astrocytoma and oligodendroglioma, with strong correlation with the CNV profiles derived from whole-genome sequencing (Pearson correlation (r) = 0.95, P < 2.2 × 10-16 to r = 0.99, P < 2.2 × 10-16 ) and methylome profiling. Furthermore, nCNV-seq can differentiate between homozygous and hemizygous deletions of CDKN2A/B. Taken together, nCNV-seq holds promise as a new, alternative approach for a rapid and simultaneous detection of the molecular signatures of IDH-mutant gliomas without capital expenditure for a sequencer.

Expression study of microRNA cluster on chromosome 19 (C19MC) in tumor tissue and serum of breast cancer patient.

BACKGROUND: Breast cancer (BC) is the most prevalent cancer among females worldwide. Numerous studies suggest that specific RNAs play a crucial role in carcinogenesis. The primate-specific microRNA gene cluster located on the 19q27.3 region of chromosome 19 (C19MC) could potentially regulate tumor cell proliferation, migration, and invasion. OBJECTIVE: The objective of this study was to compare the expression of miRNAs from the C19MC cluster in breast cancer tumor and non-tumor samples, as well as in the serum of individuals affected by BC and healthy individuals. METHODS: Peripheral blood was collected from 100 BC patients and 100 healthy individuals, and breast cancer samples including tumor and margin tissues were obtained. After RNA extraction, Real-time PCR was employed to investigate the expression of C19MC, specifically mir-515-1, mir-515-2, mir-516-A1, mir-516-A2, mir-516-B1, mir-516-B2, mir-517-A, mir-517-B, mir-517-C, and mir-518-A1, in the serum and tissue of BC patients and tumor margins. Statistical analyses and ROC curves were generated using GraphPad Prism software (v8.04), with a significance level set at p < 0.05. RESULTS: Our findings demonstrate a strong correlation between high expression of all C19MC miRNAs mentioned, except for mir-517-B, mir-517-C and mir- 518 in BC. These miRNAs show potential as notable non-invasive tumor markers. CONCLUSION: The data obtained from our study support the overall impact of C19MC miRNAs in BC detection and emphasize the potential role of several C19MC members in this process.

Radiogenomics Provides Insights into Gliomas Demonstrating Single-Arm 1p or 19q Deletion.

BACKGROUND AND PURPOSE: IDH-mutant gliomas are further divided on the basis of 1p/19q status: oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and astrocytoma, IDH-mutant (without codeletion). Occasionally, testing may reveal single-arm 1p or 19q deletion (unideletion), which remains within the diagnosis of astrocytoma. Molecular assessment has some limitations, however, raising the possibility that some unideleted tumors could actually be codeleted. This study assessed whether unideleted tumors had MR imaging features and survival more consistent with astrocytomas or oligodendrogliomas. MATERIALS AND METHODS: One hundred twenty-one IDH-mutant grade 2-3 gliomas with 1p/19q results were identified. Two neuroradiologists assessed the T2-FLAIR mismatch sign and calcifications, as differentiators of astrocytomas and oligodendrogliomas. MR imaging features and survival were compared among the unideleted tumors, codeleted tumors, and those without 1p or 19q deletion. RESULTS: The cohort comprised 65 tumors without 1p or 19q deletion, 12 unideleted tumors, and 44 codeleted. The proportion of unideleted tumors demonstrating the T2-FLAIR mismatch sign (33%) was similar to that in tumors without deletion (49%; P = .39), but significantly higher than codeleted tumors (0%; P = .001). Calcifications were less frequent in unideleted tumors (0%) than in codeleted tumors (25%), but this difference did not reach statistical significance (P = .097). The median survival of patients with unideleted tumors was 7.8 years, which was similar to that in tumors without deletion (8.5 years; P = .72) but significantly shorter than that in codeleted tumors (not reaching median survival after 12 years; P = .013). CONCLUSIONS: IDH-mutant gliomas with single-arm 1p or 19q deletion have MR imaging appearance and survival that are similar to those of astrocytomas without 1p or 19q deletion and significantly different from those of 1p/19q-codeleted oligodendrogliomas.

Evaluation of chromosome 1p/19q deletion by Fluorescence in Situ Hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy.

BACKGROUND: Either deletion or co-deletion of chromosomal arms 1p or 19q is a characteristic and early genetic event in oligodendroglial tumors that is associated with a better prognosis and enhanced response to therapy. Information of 1p/19q status is now regarded as the standard of care when managing oligodendroglial tumors for therapeutic options in anticipation of the increased survival and progression-free survival times associated with it. Keeping this in view, we first time attempted to establish the FISH based detection of 1p/19q deletion in glioma tissue samples to evaluate its role and involvement in the disease. METHOD: Overall 39 glioma cases of different histologies were evaluated by fluorescence in situ hybridization (FISH) technique using specific FISH probes with Olympus BX43 fluorescent microscope to detect chromosomes 1p and 19q or co-deletions therein. RESULTS: Of the 39 glioma samples, overall 27 (69.2%) were found to have deletion either in 1p, 19q or both. Deletions were observed in 23.0%, 7.6% and 38.4% in 1p, 19q and 1p/19q co-deletions respectively. Overall oligidendrioglioma presented with 53.8% (21 of 39) deletions, astrocytoma group showed 12.8% and GBM accounted for 2.5% deletions. Overall survival and disease free survival was seen significantly better in oligidendrioglioma and astrocytoma with deleted tumors as compared to non-deleted ones (p<0.05). CONCLUSION: Allelic losses on 1p and 19q, either discretely or shared, were more frequent in classic oligodendrogliomas than in either astrocytoma or Glioblastoma with better survival and response to therapy.

Integrated multiomics analysis of chromosome 19 miRNA cluster in bladder cancer.

With 46 microRNAs (miRNAs) embedded tandemly over a distance of ~100 kb, chromosome 19 microRNA cluster (C19MC) is the largest miRNA cluster in the human genome. The C19MC is transcribed from a long noncoding genomic region and is usually expressed simultaneously at a higher level. Hence, we performed an integrative multiomics data analysis to examine C19MC regulation, expression patterns, and their impact on bladder cancer (BCa). We found that 43 members of C19MC were highly expressed in BCa. However, its co-localization with recurrent copy number variation (CNV) gain was not statistically significant to implicate its upregulation. It has been reported that C19MC expression is regulated by a well-established CpG island situated 17.6 kb upstream of the transcription start site, but we found that CpG probes at this island were hypomethylated, which was not statistically significant in the BCa cohort. In addition, the promoter region of C19MC is strongly regulated by a group of seven transcription factors (NR2F6, SREBF1, TBP, GATA3, GABPB1, ETV4, and ZNF444) and five chromatin modifiers (SMC3, KDMA1, EZH2, RAD21, and CHD7). Interestingly, these 12 genes were found to be overexpressed in BCa patients. Further, C19MC targeted 42 tumor suppressor (TS) genes that were downregulated, of which 15 were significantly correlated with patient survival. Our findings suggest that transcription factors and chromatin modifiers at the promoter region may regulate C19MC overexpression. The upregulated C19MC members, transcription regulators, and TS genes can be further exploited as potential diagnostic and prognostic indicators as well as for therapeutic management of BCa.

Evolution of T cell receptor beta loci in salmonids.

T-cell mediated immunity relies on a vast array of antigen specific T cell receptors (TR). Characterizing the structure of TR loci is essential to study the diversity and composition of T cell responses in vertebrate species. The lack of good-quality genome assemblies, and the difficulty to perform a reliably mapping of multiple highly similar TR sequences, have hindered the study of these loci in non-model organisms. High-quality genome assemblies are now available for the two main genera of Salmonids, Salmo and Oncorhynchus. We present here a full description and annotation of the TRB loci located on chromosomes 19 and 25 of rainbow trout (Oncorhynchus mykiss). To get insight about variations of the structure and composition of TRB locus across salmonids, we compared rainbow trout TRB loci with other salmonid species and confirmed that the basic structure of salmonid TRB locus is a double set of two TRBV-D-J-C loci in opposite orientation on two different chromosomes. Our data shed light on the evolution of TRB loci in Salmonids after their whole genome duplication (WGD). We established a coherent nomenclature of salmonid TRB loci based on comprehensive annotation. Our work provides a fundamental basis for monitoring salmonid T cell responses by TRB repertoire sequencing.