IGH translocation

Next-generation sequencing is increasingly being used to detect mutations and new FISH techniques such as by flow cytometry are in development and may address some of the current test limitations. Here we review the primary and secondary cytogenetic aberrations in myeloma and discuss the range of techniques available for their assessment.

Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.

Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

A novel NGS targeted panel was designed and successfully validated, whose main novelty resides in the possibility to call CNAs from off-target reads, that can be used to define MM pts’ genomic risk factors, possibly required in the daily clinical practice. Thanks to AIRC IG2018-22059, AILBolognaODV.

We applied DLP to 7 MM patients obtaining 800-1600 single cell whole genomes per patient. All canonical IgH translocations identified by FISH were recovered in the scWGS data. Single cell copy number heterogeneity was observed in all but 1 patient, including heterogeneity affecting known drivers.

From 420 samples, 48 were collected at the precursor stage, 205 with NDMM, and 167 with relapsed disease. 39 patients had 2 assays performed, while the remainder were unique patient samples. Within NDMM, the range of induction regimens received included lenalidomide and dexamethasone with bortezomib (VRd), carfilzomib (KRd) or daratumumab (DRd), along with quadruplet therapy (DVRd or DKRd).

As we begin to prioritize the use of different immune-based therapies it will be important to consider the relative risk each patient has to develop resistance based on the preexisting loss of one target gene copy, as some targets are frequently lost (GPRC5D) while others are rarely lost (FCRL5). Some hyperdiploid patients have hyperactivation of NF-kB signaling as a result of BCMA overexpression by high level copy number gains and immunoglobulin translocations or ITD. These patients are likely dependent on BCMA mediated signaling and would likely be exquisitely sensitive to BCMA targeted therapies.

In conclusion, our study confirmed the prognostic significance of high-risk cytogenetic abnormalities in a large cohort of MM patients. We also demonstrated the importance of considering the co-occurrence of high-risk alterations to accurately assess prognosis. Thus, while del(17p) retains its adverse prognosis even as a solitary abnormality, the negative prognosis of 1q gains was mitigated if this abnormality occured as the sole aberration.

Our study highlights earlier age of presentation, higher incidence of end organ damage due to myeloma. A low incidence of high risk cytogenetic abnormalities was detected which resulted in a maximum number of patients in R-ISS II category. Though limited by retrospective nature and patient population from a tertiary care institute, the study suggests the need for prospective registry studies to document the potential difference in presentation among Indian patients and need for awareness about myeloma for early diagnosis.

Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.

Although selection-based HMR can effectively initiate at any site proximal to a driver gene fusion, it appears that the translocation breaksite is common for many translocations. In addition, evidence from HMR evolution related distal 11q mutations, numerous unbalanced CCND1/IGH translocations, and the double MAML2/KMT2A presented in this study suggest that a recombinatorial "hot spot" exists near the CCND1 gene in many rearrangements or mutations within 11q.

Among MM patients, 5-year CS was stable at 1-5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.

61.3% non-AL-type amyloidosis-MGRS patients had IgH recombination, with t (11; 14) (q13; q32) the most common. Patients with t (11; 14) may have inferior renal responses to bortezomib-based treatment. Multiple myeloma

FISH testing was established, and a pilot study performed, to assess the feasibility of FISH as a diagnostic tool for the determination of BL in a Kenyan paediatric population. This study supports FISH in limited resource settings to improve the accuracy and speed of diagnosis of BL in Africa.

In developing countries, detecting Philadelphia (Ph)-like B-lineage acute lymphoblastic leukemia is complicated and challenging due to its diverse genetic landscape. There is no well-defined and cost-effective methodology for its detection. The incidence of this high-risk subtype is very high in adult cases, and there is an urgent need for its accurate detection. We have developed an online PHi-RACE classifier for its rapid detection, followed by delineating the genomic and proteomic landscape of Ph-like acute lymphoblastic leukemias for the first time in Indian patients.

Moreover, the ISM-FISH showed a positive concordance of 96.6% and negative concordance of 98.8% with standard DC-FISH examining 1000 interphase cells. In conclusion, the ISM-FISH is a rapid and reliable diagnostic tool for the simultaneous examination of three critically important IGH translocations, which may promote risk-adapted individualized therapy in MM.

In contrast to FISH, conventional karyotyping could detect MM-related aberrations in 50% cases , of which 44% revealed highly complex karyotype with common aberrations of chromosome 1q. Overall FISH was found to be novel , easy approach with high success rate and capability of detection of all cytogenetic abnormalities that add valid information for the risk stratification of disease which in future in combination with mutation profile and Gene expression profile will help in further refinement of disease & identification of actionable targets.

The association of hypomethylated superenhancers, promoters, and CpG islands with genes over-expressed in DHITsig+ suggests these methylation patterns may contribute to the DHITsig phenotype. These results may aid in improving GCB DLBCL patient classification and reveal factors contributing to its heterogeneity.

Therefore, in addition to the detection of clinically relevant somatic mutations, the targeted NGS approach showed robust detection of recurrent MM specific IgH translocations and CNV. Furthermore, the detection of relevant abnormalities not routinely assessed in most clinical labs, such as TP53 bi-allelic inactivation, IgL and MYC rearrangements, supports the use of this small, targeted panel as a clinically relevant, single molecular assay, for the comprehensive profiling of MM.

Due to the development of a new WGS-based chronological model, we revealed the existence of SV acquired before canonical "MM-initiating" events in newly diagnosed MM patients. This data suggests that there may be alternative, previously undescribed, MM-initiating events, which can be explored in a lager dataset using our novel analytical methods.

This study comprehensively describes the detection of genetic abnormalities and prognostic survival analysis of NDMM patients by using FISH, CytoScan and targeted panel sequencing. Identifying the real high-risk patients, we can earlier take targeted and more active measures, such as intensive induction treatment, tandem transplantation or CART treatment, to better deepen and consolidate the therapeutic effect for long-term survival benefits of patients.

The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, while this assay was less informative in T/NK-cell lymphoma. These results suggest the clinical utility of NGS-based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies.

However, a high expression level of truncated P2RY8 was observed in the patients compared with healthy donors, which might be related to the aggressive clinical course and inferior outcome. In summary, we described recurrent novel P2RY8/IGH translocations with high expression levels of P2RY8, which may contribute to the guidelines for clinical diagnosis and treatment.

P2, N=401, Active, not recruiting, European Myeloma Network | Recruiting --> Active, not recruiting | Trial primary completion date: Feb 2022 --> May 2024

Conclusion Our work demonstrates that TRAF3 mutations and deletions are highly enriched in CLL patients with del-3’IGH, resulting in the biallelic inactivation of this gene. The presence of this double-hit on TRAF3 worsen the prognosis of CLL patients, being and independent prognostic factor with similar impact on TFT than the biallelic loss of TP53 .

Therefore, CD37 protein may play a role in tumor progression and may serve as a therapeutic target. However, further studies are needed to explore its significance.

Additional testing with dual FISH probe detected MYC/IGH translocation. FISH testing using BAPs alone may be falsely negative for MYC translocations creating a diagnostic challenge and compromising the treatment approach and assessment of prognosis.

The breakpoints of t(9;14)(p13;q32) were mapped 2,170 bp upstream of the coding region of PAX5 alternative exon 1B and within the IGHJ6-Eμ enhancer intron of IGH. It is suggested that t(9;14)(p13;q32) in this case was a secondary cytogenetic abnormality and the translocation is not necessarily involved in initial malignant transformation of B-cells but can occur later during the course of diffuse large B-cell lymphoma.

Instead, we find cells harbouring the same BCL2/IGH translocation but lacking CREB binding protein (CREBBP), lysine methyltransferase 2D (KMT2D) and other recurrent gene mutations. Thus, (i) the BCL2/IGH translocation can precede CPC-defining mutations in human FL, and (ii) BCL2/IGH-translocated cells can persist in clinical remission.

Subgroup analysis of IGH mutations is crucial in the identification of high-risk MM patients. We believe that our study will contribute to the determination of bone marrow biopsy and cytogenetic features of MM patients in our country.

This study aimed to evaluate the association between cytogenetic abnormalities and clinicohaematological characteristics at diagnosis, and retrospectively compare the overall response rate to 2 triple drug combinations comprised of bortezomib, cyclophosphamide, and dexamethasone (VCd) versus thalidomide, cyclophosphamide, and dexamethasone (VRd) in transplant eligible patients with untreated MM. The key differences in baseline characteristics at presentation compared to Western population could be attributed to ethnic diversity. Triplet induction therapy VRd was superior as regards to response rates compared to VCd arm.

Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients and PNA plus rituximab in 9 patients. HCL-v is a rare disease with specific clinical and immunophenotypic features but may overlap with classic hairy cell leukemia or other splenic B-cell neoplasms. Overall, it is an indolent lymphoma with recurrent progression, and the use of PNA plus rituximab in first-line treatment can result in a deeper and longer remission.