B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren's Disease: A Pilot Monocentric Exploratory Study.

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

Assessment of Bone Marrow Involvement in B-Cell non-Hodgkin Lymphoma Using Immunoglobulin Gene Rearrangement Analysis with Next-Generation Sequencing.

BACKGROUND: Assessment of bone marrow involvement (BMI) in non-Hodgkin lymphoma (NHL) is crucial for determining patient prognosis and treatment strategy. We assessed the prognostic value of next-generation sequencing (NGS)-based immunoglobulin (Ig) gene clonality analysis as an ancillary test for BMI evaluation in NHL. METHODS: A retrospective cohort of 124 patients newly diagnosed with B-cell NHL between 2019 and 2022 was included. NGS-based Ig clonality analysis was conducted using LymphoTrak IGH FR1 Assay and IGK Assay (Invivoscribe Technologies, San Diego, CA, USA) on BM aspirate samples, and the results were compared with those of histopathological BMI (hBMI). RESULTS: Among the 124 patients, hBMI was detected in 16.9% (n = 21). The overall agreement of BMI between Ig clonality analyses and histopathological analysis for IGH, IGK, and either IGH or IGK was 86.3%, 92.7%, and 90.3%. The highest positive percent agreement was observed with clonal rearrangements of either IGH or IGK gene (90.5%), while the highest negative percent agreement was observed with clonal rearrangement of IGK gene (96.1%). For the prediction of hBMI, positive prediction value ranged between 59.1% and 80.0% and the negative prediction value ranged between 91.3% and 97.9%. CONCLUSION: NGS-based clonality analysis is an analytic platform with a substantial overall agreement with histopathological analysis. Assessment of both IGH and IGK genes for the clonal rearrangement analysis could be considered for the optimal diagnostic performance of BMI detection in B-cell NHL.

Severe sperm DNA fragmentation may persist for up to 3 years after cytotoxic therapy in patients affected by Hodgkin lymphoma and non-Hodgkin lymphoma.

STUDY QUESTION: Does sperm DNA recover from damage in all men after 2 years from the end of cytotoxic treatments? SUMMARY ANSWER: The current indication of 2 years waiting time for seeking natural pregnancy after cytotoxic treatment may not be adequate for all men, since severe sperm DNA damage is present in a proportion of subjects even after this timeframe. WHAT IS KNOWN ALREADY: Data in the literature on sperm DNA fragmentation (SDF) in lymphoma patients after cytotoxic treatments are scarce. The largest longitudinal study evaluated paired pre- and post-therapy (up to 24 months) semen samples from 34 patients while one study performed a longer follow-up (36 months) in 10 patients. The median/mean SDF values >24 months after therapy did not show significant differences but the studies did not explore the proportion of patients with severe DNA damage and the analysis was done on frozen-thawed samples. STUDY DESIGN, SIZE, DURATION: In this study, 53 Hodgkin lymphoma (HL) and 25 non-Hodgkin lymphoma (NHL) post-pubertal patients were included over a recruitment period of 10 years (2012-2022). Among them, 18 subjects provided paired semen samples for SDF analysis at the three time points. SDF was evaluated in patients before (T0) and after 2 (T2) and 3 years (T3) from the end of, cytotoxic treatments (chemotherapy alone or in combination with radiotherapy). A cohort of 79 healthy, fertile, and normozoospermic men >18 years old served as controls (recruited between 2016 and 2019). PARTICIPANTS/MATERIALS, SETTING, METHODS: SDF was evaluated on fresh semen samples (i.e. spermatozoa potentially involved in natural conception) from patients and controls using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay coupled with flow cytometry. SDF median values were compared between groups: (i) HL and NHL patients versus controls at the three time points; (ii) HL versus NHL patients at baseline; and (iii) patients at T0 versus T2 and T3. Severe DNA damage (SDD) was defined for SDF levels above the 95th percentile of controls (50%) and the proportion of patients with SDD at all time points was established. MAIN RESULTS AND THE ROLE OF CHANCE: At T0, patients displayed higher median SDF than controls, reaching statistical significance in the NHL group: 40.5% [IQR: 31.3-52.6%] versus 28% [IQR: 22-38%], P < 0.05. Comparing SDF pre-treatment to that post-treatment, HL patients exhibited similar median values at the three time points, whereas NHL showed significantly lower values at T3 compared to T0: 29.2% [IQR: 22-38%] versus 40.5% [IQR: 31.3-52.6%], P < 0.05. The proportion with SDD in the entire cohort at T2 was 11.6% and 13.3% among HL and NHL patients, respectively. At T3, only one in 16 NHL patients presented SDD. LIMITATIONS, REASONS FOR CAUTION: TUNEL assay requires at least 5 million spermatozoa to be performed; hence, severe oligozoospermic men were not included in the study. Although our cohort represents the largest one in the literature, the relatively small number of patients does not allow us to establish precisely the frequency of SDD at T2 which in our study reached 11-13% of patients. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide further insights into the long-term effects of cytotoxic treatments on the sperm genome. The persistent severe DNA damage after 2 years post-treatment observed in some patients suggests that there is an interindividual variation in restoring DNA integrity. We propose the use of SDF as a biomarker to monitor the treatment-induced genotoxic effects on sperm DNA in order to better personalize pre-conceptional counseling on whether to use fresh or cryopreserved spermatozoa. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Istituto Toscano Tumori (ITT), Fondazione Ente Cassa di Risparmio di Firenze, the European Commission-Reproductive Biology Early Research Training (REPROTRAIN). C.K., G.F., V.R., and A.R.-E. belong to COST Action CA20119 (ANDRONET) which is supported by the European Cooperation in Science and Technology (www.cost.eu). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Families with non-Hodgkin lymphoma and plasma cell dyscrasias in their pedigrees.

Although reports of familial clustering of hematologic malignancies have appeared for decades, the cause(s) of this uncommon occurrence is still not completely understood. Most modern investigations, however, support a genetic rather than an environmental exposure as a cause of this observation. Most pedigrees of families with familial hematologic malignancies demonstrate age of onset anticipation, with the disease diagnosed at an earlier age in successive generations. The cause of this phenomenon is clear in some familial neurologic disorders (trinucleotide repeat expansion) but not at all clear in familial hematologic malignancies. In preparation for molecular studies of familial clustering of hematologic malignancies, we have collected pedigrees on 738 families and have previously demonstrated anticipation in those with familial plasma cell myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma (NHL). Here we present data on 36 families with both plasma cell myeloma and NHL in their pedigrees and demonstrate strong evidence for anticipation in these families. We encourage all health care personnel to ask patients multiple times about family medical history and carefully take note of family histories from individuals with uncommon illnesses and to refer families with clustering of such illnesses for further investigation.

Association of LIN28B Gene Polymorphisms (rs221634, rs221635, rs314276, rs9404590, and rs12194974) with Non-Hodgkin Lymphoma Susceptibility and Clinical/Pathological Features.

BACKGROUND AND AIM: Lymphoma is a common hematopoietic cancer.  It has been proposed that LIN28B gene and its variations may have function in cancer progression and metastasis. Therefore, the purpose of this investigation has been to examine the correlation among LIN28B gene polymorphisms (such as rs221634 A>T, rs221635 T> C, rs314276 C>A, rs9404590 T>G, and rs12194974 G>A) as well as the risk of NHL in an Iranian sample. MATERIALS AND METHODS: In the current case-control research, 175 individuals with Non-Hodgkin Lymphoma along with 175 normal controls participated; polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology has been utilized to the genotype samples. RESULTS: Our data demonstrated that rs12194974 and the rs221635 variants have been correlated with higher NHL risk, while rs221634 and rs314276 variants were correlated with lower risk of NHL (P≤0.05). In addition, we detected an association between rs221634 and treatment with R-CHOP. No substantial correlation has discovered among rs9404590 polymorphism and NHL in any inheritance models (P≥0.05). CONCLUSION: This was the first investigation evaluating the correlation among LIN28B gene polymorphisms as well as the occurrence of NLH. Further studies in different ethnic populations and large-scale sample size are needed to support results.

Cytogenetics in the management of mature B-cell non-Hodgkin lymphomas: Guidelines from the Groupe Francophone de Cytogénétique Hematologique (GFCH).

Non-Hodgkin lymphomas (NHL) consist of a wide range of clinically, phenotypically and genetically distinct neoplasms. The accurate diagnosis of mature B-cell non-Hodgkin lymphoma relies on a multidisciplinary approach that integrates morphological, phenotypical and genetic characteristics together with clinical features. Cytogenetic analyses remain an essential part of the diagnostic workup for mature B-cell lymphomas. Karyotyping is particularly useful to identify hallmark translocations, typical cytogenetic signatures as well as complex karyotypes, all bringing valuable diagnostic and/or prognostic information. Besides the well-known recurrent chromosomal abnormalities such as, for example, t(14;18)(q32;q21)/IGH::BCL2 in follicular lymphoma, recent evidences support a prognostic significance of complex karyotype in mantle cell lymphoma and Waldenström macroglobulinemia. Fluorescence In Situ Hybridization is also a key analysis playing a central role in disease identification, especially in genetically-defined entities, but also in predicting transformation risk or prognostication. This can be exemplified by the pivotal role of MYC, BCL2 and/or BCL6 rearrangements in the diagnostic of aggressive or large B-cell lymphomas. This work relies on the World Health Organization and the International Consensus Classification of hematolymphoid tumors together with the recent cytogenetic advances. Here, we review the various chromosomal abnormalities that delineate well-established mature B-cell non-Hodgkin lymphoma entities as well as newly recognized genetic subtypes and provide cytogenetic guidelines for the diagnostic management of mature B-cell lymphomas.

Correlation study of malignant lymphoma and breast Cancer in different gender European populations: mendelian randomization analysis.

BACKGROUND: Previous research has already indicated an elevated risk of breast cancer (BC) among survivors of malignant lymphoma, but the underlying reasons remain unknown. Our objective is to elucidate the causal relationship between malignant lymphoma and BC through Mendelian randomization (MR). Genome-wide association studies (GWAS) data from 181,125 Hodgkin lymphoma (HL) patients and 181,289 non-Hodgkin lymphoma (NHL) patients from the FinnGen Consortium were utilized as exposure. We selected single nucleotide polymorphisms (SNPs) strongly associated with the exposure as instrumental variables to investigate their relationship with BC in a cohort of 107,722 participants. Subsequently, we obtained data from the UK Biobank containing gender-stratified information on HL, NHL, and BC. We validated the findings from our analysis and explored the impact of gender. The Inverse-Variance Weighted (IVW) method served as the primary reference for the two-sample MR, accompanied by tests for heterogeneity and pleiotropy. RESULTS: The analysis results from the FinnGen consortium indicate that there is no causal relationship between HL and NHL with BC. HL (OR = 1.01, 95% CI = 0.98-1.04, p = 0.29), NHL (OR = 1.01, 95% CI = 0.96-1.05, p = 0.64). When utilizing GWAS data from the UK Biobank that includes different gender cohorts, the lack of association between HL, NHL, and BC remains consistent. HL (OR = 1.08, 95% CI = 0.74-1.56, p = 0.69), HL-Female (OR = 0.84, 95% CI = 0.59-1.19, p = 0.33), NHL (OR = 0.89, 95% CI = 0.66-1.19, p = 0.44), and NHL-Female (OR = 0.81, 95% CI = 0.58-1.11, p = 0.18). CONCLUSIONS: The two-sample MR analysis indicates that there is no significant causal relationship between malignant lymphoma (HL and NHL) and BC. The association between malignant lymphoma and breast cancer requires further in-depth research and exploration.

Epigenetic profiles of elevated cell free circulating H3.1 nucleosomes as potential biomarkers for non-Hodgkin lymphoma.

During cell death, nucleosomes, the basic structural unit of chromatin, are released into the blood stream and elevated levels have been found in the plasma of patients with solid cancers. In this study, we demonstrate an increase in cell free circulating H3.1-nucleosomes levels in plasma samples from patients with hematological malignancy, non-Hodgkin lymphoma (NHL), relative to healthy donors. As histone post-translational modifications (PTMs) of circulating nucleosomes are described as potential biomarkers of various solid cancers, we investigated the epigenetic profile of nucleosomes from NHL patients following nucleosome enrichment (Nu.Q® capture) combined with mass spectrometry. Eight histones PTMs, including the acetylation of histone H3 at lysine 9, 14 and 18 as well as the methylation state of histone H3 at lysine 9, 27 and 36, were identified at a higher level in the plasma of NHL patients compared to healthy donors. These results were confirmed in a larger clinical cohort by immunoassay. Subsequently, the temporal profile of these histone PTMs in NHL patients undergoing treatment course highlighted the potential use of these new biomarkers to monitor treatment response and/or disease progression. Our results substantiate that levels of H3.1-nucleosomes are particularly elevated in NHL patients and may be a useful diagnostic tool. Moreover, our work emphasizes the crucial roles of the epigenetic marks present on circulating nucleosomes to detect and monitor tumor progression and/or treatment response of non-Hodgkin Lymphoma.

Mitochondrial DNA Fragmentation and Risk of Non-Hodgkin Lymphoma.

Importance: Research suggests that increased mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of non-Hodgkin lymphoma (NHL); however, no studies to date have evaluated whether the mitochondrial DNA fraction with breaks (mtDNAfb) is associated with risk of NHL. Objective: To evaluate the association of mtDNAfb with NHL risk. Design, Setting, and Participants: This nested case-control study, which used prospectively collected samples as part of baseline enrollment (from 1985 through 1988) of 29 133 men who smoked for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study conducted in southwest Finland, included 107 incident NHL cases and 107 controls (matched on date of birth ±5 years). Analyses were conducted from January to September 2022. Exposure: High-throughput real-time polymerase chain reaction assays quantifying mtDNAfb. Main Outcomes and Measures: Incident NHL cases were identified in the ATBC Study through April 30, 2002, using the Finnish Cancer Registry and the Register of Causes of Death. The mtDNAfb was quantified and categorized based on the median, tertile, and quartile distributions among controls. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression models to assess the associations between categorized mtDNAfb and future risk of NHL, controlling for age, body mass index, number of cigarettes smoked per day, number of pack-years, and mtDNAcn. Results: A total of 29 133 men (median [IQR] age, 57.2 [52.6-62.5] years) participated in ATBC Study. Higher mtDNAfb was associated with an increased risk of NHL (median OR, 2.89; 95% CI, 1.40-5.93) in a dose-dependent manner (quartile 2 vs 1 OR, 1.24; 95% CI, 0.43-3.40; quartile 3 vs 1 OR, 3.58; 95% CI, 1.39-9.24; quartile 4 vs 1 OR, 3.42; 95% CI, 1.30- 8.99; P = .004 for trend). Conclusions and Relevance: This study's findings suggest that increased mtDNAfb is associated with an increased future risk of NHL. Additional studies are needed to confirm these findings, particularly among women and nonsmokers.

The prognostic role of gene polymorphisms in patients with indolent non-Hodgkin lymphomas and mantle-cell lymphoma receiving bendamustine and rituximab: results of the 5-year follow-up study.

The variability in disease outcome for indolent non-Hodgkin lymphomas (iNHL) and mantle-cell lymphoma (MCL) could be related to single nucleotide polymorphisms (SNPs) in genes that affect immune and inflammatory response. We investigated SNPs that could have a prognostic role for patients receiving bendamustine and rituximab (BR). All samples were genotyped for the IL-2 (rs2069762), IL-10 (rs1800890, rs10494879), VEGFA (rs3025039), IL-8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays using TaqMan SNP Genotyping Assays. We report a long-term follow-up analysis of 79 iNHL and MCL patients that received BR. Overall response rate was 97.5% (CR rate 70.9%). After a median follow-up of 63 months, median PFS and OS were not reached. We report a significant association between SNP in IL-2 (rs2069762) and reduced PFS and OS (p<.0001). We suggest a role for cytokine SNPs in disease outcome, while SNPs seem not related to long-term toxicity or secondary malignancies.

Improve the model of disease subtype heterogeneity by leveraging external summary data.

Researchers are often interested in understanding the disease subtype heterogeneity by testing whether a risk exposure has the same level of effect on different disease subtypes. The polytomous logistic regression (PLR) model provides a flexible tool for such an evaluation. Disease subtype heterogeneity can also be investigated with a case-only study that uses a case-case comparison procedure to directly assess the difference between risk effects on two disease subtypes. Motivated by a large consortium project on the genetic basis of non-Hodgkin lymphoma (NHL) subtypes, we develop PolyGIM, a procedure to fit the PLR model by integrating individual-level data with summary data extracted from multiple studies under different designs. The summary data consist of coefficient estimates from working logistic regression models established by external studies. Examples of the working model include the case-case comparison model and the case-control comparison model, which compares the control group with a subtype group or a broad disease group formed by merging several subtypes. PolyGIM efficiently evaluates risk effects and provides a powerful test for disease subtype heterogeneity in situations when only summary data, instead of individual-level data, is available from external studies due to various informatics and privacy constraints. We investigate the theoretic properties of PolyGIM and use simulation studies to demonstrate its advantages. Using data from eight genome-wide association studies within the NHL consortium, we apply it to study the effect of the polygenic risk score defined by a lymphoid malignancy on the risks of four NHL subtypes. These results show that PolyGIM can be a valuable tool for pooling data from multiple sources for a more coherent evaluation of disease subtype heterogeneity.

Mosaic chromosomal alterations detected in men living with HIV and the relationship to non-Hodgkin lymphoma.

OBJECTIVES: People with HIV (PWH) have an elevated risk of non-Hodgkin lymphoma (NHL) and other diseases. Studying clonal hematopoiesis (CH), the clonal expansion of mutated hematopoietic stem cells, could provide insights regarding elevated NHL risk. DESIGN: Cohort analysis of participants in the Multicenter AIDS Cohort Study ( N  = 5979). METHODS: Mosaic chromosomal alterations (mCAs), a type of CH, were detected from genotyping array data using MoChA. We compared CH prevalence in men with HIV (MWH) to HIV-uninfected men using logistic regression, and among MWH, assessed the associations of CH with NHL incidence and overall mortality using Poisson regression. RESULTS: Comparing MWH to HIV-uninfected men, we observed no difference in the frequency of autosomal mCAs (3.9% vs. 3.6%, P -value = 0.09) or mosaic loss of the Y chromosome (mLOY) (1.4% vs. 2.9%, P -value = 0.13). Autosomal mCAs involving copy-neutral loss of heterozygosity (CN-LOH) of chromosome 14q were more common in MWH. Among MWH, mCAs were not associated with subsequent NHL incidence (autosomal mCA P -value = 0.65, mLOY P -value = 0.48). However, two MWH with diffuse large B-cell lymphoma had overlapping CN-LOH mCAs on chromosome 19 spanning U2AF2 (involved in RNA splicing), and one MWH with Burkitt lymphoma had high-frequency mCAs involving chromosome 1 gain and chromosome 17 CN-LOH (cell fractions 22.1% and 25.0%, respectively). mCAs were not associated with mortality among MWH (autosomal mCA P -value = 0.52, mLOY P -value = 0.93). CONCLUSIONS: We found limited evidence for a relationship between HIV infection and mCAs. Although mCAs were not significantly associated with NHL, mCAs detected in several NHL cases indicate a need for further investigation.

Identification of two unannotated miRNAs in classic Hodgkin lymphoma cell lines.

MicroRNAs (miRNAs) are small non coding RNAs responsible for posttranscriptional regulation of gene expression. Even though almost 2000 precursors have been described so far, additional miRNAs are still being discovered in normal as well as malignant cells. Alike protein coding genes, miRNAs may acquire oncogenic properties in consequence of altered expression or presence of gain or loss of function mutations. In this study we mined datasets from miRNA expression profiling (miRNA-seq) of 7 classic Hodgkin Lymphoma (cHL) cell lines, 10 non-Hodgkin lymphoma (NHL) cell lines and 56 samples of germinal center derived B-cell lymphomas. Our aim was to discover potential novel cHL oncomiRs not reported in miRBase (release 22.1) and expressed in cHL cell lines but no other B-cell lymphomas. We identified six such miRNA candidates in cHL cell lines and verified the expression of two of them encoded at chr2:212678788-212678849 and chr5:168090507-168090561 (GRCh38). Interestingly, we showed that one of the validated miRNAs (located in an intron of the TENM2 gene) is expressed together with its host gene. TENM2 is characterized by hypomethylation and open chromatin around its TSS in cHL cell lines in contrast to NHL cell lines and germinal centre B-cells respectively. It indicates an epigenetic mechanism responsible for aberrant expression of both, the TENM2 gene and the novel miRNA in cHL cell lines. Despite the GO analysis performed with the input of the in silico predicted novel miRNA target genes did not reveal ontologies typically associated with cHL pathogenesis, it pointed to several interesting candidates involved in i.e. lymphopoiesis. These include the lymphoma related BCL11A gene, the IKZF2 gene involved in lymphocyte development or the transcription initiator GTF2H1.

Expression of MicroRNA-155 in Patients with Non-Hodgkin Lymphoma, Coronavirus Disease 2019, or Both: A Cross-Sectional Study.

Background: Non-Hodgkin lymphoma (NHL) is the eleventh leading cause of cancer-related death in the world. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL. Up to winter 2021-2022, the death toll caused by the coronavirus disease 2019 (COVID-19) has exceeded 5.6 million worldwide. Possible molecular mechanisms involved in the systemic inflammation, and cytokine storm in COVID-19 patients are still not fully understood. MicroRNA-155 (miR-155) plays a role in the post-transcriptional gene regulation of hematopoiesis, oncogenesis, and inflammation. The present study aimed to evaluate the expression of miR-155 in patients with DLBCL and/or COVID-19. Methods: A cross-sectional study was conducted from July to December 2020 in Tehran (Iran) to evaluate the expression of miR-155 in adult patients diagnosed with DLBCL and/or COVID-19. The real-time polymerase chain reaction technique was used to evaluate the expression of miR-155 in the sera of 92 adults who were either healthy or suffering from DLBCL and/or COVID-19. Relative quantification of gene expression was calculated in terms of cycle threshold (Ct) value. Data were analyzed using SPSS software, and P<0.05 was considered statistically significant. Results: The expression of miR-155 was not associated with the sex or age of the participants. In comparison with healthy individuals (-ΔCt -1.92±0.25), the expression of miR-155 increased in patients with COVID-19 (1.95±0.14), DLBCL (2.25±0.16), or both (4.33±0.65). Conclusion: The expression of miR-155 increased in patients with DLBCL and/or COVID-19.

Myeloid/lymphoid neoplasm with eosinophilia and BCR/FGFR1 rearrangement with transformation to cortical T-lymphoblastic lymphoma and erythroid precursors: a case report.

BACKGROUND: Myeloproliferative neoplasms are a group of diseases with diverse biological and clinical characteristics. As a provisional separate entity, myeloid/lymphoid neoplasms with eosinophilia and genetic rearrangement have been described, which may present an initial clinical behavior of myeloproliferation and be characterized by varied genetic rearrangements. One of these entities is associated with FGFR1 rearrangements, characterized by its low prevalence and few treatment options. CASE PRESENTATION: We present the case of a 53-year-old Mestizo male patient of Hispanic origin who initially presented weight loss and fatigue, with a complete blood count showing leukocytosis and eosinophilia, with an initial diagnosis of nonspecific myeloproliferative disorder. In a next-generation sequencing study, BCR::FGFR1 rearrangement was documented, a diagnosis of myeloid/lymphoid neoplasia with eosinophilia and BCR::FGFR1 rearrangement was made, and hydroxyurea therapy was initiated. Subsequently, transformation to cortical T-lymphoblastic leukemia/lymphoma and erythroid precursors was documented, requiring management with chemotherapy. CONCLUSIONS: Myeloid/lymphoid neoplasms with eosinophilia and genetic rearrangements constitute a group of deeply heterogeneous diseases with variable clinical and diagnostic characteristics and whose treatment is not clearly defined.

The Effect of Caspase 8, 9 Gene Polymorphisms on Non-Hodgkin Lymphoma Susceptibility and Clinical/Pathological Features.

BACKGROUND: Caspases (CASPs) are the main executors of the apoptotic process. Studies to date have shown the role of caspase-8 (CASP8) and caspase-9 (CASP9) in carcinogenesis. Therefore, the aim of this study was to investigate the associations between CASP9-rs4233532, CASP9-rs4646018, and CASP8- rs1045485 gene polymorphisms and non-Hodgkin lymphoma (NHL) susceptibility in an Iranian population-based study. Moreover, it was examined whether such the genotype of these polymorphisms is related with clinicopathological characteristics of NHL. METHODS: 175 patients with NHL and 175 age- and sex-matched controls were enrolled in this study. We determined the genotypes of single nucleotide polymorphisms (SNPs) from CASP genes with Tetra ARMS-PCR (Amplification refractory mutation system) method. RESULTS: Statistically significant association were observed between CASP9-rs4646018 and increased risk of NHL under codominant CC, codominant TC, and dominant TC+CC genetic models. Our results showed that the A allele of CASP8-rs1045485 was a protective factor for NHL and GArs1045485 genotype significantly reduced risk of NHL. In contrast, CASP9- rs4233532 was not linked to NHL susceptibility. No relationship was detected between CASP8-rs1045485 and CASP9-rs4233532 and NHL clinicopathological characteristics, however genetic variation in CASP9-rs4646018 was associated with histology, treatment and radio therapy of NHL. CONCLUSIONS: Our study presented that the CASP8- rs1045485 and CASP9-rs4646018 polymorphisms could affect the risk of NHL in Iranian populations which was the first report to show the significant relationship between rs1045485, rs4646018 polymorphisms and NHL susceptibility. Replication large-scale case-control studies in different ethnicities are warranted to verify these findings.

Genomic landscape of mature B-cell non-Hodgkin lymphomas - an appraisal from lymphomagenesis to drug resistance.

BACKGROUND: Mature B-cell non-Hodgkin lymphomas are one of the most common hematological malignancies with a divergent clinical presentation, phenotype, and course of disease regulated by underlying genetic mechanism. MAIN BODY: Genetic and molecular alterations are not only critical for lymphomagenesis but also largely responsible for differing therapeutic response in these neoplasms. In recent years, advanced molecular tools have provided a deeper understanding regarding these oncogenic drives for predicting progression as well as refractory behavior in these diseases. The prognostic models based on gene expression profiling have also been proved effective in various clinical scenarios. However, considerable overlap does exist between the genotypes of individual lymphomas and at the same time where additional molecular lesions may be associated with each entity apart from the key genetic event. Therefore, genomics is one of the cornerstones in the multimodality approach essential for classification and risk stratification of B-cell non-Hodgkin lymphomas. CONCLUSION: We hereby in this review discuss the wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas.