scholarly journals Association of AID and MUM1 by Immunohistochemistry in Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 13 (1) ◽  
pp. 48-54
Author(s):  
Mardiah Suci Hardianti ◽  
Syahru Agung Setiawan ◽  
Nungki Anggorowati ◽  
Wiwiek Probowati
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Prevalence Ratio ◽  
B Cell Lymphoma ◽  
Molecular Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Discordant Group ◽  
Large B Cell

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with dysregulation of somatic hypermutation (SHM) and class switch recombination (CSR) have been known to contribute for its lymphomagenesis. Activation-induced cytidine deaminase (AID) enzyme plays a vital role for both processes. Multiple myeloma oncogene 1 (MUM1) is known to upregulate the AID expression in normal and pathological conditions. However, both AID and MUM1 expression association in DLBCL is still unexplored using immunohistochemistry method. We examined DLBCL samples and then retrospectively tested its correlation with clinical findings.METHODS: A retrospective cohort study with 20 cases of DLBCL biopsy tissue with AID and MUM1 antibody was conducted. The samples were then classified into concordant (AID+/MUM1+ or AID-/MUM1-) and discordant group (AID-/MUM1+). The clinicopathological comparison was performed to observe any association between immunohistochemistry expression and clinical findings.RESULTS: Among 20 samples of DLBCL, concordant expression rate of AID and MUM1 was 80% with kappa Cohen’s of 0.578 (p=0.004). A significant association was observed between AID and MUM1 expression with a prevalence ratio of 2.25 (95% CI: 1.08-4.67; p=0.008). Clinical characteristics were not significantly different between each group. Restricted mean survival time was shorter in the concordant group compared with the discordant group but statistically insignificant (21.16 vs. 22.5 months; p=0.531).CONCLUSION: The result of this study showed the association between AID and MUM1 expression in DLBCL. However, whether the association may add further molecular heterogeneity of DLBCL is still to be confirmed by expanding the study.KEYWORDS: AID, CSR, DLBCL, MUM1, SHM

MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3500-3504 ◽  
Author(s):  
Alexander J. A. Deutsch ◽  
Ariane Aigelsreiter ◽  
Philipp B. Staber ◽  
Alfred Beham ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
B Cell ◽  
Malt Lymphoma ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
B Cell Lymphoma ◽  
Tissue Type ◽  
Low Grade ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractRecently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, PAX5, RhoH/TTF, and c-MYC in 17 MALT lymphomas and 17 extranodal diffuse large B-cell lymphomas (DLBCLs) still exhibiting a low-grade MALT lymphoma component (transformed MALT lymphoma). Mutations in one or more genes were detected in 13 (76.5%) of 17 cases of MALT lymphomas and in all of 17 (100%) cases of extranodal DLBCL. A total of 100 sequence variants were found in 30 of 34 cases, 28 in the MALT lymphomas and 72 in extranodal DLBCL. Further, in PIM1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. Expression levels of activation-induced cytidine deaminase (AID), an enzyme essential for somatic hypermutation (SHM), was associated with the mutational load. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes, ASHM may represent a major contributor to their pathogenesis.

Primary cutaneous follicle center lymphoma and primary cutaneous large B-cell lymphoma, leg type, are both targeted by aberrant somatic hypermutation but demonstrate differential expression of AID

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4926-4929 ◽  
Author(s):  
Remco Dijkman ◽  
Cornelis P. Tensen ◽  
Maike Buettner ◽  
Gerald Niedobitek ◽  
Rein Willemze ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
B Cell Lymphoma ◽  
Molecular Features ◽  
Large B Cell Lymphoma ◽  
Activation Induced Cytidine Deaminase ◽  
Single Base Pair ◽  
Large B Cell

AbstractWe assessed primary cutaneous large B-cell lymphoma, leg type (PCLBCL, leg type; n = 13), and primary cutaneous follicle center lymphoma (PCFCL; n = 19) for somatic hypermutation (SHM) of BCL6, and aberrant SHM of MYC, RhoH/TTF, and PAX5. We demonstrate SHM of BCL6 in 8 PCLBCLs (62%), leg type, and 7 PCFCL patients (37%), and aberrant SHM in PAX5, RhoH/TTF, and/or MYC in 7 PCLBCLs (54%), leg type, and 10 PCFCL patients (53%). The majority of mutations consisted of single base-pair substitutions (n = 54) with rare deletions/insertions (n = 4), and displayed molecular features typical of the SHM process. Quantitative real-time PCR and immunohistochemical stainings for activation-induced cytidine deaminase, which is indispensable for SHM, demonstrated significantly higher expression in PCLBCL, leg type. Our results suggest that (aberrant) SHM may contribute to the pathogenesis of PCLBCL, leg type, and PCFCL and is not restricted to diffuse large B-cell lymphomas with an aggressive clinical behavior.

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4503-4506 ◽  
Author(s):  
Anja Mottok ◽  
Christoph Renné ◽  
Marc Seifert ◽  
Elsie Oppermann ◽  
Wolf Bechstein ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Rare Mutations ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Follicular Lymphomas ◽  
Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

scholarly journals Prognostic significance evaluation of B-cell lymphoma 2 (BCL2) and Ki-67 expression in diffuse large B-cell lymphoma patients

2019 ◽  
Vol 6 (1) ◽  
pp. e07-e07
Author(s):  
Hossein Rahimi ◽  
Zahra Rezaei Borojerdi ◽  
Sajad Ataei Azimi ◽  
Elnaz Rashidian ◽  
Amirhossein Jafarian
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Molecular Heterogeneity ◽  
Clinical Genetic ◽  
Ki 67 ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Bcl2 Expression

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphatic neoplasm, accounting for about 30–40% of non-Hodgkin’s lymphoma cases. Objectives: DLBCL is a progressive disease with clinical, genetic and molecular heterogeneity. The prognostic value of B-cell lymphoma 2 (BCL2) and Ki-67 in DLBCL patients has been controversial. Patients and Methods: In this study, we investigated the correlation of BCL2 and Ki-67 expression with clinical features such as age, gender, B symptoms and lactate dehydrogenase (LDH) levels, subtypes of DLBCL, its staging and prognosis in 36 cases of DLBCL. The expression of BCL2 and Ki-67 was measured by immunohistochemistry. Results: There was no significant correlation between BCL2 expression and staging (P=0.082), however Ki-67 expression had a significant correlation with staging (P=0.002). There was no statistically significant correlation between BCL2 and Ki-67 with prognosis of the disease. We found a significant correlation between the germinal center B-cell (GCB) and non- GCB subtypes with BCL2 expression (P=0.024), since patients with non- GCB subtype had a higher BCL2 expression. Our study also demonstrated a significant relationship between BCL2 and Ki-67 expression, therefore, with the increase of the expression of a marker, another increases (P=0.045). Conclusion: BCL2 and Ki-67 expressions were not associated with prognosis. Overexpression of Ki-67 was associated with higher clinical stages. BCL2 expression is higher in non-GCB subtype of DLBCL. Therefore, our study shows that the subsequent studies of BCL2 and other biomarkers in the DLBCL should be based on the DLBCL subtypes.

Frequent expression of activation-induced cytidine deaminase in diffuse large B-cell lymphoma tissues from persons living with HIV

AIDS ◽  
2020 ◽  
Vol 34 (14) ◽  
pp. 2025-2035
Author(s):  
Volodymyr Shponka ◽  
Candace Y. Reveles ◽  
Sinthia Alam ◽  
Melba Jaramillo ◽  
Alanna Maguire ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Cytidine Deaminase ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Persons Living With Hiv ◽  
Activation Induced Cytidine Deaminase ◽  
Living With Hiv ◽  
Large B Cell

scholarly journals Prognostic analysis of aberrant somatic hypermutation of RhoH gene in diffuse large B cell lymphoma

Leukemia ◽  
2007 ◽  
Vol 21 (8) ◽  
pp. 1846-1847 ◽  
Author(s):  
J Hiraga ◽  
A Katsumi ◽  
T Iwasaki ◽  
A Abe ◽  
H Kiyoi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Prognostic Analysis ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Aberrant Somatic Hypermutation in Primary Mediastinal Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2268-2268 ◽  
Author(s):  
Davide Rossi ◽  
Michaela Cerri ◽  
Daniela Capello ◽  
Clara Deambrogi ◽  
Eva Berra ◽  
...  
Keyword(s):  
B Cell ◽  
Base Pair ◽  
Mutation Frequency ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Single Base ◽  
Large B Cell Lymphoma ◽  
Single Base Pair ◽  
Large B Cell

Abstract Primary mediastinal large B-cell lymphoma (PMLBCL) is recognised as a subtype of diffuse large B-cell lymphoma (DLBCL) arising in the mediastinum. With respect to DLBCL, PMLBCL displays specific clinical, molecular and morphological features suggesting that PMLBCL may represent a distinct clinico-pathologic entity. Aberrant somatic hypermutation (SHM) of PIM-1, PAX-5, RhoH/TTF and c-MYC has been advocated as a molecular feature distinctive of DLBCL. To investigate wether the same mechanism is associated with PMLBCL, we performed mutational analysis of PIM-1, PAX-5, RhoH/TTF and c-MYC in a panel of 19 PMLBCL. For comparison, 19 DLBCL were also analysed. For each gene, a region previously shown to contain >90% of mutations was analysed by PCR amplification and DNA direct sequencing. Overall, the prevalence of mutated cases was similar among DLBCL and PMLBCL. Mutations targeting at least one of the 4 genes were found in 14/19 (73.6%) PMLBCL and 13/19 (68.4%) DLBCL, while mutations in more than one gene were found in 7/19 (36.8%) PMLBCL and 9/19 (47.3%) DLBCL. Among the four genes, the prevalence of mutation and the mutation frequency was superimposable between PMLBCL and DLBCL. In fact, PAX-5 was mutated in 9/19 (47.3%) PMLBCL with a mean mutation frequency of 0.20 x 10−2/bp and in 7/19 (36.8%) DLBCL with a mean mutation frequency of 0.18 x 10−2/bp; RhoH/TTF was mutated in 6/19 (31.5%) PMLBCL with a mean mutation frequency of 0.08 x 10−2/bp and in 8/19 (42.1%) DLBCL with a mean mutation frequency of 0.27 x 10−2/bp; PIM-1 was mutated in 3/19 (15.7%) PMLBCL with a mean mutation frequency of 0.09 x 10−2/bp and in 7/19 (36.8%) DLBCL with a mean mutation frequency of 0.11 x 10−2/bp; c-MYC was mutated in 6/19 (31.5%) PMLBCL with a mean mutation frequency of 0.23 x 10−2/bp and in 5/19 (26.3%) DLBCL with a mean mutation frequency of 0.11 x 10−2. The mutation pattern was also similar between PMLBCL and DLBCL and was consistent with the SHM process. A total of 74 mutational events were detected in PMLBCL. The majority of mutations were represented by single base-pair substitution (n=66), whereas only 8 deletions of a short DNA stretch were observed. Of the 66 single base-pair substitutions, 41 were transitions and 25 were transversions, with a transition/transversion ratio of 1.64 and a G+C/A+T ratio of 3.6. Eleven out of 66 (16.6%) single base-pair substitutions felt within RGYW/WRCY motifs. Among DLBCL a total of 87 mutational events were detected. Mutations were preferentially represented by single base-pair substitutions (n=81), whereas only 4 deletions and 2 insertions of a short DNA stretch were observed. Of the 81 single base-pair substitutions, 42 were transitions and 39 were transversions, with a transition/transversion ratio of 1.07 and a G+C/A+T ratio of 1.89. Twenty six out of 81 (32.1%) single base-pair substitutions felt within RGYW/WRCY motifs. The implication of our results are twofold. First, aberrant SHM is involved in the pathogenesis of PMLBCL. Second, our results indicate that aberrant SHM targets both PMLBCL and DLBCL with similar prevalence, distribution and mutation pattern. Since aberrant SHM has been advocated as a molecular marker of DLBCL, our results corroborate the notion that PMLBCL represent a subtype of DLBCL rather than a distinct clinico-pathologic entity.

Aberrant Somatic Hypermutation Targets an Extensive Set of Genes in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1528-1528 ◽  
Author(s):  
Laura Pasqualucci ◽  
Roberta Guglielmino ◽  
Sami N. Malek ◽  
Urban Novak ◽  
Mara Compagno ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Chromosomal Translocations ◽  
Total N ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Genomic instability is a driving force in tumor development that can be achieved by a variety of mechanisms, such as defective chromosome segregation or inactivation of the DNA mismatch repair pathway. Although B-cell lymphomas are associated with chromosomal translocations deregulating oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has long not been described. We have reported that the somatic hypermutation process (SHM), which normally targets the immunoglobulin variable region (IgV) and BCL6 genes in germinal center (GC) B-cells, functions aberrantly in >50% of diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (Pasqualucci et al., Nature412:341, 2001). As a consequence, multiple somatic mutations are introduced into the 5′ region of genes that do not represent physiologic SHM targets, including known proto-oncogenes such as PIM1, PAX5, RhoH/TTF and cMYC. To further define the extent of this phenomenon, termed aberrant somatic hypermutation (ASHM), and to identify additional hypermutated loci of possible pathogenetic significance in DLBCL, we screened 113 genes for the presence of mutations affecting their 5′ sequences (≥1.3 Kb from the transcription start site, the target region for SHM) in 10 DLBCL cell lines. Fifteen genes (13.3%) were found to harbor a significant number of mutations (p<0.05), with 70% of the cell lines being mutated in 7 or more genes; among these, six B-cell specific loci -BCL7A, CIITA, IRF4, LRMP, NCOA3 and SIAT1- carried 9–53 mutational events distributed in 20 to 70% of the cases, corresponding to an overall mutation frequency of 0.032–0.15% (frequency in the mutated cases: 0.07–0.25%). The same genes were found hypermutated in a panel of 20 primary DLBCL biopsies, which displayed an overall mutation load of 7 to 45 distinct events/gene (total N=125). Mutations were of somatic origin, independent of chromosomal translocations to the Ig loci and were restricted to the first 1.5–2 Kb from the promoter. In addition, analogous to previously identified SHM and ASHM targets, the mutations exhibited characteristic features, including a bias for transitions over transversions, preferential hotspot (RGYW/WRCY motifs) targeting, and higher frequencies at G:C pairs. However, in contrast to physiologic SHM targets such as IgV and BCL6, none of the 4 newly identified hypermutated genes that have been analyzed so far (BCL7A, CIITA, SIAT1, LRMP) displayed significant levels of mutations in purified normal GC B-cells as well as in other B-cell malignancies. This finding indicates that these genes represent aberrant hypermutation targets resulting from a tumor-associated malfunction, possibly a loss of target specificity of the physiologic SHM process. Considering previous results and the present survey, 17 (13%) out of 130 genes investigated have been found involved in ASHM, suggesting that this aberrant activity may involve an extensive set of target genes in DLBCL. Since the mutations affect both regulatory and coding sequences of the targeted genes, aberrant SHM may represent a major contributor to the pathogenesis of this disease and may explain in part its phenotypic and clinical heterogeneity.

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