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At least 19 recordsLinked to original sources
PubMed2000

Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint-flanking probes.

Rearrangement of the BCL2 gene is an important parameter for the differential diagnosis of non-Hodgkin lymphomas. Although a relatively large proportion of breakpoints is clustered, many are missed by standard PCR. A FISH assay is therefore desired. Up to now, a lack of probes flanking the BCL2 gene has limited the possibilities for a FISH assay to an approach based on colocalization of probes for BCL2 and the immunoglobulin heavy chain (IGH) locus. Intrinsically high rates of false positive nuclei and high interobserver variability make such assays unsuitable for use on lymphoma tissue samples, where tumor cells often form only a minority of the cell population. Using YAC end cloning techniques and screening of a PAC library, we have isolated PAC clones flanking the BCL2 gene. Using these PACs, and several cosmid clones in the second BCL2 intron, we developed a segregation-based interphase FISH assay with two probe combinations enabling separate detection of 5' and 3' (mbr/mcr) breakpoints. The assay was applied to a series of 40 follicular lymphomas. To evaluate the results, the same lymphomas were analyzed by DNA fiber FISH with a 600-kb set of BCL2 DNA clones labeled in alternating colors in combination with a color barcode covering the IGH locus. This approach allowed precise mapping of BCL2 breakpoints, and simultaneously showed juxtaposition of IGH genes to BCL2. Comparison of the results of interphase and fiber FISH showed complete correlation. Five cases were negative with both FISH techniques as well as with Southern blotting. Interestingly, all of these 5 cases lacked BCL2 overexpression as determined by immunohistochemistry, against 3 of 35 rearrangement-positive follicular lymphomas. Furthermore, absence of t(14;18) seemed to be correlated with a higher histologic grade (grades 2 and 3 according to Berard). These data indicate that the segregation-based interphase FISH assay detects 100% of BCL2 rearrangements. Because interpretation of the results is straightforward and requires no extensive experience, this assay may be the best available diagnostic test for BCL2 rearrangement. Genes Chromosomes Cancer 27:85-94, 2000.

3' Untranslated Regions↗
PubMed2026

Testicular aggressive B-cell lymphoma with plasmablastic morphology harboring concurrent IGH::MYC and IGH::BCL2 rearrangements.

BACKGROUND: Aggressive B-cell lymphomas with plasmablastic morphology are uncommon neoplasms that may exhibit overlapping morphologic, immunophenotypic, and genetic features of plasmablastic lymphoma (PBL) and double-hit lymphoma (DHL). Concurrent IGH::MYC and IGH::BCL2 rearrangements are rarely encountered in this setting, particularly in the testis. Here, we describe an unusual case presenting significant diagnostic challenges at the interface between PBL and DHL. CASE PRESENTATION: We report a 66-year-old, immunocompetent man presenting with a 5 cm left testicular mass. Histologic examination revealed diffuse proliferation of large atypical lymphoid cells with plasmablastic morphology. Immunohistochemically, the tumor expressed CD138, CD38, and MUM1, with focal BCL2, c-MYC protein, and CD79a positivity, while CD20, CD19, PAX5, CD10, BCL6, and ALK were negative. EBV-encoded RNA in situ hybridization was negative. Fluorescence in situ hybridization identified IGH::MYC [t(8;14)] rearrangement in 45% and IGH::BCL2 [t(14;18)] rearrangement in 21% of analyzed nuclei. Next-generation sequencing additionally revealed BRAF V600E mutation, CDKN2A deletion, and human leukocyte antigen class I genomic alterations. CONCLUSION: This case highlights a rare testicular aggressive B-cell lymphoma with plasmablastic morphology and concurrent IGH::MYC and IGH::BCL2 rearrangements, representing a diagnostically challenging neoplasm at the interface between PBL and DHL. Our findings underscore the value of integrated morphologic, immunophenotypic, cytogenetic, and molecular analyses in evaluating aggressive B-cell lymphomas with plasmablastic features arising in immune-privileged sites.

Humans↗
PubMed1994

B-cell non-Hodgkin's lymphoma cell line (Karpas 1106) with complex translocation involving 18q21.3 but lacking BCL2 rearrangement and expression.

A B-cell non-Hodgkin's lymphoma (B-NHL) cell line (Karpas 1106) with an unusual three-way translocation involving 18q21.3 has been derived from a patient with mediastinal lymphoblastic B-NHL. Although conventional cytogenetics showed a derivative 18q-identical to that seen in cases with t(14;18)(q32.3;q21.3), no translocations of either chromosome 14 could be detected. Instead fluorescent in situ hybridization analysis using a chromosome-18 paint showed that the segment 18q21.3-18qter had become sandwiched on a derivative chromosome X between segments Xqter-c-Xq28 and 13q12-qter, with the centrometric site of 18q21.3 subband juxtaposed to the X sequences. Pulsed-field DNA blots failed to detect rearrangement of the BCL2 gene. Conventional DNA blots using a variety of restriction digests and both 5' and 3' BCL2 and FVT 1 probes also failed to detect rearrangement in Karpas 1106. A rearranged fragment seen only in HindIII digests with 5' BLC2 probes may represent a local microalteration, which is either a mutation or small deletion involving the HindIII site as seen in other cases of B-NHL. Neither BCL2 RNA nor BCL2 protein expression were detected. These and other data suggest that genes at 18q21.3, other than BCL2 and FVT1, may be targets for translocation in certain subgroups of B-NHL.

Adult↗
PubMed1996

Rearrangement of the BCL6 gene in B-cell lymphoid neoplasms: comparison with lymphomas associated with BCL2 rearrangement.

We report a series of B-cell neoplasms with regard to rearrangement of the BCL6 gene on chromosome band 3q27. Southern blot analysis using probes from the major translocation cluster (MTC) region of the BCL6 revealed rearrangement in 21/197 patients (10.7%) with B-cell neoplasms studied at presentation, and 11/25 patients (44%) first studied at relapse. In non-Hodgkin's lymphoma (NHL) studied at diagnosis, rearrangements of the BCL6 gene were not closely associated with a specific histopathologic subtype but distributed in subcategories in the Working Formulation. The incidence in follicular lymphoma was 12.1%, with significantly higher frequency in mixed and large cell subtypes, and that in diffuse aggressive lymphoma was 14.1%. Comigration analysis using probes from the immunoglobulin genes revealed association of the BCL6 gene with one of the three immunoglobulin loci in 9/25 cases analysed. A comparative study between NHL associated either with BCL2 or BCL6 rearrangement showed that advanced disease and bone marrow involvement were more frequent in BCL2(+) NHL. In contrast, extranodal involvement was more frequently observed in the BCL6(+) NHL. The survival curve of BCL6(+) NHL was characterized by a rapid decline followed by a plateau. Of the total of 32 BCL6(+) patients, six carried both BCL2 and BCL6 rearrangements; five of these six showed clinicopathological properties characteristic of follicular lymphoma, suggesting that the presence of the two genetic abnormalities does not necessarily have synergistic effects on malignant phenotypes. The high level of BCL6 expression in follicular lymphoma cell lines carrying a BCL2 rearrangement suggests that the deregulated BCL2 gene may have an effect on the development of genetic abnormalities of the BCL6 gene. The present study suggests that BCL6 gene rearrangement is primarily involved in large cell lymphoma irrespective of growth pattern of neoplastic cells, and that BCL6(+)BCL2(-) NHL could be curable with modern intensive chemotherapy.

Aged↗
PubMed1994

A new B-cell line showing a complex translocation (8;14;18) and BCL2 rearrangement.

A cell line named ROS-50 (Rotterdam suspension cell line no. 50) has been established from peripheral blood of a 69-year-old male with acute lymphoblastic leukemia (FAB type L3). Among the aberrations, cytogenetic analysis showed the presence of 14q+, 18q-, and two 8q- marker chromosomes. With fluorescence in situ hybridization (FISH) we characterized the chromosomal translocations, t(8;14) and t(14;18), in which the same chromosome 14 is involved. PCR analysis demonstrated the presence of on IGH-BCL2 rearrangement with a breakpoint in the minor cluster region (mcr) confirming the t(14;18) characteristic for follicular lymphoma. Additional studies showed high expression of BCL2 protein, an early B-cell immunophenotype, and an unusual pattern of IGH gene rearrangement.

Aged↗
PubMed1993

Lack of 5' BCL2 rearrangements in B-cell leukemia.

We found no rearrangements in the 5' region of the BCL2 gene in DNA samples from 60 patients with chronic B-cell leukemia (CLL). This compares with the presence of these rearrangements in up to 10% of patients in other reports, and suggests that the incidence of 5' BCL2 rearrangements in CLL is considerably less than 10%.

DNA, Neoplasm↗
PubMed1994

Detection of BCL2 rearrangement in archival cytological smears of B-cell lymphomas.

The application of polymerase chain reaction (PCR) to cytological material represents a promising, relatively noninvasive approach to clinical molecular genetic analysis. The detection rate of the t(14;18), the most common translocation in B-cell lymphomas, which results in rearrangement of the immunoglobulin heavy chain (IGH) and BCL2 genes, has not been examined in archival cytological smears. We studied 10 cases of lymphoma that showed a cytogenetic t(14;18) in a surgical specimen and for which were available both lymphoma DNA from the same specimen and prior or subsequent archival cytological smears, either FNA or exfoliative, diagnosed as positive for lymphoma. The paired DNA samples, respectively extracted from the archival smears and frozen surgical biopsy tissue, representing clinical intervals of up to 20 mo, were studied in each case by PCR with IGH and BCL2 major breakpoint region primers. In four cases, the same clonotypical PCR product was seen in both samples. In four other cases, neither sample yielded a PCR product--these cases were also negative by Southern blotting using a BCL2 major breakpoint region probe. In one case, the PCR product could only be demonstrated in DNA from frozen tissue. Finally, in one other case, a PCR product was only detected in DNA from archival cytological smears. Thus, the overall concordance of PCR results in the paired DNA samples was 80%. Our findings suggest that, in cases of B-cell lymphoma previously characterized by PCR, the t(14;18) can be detected in archival cytological smears in the majority of cases, thereby providing valuable data regarding the clonal derivation of metachronous lymphoma samples in which only cytological material is obtained.

Adult↗
PubMed2006

Interphase fluorescence in situ hybridization is more sensitive than BIOMED-2 polymerase chain reaction protocol in detecting IGH-BCL2 rearrangement in both fixed and frozen lymph node with follicular lymphoma.

The detection of t(14;18)(q32;q21) is advisable for the diagnosis of follicular lymphoma (FL). In 51 patients with FL, we evaluated the applicability and sensitivity of interphase fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) using commercially available reagents. In 23 patients, only a formalin-fixed lymph node was available. In 28 patients, both frozen and formalin-fixed lymph nodes were evaluated. Fluorescence in situ hybridization was found to be 100% applicable whatever the material type. With the use of IGH-BCL2 dual-fusion, dual-color probes, t(14;18) translocation was detected in 47 (92%) of 51 FL cases with concordant results between isolated nuclei (n = 41) and frozen cytologic imprints (n = 28). Twenty-two IGH-BCL2-positive cases were also studied on fixed sections with BCL2 split signal probes showing a BCL2 split in all. Conversely, no BCL2 split was observed in IGH-BCL2-negative cases (n = 4). Owing to DNA degradation as assessed by the failure of control genes amplification, the applicability of PCR was found to be 76% in fixed lymph nodes (n = 51). After exclusion of the 12 noninformative cases, the BIOMED-2 protocol allowed the detection of an IGH-BCL2 fusion in 25 (64%) of 39 fixed specimens with 11 PCR-negative (31%) of 36 FISH-positive cases. Even on frozen material with 100% applicability, the amplification of a BCL2-JH breakpoint was achieved in only 20 (71%) of 28 cases with 5 PCR-negative (20%) out of 25 FISH-positive cases. Therefore, FISH was found superior to PCR (using BIOMED-2 protocol) in detecting IGH-BCL2 fusion. Finally, FISH individualized 4 IGH-BCL2-negative FL cases without specific histopathologic features. With the use of split signal DNA probes, 1 case showed a trisomy of the BCL2 locus and another displayed BCL6 and IGH breakpoints that would suggest a t(3;14). Whether such IGH-BCL2-negative cases are characterized by alternative oncogenetic pathways remains to be determined.

Chromosomes, Human, Pair 14↗
PubMed1988

Evolution of B-cell malignancy: pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene.

We have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the JH4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in VH-DH-JH joining (where VH and DH are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the C gamma 2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the t(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient.

Base Sequence↗
PubMed1997

PCR analysis of IgH and BCL2 gene rearrangement in the diagnosis of follicular lymphoma in lymph node fine-needle aspiration. A critical appraisal.

In order to improve the cytomorphologic diagnosis of malignant lymphoma on lymph node fine-needle aspiration (FNA), and to make a confident discrimination between low-grade follicular non-Hodgkin's lymphoma (NHL) and lymphoid hyperplasia, polymerase chain reaction (PCR) analysis was performed of the Ig CDR3 region and BCL2 breakpoint region in 25 nonselected cases of malignant lymphoma (17 NHL and 8 Hodgkin's disease [HD]) with histologic control, and 22 cases of lymph nodal hyperplasia with histologic and/or clinical control. Among lymphomas, IgH monoclonality was detected in 7 (77%) of 9 NHLs and BCL2 rearrangement in 3 (17.6%) of 17 NHLs, all of which were follicular centroblastic-centrocytic (FCBCC). Three BCL2/JH negative FCBCC cases were monoclonal for CDR3. Neither IgH monoclonality nor BCL2 rearrangement were found in HD. Among cytologically diagnosed lymphoid hyperplasias, one IgH polyclonal case was considered false-negative, being histologically diagnosed as lymphoplasmacytic NHL on the subsequent excisional biopsy. Another 4 cases (2 BCL2 rearranged and 2 monoclonal for IgH) were considered false-positive on the basis of histologic features or clinical control. These data indicate that the combined PCR analysis of IgH and BCL2 rearrangements can confirm a cytologic diagnosis of lymphoma in FNAs while, due to the occurrence of both false-positive and false-negative results, it is of limited value in the distinction between follicular lymphoma and lymphoid hyperplasia without morphologic or clinical support.

Biopsy, Needle↗
PubMed1993

BCL2 complex rearrangement in follicular lymphoma: translocation mbr/JH and deletion in the vcr region of the same BCL2 allele.

Two rearrangements affecting the same allele of the BCL2 gene were characterized by molecular analysis of an untreated follicular lymphoma. The first rearrangement interested the major breakpoint region (mbr) on chromosome 18 and a JH segment on chromosome 14. The other one was located at the 5' end of the BCL2 gene, in the so called variant cluster region (vcr), and consisted of a series of deletions that removed part of a DNA region where initiation of transcription normally occurs. Interestingly, both rearrangements involved the same BCL2 allele. The simultaneous presence of mbr (or mcr) translocations and of minor rearrangements in vcr has been previously suggested by restriction map analysis in a significant number of follicular lymphomas. The significance of these abnormalities on the oncogenic process is discussed.

Alleles↗
PubMed1998

Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers.

Blotting, Southern↗
PubMed2000

Characterisation of BCL2-JH rearrangements in follicular lymphoma: PCR detection of 3' BCL2 breakpoints and evidence of a new cluster.

Follicular lymphomas (FL) are closely associated with a t(14;18)(q32;q21) translocation, leading to a bcl2 protein over-production. This translocation probably constitutes a very early step in the development of the disease. Besides the cytogenetic assay, t(14;18) detection can be achieved using either Southern blot or polymerase chain reaction (PCR). Since 1990, several publications have reported discrepancies between the results of cytogenetic and molecular analysis of t(14;18). Using methods able to explore long DNA fragments, several authors reported breakpoints located outside the usual breakpoint regions. However, these techniques cannot be easily used in routine. The aim of this study was to develop a simple PCR assay to amplify rearrangements usually not detected in FL. We selected a group of 83 patients with a t(14;18) on cytogenetic analysis: using usual probes and primers, 54/83 (65.1%) showed a MBR rearrangement, 7/83 (8.4%) were mcr positive and 22/83 (26.5%) remained negative. Among these 22 rearrangements, nine could be detected using this new PCR assay. Four breakpoints were located in a 20 bp area suggesting a recurrent breakpoint cluster close to an Alu repetitive sequence. Finally, remaining negative cases (13/83, 15.6%) suggest that other breakpoints are located between the MBR and mcr regions.

Base Sequence↗
PubMed2004

Neoplastic cells do not carry bcl2-JH rearrangements detected in a subset of primary cutaneous follicle center B-cell lymphomas.

Whether primary cutaneous follicular lymphoma (PCFL) may or not represent a cutaneous equivalent to nodal follicular lymphoma (FL) is not determined. We have therefore investigated a series of PCFL to determine if tumoral cells carry or not the t(14;18)(q32;q21) translocation, a cytogenetic hallmark of nodal FL. Thirty cases of PFCL were selected according to the criteria of both the European Organisation for Research and Treatment of Cancer and the World Health Organization with 21 cases classified as grade 1 or 2 and 9 cases as grade 3. First, cutaneous tumors were studied by PCR for the amplification of bcl-2/JH rearrangements and by interphase fluorescence in situ hybridization using a dual color probe spanning t(14;18) breakpoints. Second, we tried to determine the origin of bcl2-JH-positive cells by a parallel bcl2-JH and immunoglobulin heavy chain gene amplification of blood mononuclear cells DNA and of DNA extracted from single microdissected B cells. Bcl2-JH rearrangements were amplified by PCR in skin of 9 of 30 (30%) patients with a similar-sized bcl2-JH rearrangement detected in the blood of 7 of these 9 cases. No t(14;18) breakpoint was detected by interphase fluorescence in situ hybridization analysis of 11 bcl2-JH-negative and 5 bcl2-JH-positive PCFL in contrast with its detection in the secondary cutaneous FL and in the nodal FL cases. Single-cell/multigene analysis showed that no single monoclonal B cells of PCFL carried the bcl2-JH rearrangement. Bystander or nontumoral t(14;18)+ B cells emigrating from blood may account for the detection of bcl2-JH rearrangements within PCFL material. Our study also underlines the diagnostic value of interphase fluorescence in situ hybridization to discriminate between t(14;18)-negative PCFL and extracutaneous FL involving the skin.

Bystander Effect↗
PubMed2000

Association of a duodenal follicular lymphoma and hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited predisposition to colorectal and endometrial cancers caused by germline mutation of mismatch repair genes, with hMLH1 and hMSH2 underlying the majority of the cases. Although lymphoid tumors are the most common tumors in mouse models for HNPCC, lymphomas are almost never encountered in patients who have HNPCC, except in rare families with germline homozygous deletion of hMLH1. We report the case of a 53-year-old man who had a history of colon cancers related to constitutional hMLH1 mutation and who was diagnosed as having a duodenal follicular lymphoma This diagnosis was supported by IgH-BCL2 rearrangement and BCL2 immunoreactivity in tumor cells. The association of both of these possibly related rare diseases has never been reported. To clarify this relationship, we searched for hMLH1 expression and mismatch repair deficiency in the duodenal lymphoma. hMLH1 immunostaining was positive in lymphoid tumor cells, and no microsatellite instability was detected. In agreement with mouse models for HNPCC, these results suggest the involvement of alternative mechanisms to complete mismatch repair deficiency for lymphomagenesis in HNPCC syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed1999

BCL2 overexpression in diffuse large B-cell lymphoma.

Translocation (14;18)(q32;q21), which is detected in 20-30% of diffuse large B-cell lymphomas (DLBCL), is regarded as a major mechanism for BCL2 protein overexpression. Nevertheless, BCL2 overexpression is not always caused by t(14;18), because it is often detected in lymphomas without BCL2 rearrangement. Recent studies have shown that increased expression of BCL2 may also result from BCL2 gene amplification in DLBCL. Similarly, it has been speculated that the mutations of the open reading frame might cause increased expression of BCL2 by affecting the interactions of BCL2 with other proteins. The results obtained from studies on the association of BCL2 protein overexpression with survival of DLBCL are controversial, although a correlation with decreased overall survival seems to exist. However, BCL2 rearrangement does not seem to have any major association with poor prognosis, but it is difficult to assess its true impact on prognosis due to differences in treatment and follow-up, and methodologies applied to study the BCL2 rearrangement. This review summarizes the BCL2 expression studies in DLBCL and discusses the prognostic relevance of BCL2 overexpression and its mechanisms.

Animals↗