IGK

Gene Summary

Gene:IGK; immunoglobulin kappa locus
Aliases: IGK@
Location:2p12
Summary:-
Databases:HGNC, GeneCard, Gene
Source:NCBIAccessed: 17 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 2
  • Residual Disease
  • RTPCR
  • FISH
  • myc Genes
  • Immunoglobulin Heavy Chains
  • T-Cell Antigen Receptors
  • Immunoglobulin kappa-Chains
  • Gene Rearrangement, B-Lymphocyte
  • Childhood Cancer
  • Multiple Myeloma
  • Translocation
  • Clone Cells
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Genes, Immunoglobulin
  • T-Lymphocyte Gene Rearrangement
  • B-Lymphocytes
  • Receptors, Antigen, T-Cell, alpha-beta
  • Reproducibility of Results
  • bcl-X Protein
  • MALT Lymphoma
  • Burkitt Lymphoma
  • Polymerase Chain Reaction
  • B-Cell Lymphoma
  • Southern Blotting
  • Immunophenotyping
  • Recurrence
  • Gene Rearrangement
  • Acute Myeloid Leukaemia
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Adolescents
  • Trisomy
  • Infant
  • Acute Lymphocytic Leukaemia
  • Twins, Monozygotic
  • Mutation
  • Immunoglobulins
  • Genetic Recombination
  • Restriction Mapping
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IGK (cancer-related)

Aricò A, Ferraresso S, Bresolin S, et al.
Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma.
PLoS One. 2014; 9(11):e111817 [PubMed] Free Access to Full Article Related Publications
Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (>30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (>41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRα are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL.

Watson CT, Steinberg KM, Graves TA, et al.
Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity.
Genes Immun. 2015 Jan-Feb; 16(1):24-34 [PubMed] Free Access to Full Article Related Publications
Germline variation at immunoglobulin (IG) loci is critical for pathogen-mediated immunity, but establishing complete haplotype sequences in these regions has been problematic because of complex sequence architecture and diploid source DNA. We sequenced BAC clones from the effectively haploid human hydatidiform mole cell line, CHM1htert, across the light chain IG loci, kappa (IGK) and lambda (IGL), creating single haplotype representations of these regions. The IGL haplotype generated here is 1.25 Mb of contiguous sequence, including four novel IGLV alleles, one novel IGLC allele, and an 11.9-kb insertion. The CH17 IGK haplotype consists of two 644 kb proximal and 466 kb distal contigs separated by a large gap of unknown size; these assemblies added 49 kb of unique sequence extending into this gap. Our analysis also resulted in the characterization of seven novel IGKV alleles and a 16.7-kb region exhibiting signatures of interlocus sequence exchange between distal and proximal IGKV gene clusters. Genetic diversity in IGK/IGL was compared with that of the IG heavy chain (IGH) locus within the same haploid genome, revealing threefold (IGK) and sixfold (IGL) higher diversity in the IGH locus, potentially associated with increased levels of segmental duplication and the telomeric location of IGH.

Abbas F, Yazbek SN, Shammaa D, et al.
Invivoscribe BIOMED-2 primer mixes in B-cell immunoglobulin gene rearrangement studies: experience of a molecular diagnostics laboratory in a major tertiary care center.
Genet Test Mol Biomarkers. 2014; 18(12):787-90 [PubMed] Related Publications
AIMS: To determine the frequency of positive reactions obtained using the Invivoscribe BIOMED-2 kit for B-cell gene rearrangement studies in leukemias and lymphomas.
MATERIALS AND METHODS: We reviewed the gel patterns for 192 samples tested, using the above-mentioned kit and matched the positive signal with the corresponding mix available in the assay kit.
RESULTS: 92.2% had immunoglobulin heavy-chain clonality, of which 74% were detected by the IgH VH-FR1+JH primer set, 75.5% by IgH VH-FR2+JH primer set, 65.1% by IgH VH-FR3+JH primer set, 26% by IgH DH+JH primer set, and 2.1% by IgH DH7+JH primer set. In addition, 55.7% had clonality in the kappa light chain, where 33.3% were positive by the IgK Vκ +Jκ primer set and 39.6% by IgK Vκ and INTR+Kde primer sets. Clonality in the lambda light chain of immunoglobulins was detected in 17.7% of specimens tested using the IgL Vλ +Jλ primer set.
CONCLUSION: All primer mixes provided by the assay were positive. Thus, the Invivoscribe BIOMED-2 B-cell gene rearrangement kit is very reliable in adequately covering all targets represented by the master mixes. This assay is an integral part of the differential diagnosis of clonal populations of cells. Our report is the first in the literature that describes the full range of coverage of the BIOMED-2 primer mixes provided in this assay.

Li K, Johnson RL, Li S, et al.
Nodal involvement by marginal zone B-cell lymphoma harboring t(14;22)(q32;q11) involving immunoglobulin heavy chain and light chain lambda as the sole karyotypically recognizable abnormality in a patient with systemic lupus erythematosus.
Int J Clin Exp Pathol. 2014; 7(8):5221-31 [PubMed] Free Access to Full Article Related Publications
Recurrent non-random balanced chromosomal translocation, usually involving the immunoglobulin heavy chain (IgH) gene or an immunoglobulin light chain gene and a proto-oncogene, which results in the overexpression of the latter under the control of an enhancer or promoter of the former, is a hallmark of many types of non-Hodgkin lymphoma (NHL) of B-cell origin. However, translocations between IgH and the immunoglobulin (Ig) light chain lambda gene (IgL), namely, a t(14;22)(q32;q11), have rarely been described in B-cell NHL. Herein we report the first case of marginal zone B-cell lymphoma harboring a t(14;22)(q32;q11) as its sole genetic abnormality in a patient with a 12-year history of systemic lupus erythematosus (SLE). Other interesting findings of this case include: 1) the neoplastic B-cells lack expression of both surface and cytoplasmic Ig light chain as revealed by flow cytometry and 2) monoclonal rearrangement of Ig light chain kappa (IgK) only due to k-deleting element (kde) recombination event. This case illustrates the necessity of utilizing a multi-modality approach in the diagnosis of B-cell NHL.

Ai X, Fu Q, Wang J, et al.
[Significance of BIOMED-2 standardized IG/TCR gene rearrangement detection in paraffin-embedded section in lymphoma diagnosis].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(6):495-8 [PubMed] Related Publications
OBJECTIVE: To explore the feasibility of detecting lymphoma with the application of BIOMED-2 standardized immunoglobulin/T cell receptor (IG/TCR) gene rearrangement system in formalin fixed paraffin-embedded (FFPE) tissue samples, and to discuss the relationship between the longest amplification fragment of extracted DNA and positive detection rate of different IGH V-J primers.
METHODS: DNA was extracted from 50 cases of FFPE tissue samples. Multiplex-PCR amplifications were performed and then the IG/TCR gene rearrangements were analyzed using BIOMED-2 standardized clonality analysis system.
RESULTS: (1)When the DNA concentration was diluted to 50-100 ng/μl from 100-500 ng/μl, the proportion of the longest amplification fragment (300-400 bp) of DNA was improved from 10.0% to 90.0% in 30 cases of diffuse large B cell lymphoma (DLBCL) wax roll samples (P<0.01). The positive rate of IGH+IGK was increased from 46.7% to 83.3%, the difference was statistically significant (P=0.006). The lengths of the longest amplification fragments of DNA were all longer than 300 bp in the paraffin section samples of DLBCL. The positive rate of IGH+IGK of these samples was 96.7%. The difference of the positive rate of IGH+IGK between the wax roll samples and the paraffin section samples had no statistical significance (P=0.195). (2)When the concentration of DNA was high, most of the longest amplification fragments of extracted DNA were 100 bp or 200 bp, and the detection rate of short fragment IGH FR3 was more stable than that of long fragment IGH FR1. (3)The clonality analysis of TCRG+TCRB in all 13 cases of peripheral T cell lymphoma samples showed positive results, while no positive IG/TCR clones were found in 7 cases of reactive lymphoid tissue hyperplasia in control group.
CONCLUSION: Dilution of DNA is the only method to improve not only the proportion of longest fragment amplification but also the detection rate of clonality. The detection rate of IGH FR3 would not be affected by the concentration of DNA. The application of BIOMED-2 standardized IG/TCR gene rearrangement system in FFPE tissue samples plays an important role in the lymphoma diagnosis.

Jeffries SJ, Jones L, Harrison CJ, Russell LJ
IGH@ translocations co-exist with other primary rearrangements in B-cell precursor acute lymphoblastic leukemia.
Haematologica. 2014; 99(8):1334-42 [PubMed] Free Access to Full Article Related Publications
Primary established genetic abnormalities in B-cell precursor acute lymphoblastic leukemia include high hyperdiploidy (51-65 chromosomes), the translocations t(12;21)(p13;q22)/ETV6-RUNX1 fusion and t(9;22)(q34;q11)/BCR-ABL1 fusion, MLL rearrangements and intrachromosomal amplification of chromosome 21. These rearrangements are of prognostic and therapeutic relevance and are usually mutually exclusive. We identified 28 patients at diagnosis with both a primary genetic rearrangement and an immunoglobulin heavy chain locus translocation using chromosomal analysis and fluorescence in situ hybridization. Among these patients, the immunoglobulin heavy chain locus translocation partner gene was identified in six (CRLF2, CEBPA, CEBPB, TRA/D@, IGF2BP1 and IGK@). Clonal architecture was investigated in 17 patients using multiple color interphase fluorescence in situ hybridization analysis, which showed that the translocation was acquired as a secondary abnormality in ten patients, in four patients the etiology was undetermined and in three patients it was observed in a separate clone from the primary chromosomal rearrangement. These findings demonstrate the co-existence of immunoglobulin heavy chain locus translocations with other primary chromosomal rearrangements either in the same or separate clones, which may have prognostic significance in B-cell precursor acute lymphoblastic leukemia. Clinical trials: UKALLXII: Study ID n. ISRCTN77346223 and ALL2003: Study ID n. ISRCTN07355119.

Logan AC, Vashi N, Faham M, et al.
Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival.
Biol Blood Marrow Transplant. 2014; 20(9):1307-13 [PubMed] Related Publications
Minimal residual disease (MRD) quantification is an important predictor of outcome after treatment for acute lymphoblastic leukemia (ALL). Bone marrow ALL burden ≥ 10(-4) after induction predicts subsequent relapse. Likewise, MRD ≥ 10(-4) in bone marrow before initiation of conditioning for allogeneic (allo) hematopoietic cell transplantation (HCT) predicts transplantation failure. Current methods for MRD quantification in ALL are not sufficiently sensitive for use with peripheral blood specimens and have not been broadly implemented in the management of adults with ALL. Consensus-primed immunoglobulin (Ig), T cell receptor (TCR) amplification and high-throughput sequencing (HTS) permit use of a standardized algorithm for all patients and can detect leukemia at 10(-6) or lower. We applied the LymphoSIGHT HTS platform (Sequenta Inc., South San Francisco, CA) to quantification of MRD in 237 samples from 29 adult B cell ALL patients before and after allo-HCT. Using primers for the IGH-VDJ, IGH-DJ, IGK, TCRB, TCRD, and TCRG loci, MRD could be quantified in 93% of patients. Leukemia-associated clonotypes at these loci were identified in 52%, 28%, 10%, 35%, 28%, and 41% of patients, respectively. MRD ≥ 10(-4) before HCT conditioning predicted post-HCT relapse (hazard ratio [HR], 7.7; 95% confidence interval [CI], 2.0 to 30; P = .003). In post-HCT blood samples, MRD ≥10(-6) had 100% positive predictive value for relapse with median lead time of 89 days (HR, 14; 95% CI, 4.7 to 44, P < .0001). The use of HTS-based MRD quantification in adults with ALL offers a standardized approach with sufficient sensitivity to quantify leukemia MRD in peripheral blood. Use of this approach may identify a window for clinical intervention before overt relapse.

Türkmen S, Binder A, Gerlach A, et al.
High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.
Genes Chromosomes Cancer. 2014; 53(8):650-6 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases.

Poopak B, Saki N, Purfatholah AA, et al.
Pattern of immunoglobulin and T-cell receptor-δ/γ gene rearrangements in Iranian children with B-precursor acute lymphoblastic leukemia.
Hematology. 2014; 19(5):259-66 [PubMed] Related Publications
INTRODUCTION: Acute lymphoblastic leukemia (ALL) cells have unique rearranged immunoglobulin heavy chain (IgH), immunoglobulin light chain (IgK), and T-cell receptor (TCR) genes, which can be used as markers for clonality assay and evaluation of minimal residual disease. In this study, we have evaluated the pattern of IgH, IgK chains, and TCRG/D gene rearrangements in precursor-B ALL.
MATERIALS AND METHODS: In our prospective study, hyper-variable regions (CDRI and III) of IgH, TCRD (Vδ2-Dδ3 and Dδ2-Dδ3), TCRG (Vγ, VγI, and VγII), and IgK (Vκ-Kde) were studied in 126 cases with diagnosis of B-precursor ALL.
RESULTS: One hundred and fourteen (90.5%) out of 126 patients had clonal rearrangements of IgH using consensus primers for CDRI and/or CDRIII regions. Monoclonal, biclonal, and oligoclonal patterns were observed in 63 (57.8%), 38 (34.9%), and 6 (5.5%) patients with IgH (CDRIII) rearrangements, respectively. Clonal rearrangements of TCRG (Vγ) and VγI/II were present in 79.3 and 64.9% of patients, respectively, and only 5% of cases showed biclonal pattern. The VγII rearrangement was the most common (46.8%) type in TCRG. Vδ2-Dδ3 and Dδ2-Dδ3 partial gene rearrangements were observed in 47 (45.2%; n = 104) and 11 (16.6%; n = 66) patients, respectively. Biclonal/oligoclonal patterns were present in 13 (27.7%) and 2 (4.3%) cases with Vδ2-Dδ3 rearrangement, respectively. Only one patient had biclonal Dδ2-Dδ3 rearrangement. Clonal pattern of IgK-Kde was detected in 59 cases (67%; n = 88).
CONCLUSION: Our findings showed that clonal rearrangements of IgH and TCRD (Vδ2-Dδ3 and Dδ2-Dδ3) genes had similar patterns to other studies. Frequency of TCRG (VγI and VγII) and IgK rearrangements was found to be slightly higher than previous reports. Among the IgK rearrangements, VKI (25%) was the most common.

Affer M, Chesi M, Chen WD, et al.
Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma.
Leukemia. 2014; 28(8):1725-35 [PubMed] Free Access to Full Article Related Publications
MYC locus rearrangements-often complex combinations of translocations, insertions, deletions and inversions-in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet, germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS (monoclonal gammopathy of undetermined significance)-prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have biallelic MYC expression at significantly higher levels than in MGUS. We also have shown that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

Martinez-Lopez J, Fernández-Redondo E, García-Sánz R, et al.
Clinical applicability and prognostic significance of molecular response assessed by fluorescent-PCR of immunoglobulin genes in multiple myeloma. Results from a GEM/PETHEMA study.
Br J Haematol. 2013; 163(5):581-9 [PubMed] Related Publications
Minimal residual disease monitoring is becoming increasingly important in multiple myeloma (MM), but multiparameter flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) techniques are not routinely available. This study investigated the prognostic influence of achieving molecular response assessed by fluorescent-PCR (F-PCR) in 130 newly diagnosed MM patients from Grupo Español Multidisciplinar de Melanoma (GEM)2000/GEM05 trials (NCT00560053, NCT00443235, NCT00464217) who achieved almost very good partial response after induction therapy. As a reference, we used the results observed with simultaneous MFC. F-PCR at diagnosis was performed on DNA using three different multiplex PCRs: IGH D-J, IGK V-J and KDE rearrangements. The applicability of F-PCR was 91·5%. After induction therapy, 64 patients achieved molecular response and 66 non-molecular response; median progression-free survival (PFS) was 61 versus 36 months, respectively (P = 0·001). Median overall survival (OS) was not reached (NR) in molecular response patients (5-year survival: 75%) versus 66 months in the non-molecular response group (P = 0·03). The corresponding PFS and OS values for patients with immunophenotypic versus non-immunophenotypic response were 67 versus 42 months (P = 0·005) and NR (5-year survival: 95%) versus 69 months (P = 0·004), respectively. F-PCR analysis is a rapid, affordable, and easily performable technique that, in some circumstances, may be a valid approach for minimal residual disease investigations in MM.

Chonabayashi K, Tamori S, Taniwaki M, et al.
Refractory IGκ/IRF4-positive DLBCL with CDKN2A/2B deletion.
Ann Hematol. 2014; 93(5):893-4 [PubMed] Related Publications

Johnson RC, Ma L, Cherry AM, et al.
B-cell transcription factor expression and immunoglobulin gene rearrangement frequency in acute myeloid leukemia with t(8;21)(q22;q22).
Am J Clin Pathol. 2013; 140(3):355-62 [PubMed] Related Publications
OBJECTIVES: To assess a large series of patients with acute myeloid leukemia (AML) with t(8;21) for both IGH@ and IGK@ B-cell gene rearrangements and for expression of PAX5, OCT2, and Bob.1 by immunohistochemistry and expression of CD19, CD79a, CD20, and CD22 by flow cytometry immunophenotyping.
METHODS: A total of 48 cases of AML with t(8;21)(q22;q22) were evaluated by immunohistochemistry and/or heavy chain and light chain immunoglobulin rearrangement studies where paraffin-embedded and/or fresh frozen material was available for study; previously performed flow cytometry studies were also reviewed in available cases.
RESULTS: Our study yielded 1 of 19 cases of AML with t(8;21) with an IGH@ gene rearrangement; blasts were associated with weak PAX5 expression. In addition, expression of antigens CD79a by flow cytometry and OCT2 by immunohistochemistry were highly associated with PAX5 expression, and CD19 was expressed in most cases assessed.
CONCLUSIONS: Although B-cell antigen and B-cell transcription factor expression is seen in the majority of AMLs with t(8;21)(q22;q22) and correlates with PAX5 expression, immunoglobulin gene rearrangements are an uncommon event in this group of leukemias.

Zur Hausen A, Rennspiess D, Winnepenninckx V, et al.
Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry.
Cancer Res. 2013; 73(16):4982-7 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine nonmelanoma skin cancer, which is associated with the Merkel cell polyoma virus (MCPyV). Recently, expression of the terminal deoxynucleotidyl transferase (TdT) and the paired box gene 5 (PAX 5) has been consistently reported in the majority of MCCs. We tested 21 MCCs for the expression of MCPyV, TdT, PAX5, IgG, IgM, IgA, kappa, and lambda by immunohistochemistry and assessed IgH and Igk rearrangement in all 21 MCCs. All of the MCCs revealed specific expression of PAX5 and 72.8% of the MCCs expressed TdT. In addition, most of the MCCs revealed specific expression of one or more Ig subclasses and kappa or lambda. One MCC did reveal monoclonal IgH and Igk rearrangement next to two other MCCs showing Igk rearrangement. As coexpression of TdT and PAX5 under physiologic circumstances is restricted to pro/pre- and pre-B cells we propose, on the basis of our results, that the cell of origin of MCCs is a pro/pre- or pre-B cell rather than the postmitotic Merkel cells. MCPyV infection and transformation of pro-/pre-B cells are likely to induce the expression of simple cytokeratins as has been shown for SV40 in other nonepithelial cells. This model of cellular ancestry of MCCs might impact therapy and possibly helps to understand why approximately 20% of MCCs are MCPyV-negative.

Boone E, Verhaaf B, Langerak AW
PCR-based analysis of rearranged immunoglobulin or T-cell receptor genes by GeneScan analysis or heteroduplex analysis for clonality assessment in lymphoma diagnostics.
Methods Mol Biol. 2013; 971:65-91 [PubMed] Related Publications
The assessment of the presence of clonal lymphoproliferations via polymerase chain reaction (PCR)-based analysis of rearranged immunoglobulin (Ig) or T-cell receptor (TCR) genes is a valuable technique in the diagnosis of suspect lymphoproliferative disorders. Furthermore this technique is more and more used to evaluate dissemination of non-Hodgkin lymphoma and/or the presence of (minimal) residual disease. In this chapter we describe an integrated approach to assess clonality via analysis of Ig heavy chain (IGH), Ig kappa (IGK), TCR beta (TCRB), and TCR gamma (TCRG) gene rearrangements. The described PCR protocol is based on the standardized multiplex PCRs as developed by the European BIOMED-2 collaborative study (Concerted Action BMH4-CT98-3936). Furthermore it also includes the pre-analytical DNA isolation step from various tissues (formalin fixed paraffin-embedded tissue, fresh tissues, body fluids, peripheral blood and bone marrow), GeneScan analysis of labeled PCR products on a genetic analyzer, heteroduplex analysis of unlabeled PCR products, and post-analytical guidelines for the interpretation of the obtained "molecular morphology" patterns.

Salaverria I, Royo C, Carvajal-Cuenca A, et al.
CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma.
Blood. 2013; 121(8):1394-402 [PubMed] Free Access to Full Article Related Publications
Cyclin D1(-) mantle cell lymphomas (MCLs) are not well characterized, in part because of the difficulties in their recognition. SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1(-) variant. We investigated 40 lymphomas with MCL morphology and immunophenotype that were negative for cyclin D1 expression/t(11;14)(q13;q32) but positive for SOX11. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and poor outcome (5-year overall survival, 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18 of 22, in particular with light chains (10 IGK@ and 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2, or CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1(-) SOX11(+) MCL patients analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11 MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome for the patients. This comprehensive characterization of a large series of cyclin D1(-) MCL patients indicates that these tumors are clinically and biologically similar to the conventional cyclin D1(+) MCL and provides a basis for the proper identification and clinical management of these patients.

Parker EP, Siebert R, Oo TH, et al.
Sequencing of t(2;7) translocations reveals a consistent breakpoint linking CDK6 to the IGK locus in indolent B-cell neoplasia.
J Mol Diagn. 2013; 15(1):101-9 [PubMed] Related Publications
The translocation t(2;7)(p11;q21) has repeatedly been documented in association with indolent B-cell lymphoproliferative disorders (BLPDs). However, the chromosomal breakpoints associated with this recurrent translocation have rarely been characterized. Using an approach based on long-range PCR, we mapped the t(2;7) breakpoints in five patients presenting with indolent B-cell neoplasia. The sequencing of these rearrangements revealed several striking parallels across the t(2;7) breakpoints. The junction sites on 2p11 consistently mapped to the heptamer recombination signal sequence (RSS) of an immunoglobulin kappa variable gene (IGK) within the Vκ3 family, while the breakpoints on 7q21 each localized to within 4 bp of an RSS-like element located approximately 0.5 kb upstream of the transcription start site of the cyclin-dependent kinase 6 gene (CDK6). These findings confirm the significant genetic overlap arising in BLPD-associated t(2;7) translocations, and implicate the deregulated expression of CDK6 as a common molecular mechanism involved in the emergence of clonal B-cell proliferations presenting with this recurrent abnormality. In addition, the successful mapping of the t(2;7) translocations in each of five patients using a simple PCR-based protocol highlights the potential diagnostic utility of this approach during characterization of cases harboring analogous rearrangements.

Liu Q, Salaverria I, Pittaluga S, et al.
Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma.
Am J Surg Pathol. 2013; 37(3):333-43 [PubMed] Free Access to Full Article Related Publications
Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. Most pediatric cases have been described as grade 3, but the criteria to distinguish the pediatric variant of FL (PFL) from usual FL (UFL) seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as PFL: 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as UFL, 28 of which presented in lymph nodes. The nodal PFLs were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. PFLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. UFLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results indicate that histologic and immunophenotypic criteria can reliably separate PFL and UFL and that UFL is exceptionally rare in the pediatric age group. PFL associated with particular anatomic sites have distinctive features and should be evaluated separately in future clinical and biological studies.

Puig N, Sarasquete ME, Alcoceba M, et al.
Kappa deleting element as an alternative molecular target for minimal residual disease assessment by real-time quantitative PCR in patients with multiple myeloma.
Eur J Haematol. 2012; 89(4):328-35 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) assessment by PCR in multiple myeloma (MM) has several shortcomings, including the lack of a suitable target. Kappa deleting element (KDE) rearrangements occur in virtually all Ig-lambda B-cell malignancies and in 1/3 of Ig-kappa are not affected by somatic hypermutation and, as in ALL, could be used as PCR targets.
METHODS: We have first investigated the incidence, gene segment usage, and CDR3 composition of IGK-KDE rearrangements in 96 untreated myeloma patients. Second, we tested 16 KDE gene rearrangements as molecular targets for MRD assessment by RQ-PCR using a germline reverse primer and a germline Taqman probe in combination with allele-specific oligonucleotides (ASO) as forward primers.
RESULTS: Monoclonal KDE rearrangements were amplified in 45% (43/96) of cases, monoallelic in 2/3 of them (29 cases), and biallellic in the remaining 14 cases. Overall, 88% of cases were successfully sequenced, KDE being equally frequently rearranged with VK and with intron-Recombination signal sequence (RSS). Median numbers of inserted and deleted nucleotides in the junctional region were one and five, respectively.
CONCLUSIONS: Using KDE rearrangements as additional PCR target for MRD assessment in MM improves the applicability of these studies in 9% of cases overall and in 20% of lambda cases. Its use in the latter subset could represent a significant advance.

Fujiwara M, Morales AV, Seo K, et al.
Clonal identity and differences in primary cutaneous B-cell lymphoma occurring at different sites or time points in the same patient.
Am J Dermatopathol. 2013; 35(1):11-8 [PubMed] Related Publications
Primary cutaneous B-cell lymphomas (PCBCL) are rare. Marginal zone lymphomas and follicle center lymphomas (FCL) represent a majority of these cases, and a significant number of cases present with multiple lesions. It is unclear whether multiple lesions in PCBCL represent dissemination of a single clone or multiple new primary lymphomas. In the current study, we analyzed paired samples from 20 PCBCL patients at more than 1 site (16) or at the same site at different time points (4) and 12 patients with benign lymphoid infiltrates to investigate for the presence or absence of a clone, and if present, whether the clones were identical. Both IGH@ and IGK@ rearrangements were tested using the BIOMED-2 protocol. We identified a clone (IGH@ and/or IGK@) in 19 of 20 (95%) PCBCL patients and 2 of 12 (17%) benign lymphoid infiltrate patients. The B-cell clones were proven to be identical in 11 of 20 (55%) PCBCL patients, including 7 of 16(44%) biopsies from patients with 2 different sites and 4 of 4 biopsies (100%) from patients at the same site but different time points. In 4 cases (3 FCL and 1 marginal zone lymphoma), different clones were detected at different sites, suggesting the possibility of a second simultaneous primary lymphoma. Our results indicate that the presence of identical clones is highly suggestive of lymphoma. To our knowledge, this is the first report to investigate the detection of identical clones in 2 distinct biopsies in PCBCL patients. Although the study is small and the results need to be confirmed in a larger study, these findings suggest that a subset of PCBCL at different sites may represent different primary tumors rather than occurrence of a single disease.

Wu RQ, Qiao C, Tong Y, et al.
[Study of immunoglobulin and T-cell receptor gene rearrangements in patients with non-Hodgkin's lymphoma].
Zhonghua Xue Ye Xue Za Zhi. 2012; 33(1):10-5 [PubMed] Related Publications
OBJECTIVE: To investigate immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements in bone marrow or peripheral blood of patients with non-Hodgkin's lymphoma (NHL), and to explore the potential clinical significance.
METHODS: The Ig/TCR gene rearrangements in bone marrow or peripheral blood of 139 NHL patients were analyzed by using BIOMED-2 multiple primers system and Multiplex PCR assay.
RESULTS: Ig clonality was detected in 85.4% (70/82) of chronic lymphocytic leukemia (CLL), including 46.3% (38/82) IgH rearrangement, 62.2% (51/82) IgK rearrangement and 1.2% (1/82) IgL rearrangement, and in 39.4% (13/33) of other categories of B-lineage NHL (B-NHL), including 33.3% (11/33) IgH and 39.4% (13/33) IgK rearrangements. TCR clonality was detected in 50.0% (12/24) of all definite T-lineage NHL (T-NHL), including 8.3% (2/24) TCRB and 45.8% (11/24) TCRG, no TCRD was detected. The detection rate of gene rearrangements of NHL diversed in different clinical stages \[36.4% in early stage (Ann Arbor stage I and II) and 45.6% in late stage (III and IV)\] and in different degrees of malignancy (40.0% indolent NHL and 45.6% aggressive NHL), but no obvious statistical significance was obtained (P > 0.05). The detection rate of bone marrow invasions of NHL (except CLL) with examinations of bone marrow smear under the microscope was 12.3% (7/57), much lower than the clonality testing (43.9%, 25/57) (P < 0.05). Sensitivity test showed that the sensitivity of malignant clonality testing by multiplex PCR was 3.12% - 6.25%.
CONCLUSIONS: The detection rate of gene rearrangements diverses in different clinical stages and degrees of malignancy of NHL, but the correlation has not been proved in this research. The sensitivity of multiplex PCR-based clonality testing is enhanced with the combination of BIOMED-2 primers system. It is more sensitive than the morphological examinations of bone marrow smear in detecting bone marrow invasions, and may provide a powerful strategy in the routine diagnosis and assessment after treatment.

Whiteside TL, Ferrone S
For breast cancer prognosis, immunoglobulin kappa chain surfaces to the top.
Clin Cancer Res. 2012; 18(9):2417-9 [PubMed] Free Access to Full Article Related Publications
The stromal immunoglobulin kappa chain (IGKC) has been validated as an immunologic biomarker of prognosis and response to therapy in human breast cancer and other cancers. This validation emphasizes the key role of humoral immunity in control of cancer progression and has major implications for determining prognosis of patients with cancer.

Liu H, Duan Z, Zheng H, et al.
EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling.
PLoS One. 2012; 7(3):e32624 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence indicates that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cells, express immunoglobulins (Igs). We previously found that the expression of the kappa light chain protein in NPC cells can be upregulated by the EBV-encoded latent membrane protein 1 (LMP1). In the present study, we used NPC cell lines as models and found that LMP1-augmented kappa production corresponds with elevations in ERKs phosphorylation. PD98059 attenuates LMP1-induced ERKs phosphorylation resulting in decreased expression of the kappa light chain. ERK-specific small interfering RNA blunts LMP1-induced kappa light chain gene expression. Luciferase reporter assays demonstrate that immunoglobulin κ 3' enhancer (3'E(κ)) is active in Igκ-expressing NPC cells and LMP1 upregulates the activity of 3'E(κ) in NPC cells. Moreover, mutation analysis of the PU binding site in 3'E(κ) and inhibition of the MEK/ERKs pathway by PD98059 indicate that the PU site is functional and LMP1-enhanced 3'E(κ) activity is partly regulated by this site. PD98059 treatment also leads to a concentration-dependent inhibition of LMP1-induced Ets-1 expression and phosphorylation, which corresponds with a dose-dependent attenuation of LMP1-induced ERK phosphorylation and kappa light chain expression. Suppression of endogenous Ets-1 by small interfering RNA is accompanied by a decrease of Ig kappa light chain expression. Gel shift assays using nuclear extracts of NPC cells indicate that the transcription factor Ets-1 is recruited by LMP1 to the PU motif within 3'E(κ)in vitro. ChIP assays further demonstrate Ets-1 binding to the PU motif of 3'E(κ) in cells. These results suggest that LMP1 upregulates 3'E(κ) activity and kappa gene expression by activating the Ets-1 transcription factor through the ERKs signaling pathway. Our studies provide evidence for a novel regulatory mechanism of kappa expression, by which virus-encoded proteins activate the kappa 3' enhancer through activating transcription factors in non-B epithelial cancer cells.

Schmidt M, Hellwig B, Hammad S, et al.
A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors.
Clin Cancer Res. 2012; 18(9):2695-703 [PubMed] Related Publications
PURPOSE: Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available.
EXPERIMENTAL DESIGN: On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell-derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non-small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy.
RESULTS: We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression.
CONCLUSION: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.

Onozawa M, Aplan PD
Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy.
Genes Chromosomes Cancer. 2012; 51(6):525-35 [PubMed] Free Access to Full Article Related Publications
V(D)J recombination of antigen receptor loci (IGH, IGK, IGL, TCRA, TCRB, TCRG, and TCRD) is an essential mechanism that confers enormous diversity to the mammalian immune system. However, there are now at least six examples of intrachromosomal interstitial deletions caused by aberrant V(D)J recombination between nonantigen receptor loci; five of out these six are associated with lymphoid malignancy. The SIL-SCL fusion and deletions of CDKN2A, IKZF1, Notch1, and Bcl11b are all associated with lymphoid malignancy. These interstitial deletions seem to be species specific, as the deletions seen in mice are not seen in humans; the converse is true as well. Nucleotide sequence analysis of these rearrangements reveals the hallmarks of V(D)J recombination, including site specificity near cryptic heptamer signal sequences, exonucleolytic "nibbling" at the junction site, and nontemplated "N"-region nucleotide insertion at the junction site. Two of these interstitial deletions (murine Notch1 and Bcl11b deletions) have been detected, at low frequency, in tissues from healthy mice with no evidence of malignancy, similar to the finding of chromosomal translocations in the peripheral blood or tonsils of healthy individuals. The contention that these are mediated via V(D)J recombination is strengthened by in vivo assays using extrachromosomal substrates, and chromatin immunoprecipitation-sequence analysis which shows Rag2 binding at the sites of rearrangement. Although the efficiency of these "illegitimate" recombination events is several orders of magnitude less than that at bona fide antigen receptor loci, the consequence of such deletions, namely activation of proto-oncogenes or deletion of tumor suppressor genes, is devastating, and a major cause for lymphoid malignancy.

Tapia G, Sanz C, Mate JL, et al.
Improved clonality detection in Hodgkin lymphoma using the BIOMED-2-based heavy and kappa chain assay: a paraffin-embedded tissue study.
Histopathology. 2012; 60(5):768-73 [PubMed] Related Publications
AIMS: Although BIOMED-2 polymerase chain reaction (PCR) standardization protocols allow clonality detection in nearly 100% of non-Hodgkin B cell lymphomas, they have not been widely validated for Hodgkin lymphoma (HL). Our aim was to assess BIOMED-2 protocol sensitivity when using non-microdissected, formalin-fixed, paraffin-embedded (FFPE) tissue from HL cases.
METHODS AND RESULTS: We studied 69 consecutive HL cases, of which 61 corresponded to classic HL (cHL) and eight to nodular lymphocyte-predominant HL (NLPHL). CD30-positive cell numbers (<10, 10-25 or >25 per ×200 field), background CD20-positive cell density (low or high) and tumour cell immunophenotype were evaluated. IGH and IGK clonality was assessed on FFPE tissue following BIOMED-2 protocols. Of the 58 assessable cHL cases, 15 (25.9%) exhibited IGH and/or IGK clonality; IGH clonality was shown by nine (15.5%) and IGK clonality by 12 (20.7%). Clonality detection rates in cHL improved as CD30-positive Reed-Sternberg (RS) cell density increased and CD20-positive B cell density decreased, although these correlations did not reach statistical significance. Of the eight NLPHL cases studied, none showed clonal rearrangement.
CONCLUSIONS: Combined study of IGH and IGK rearrangement according to BIOMED-2 protocols improves clonality detection rate (up to 25% of cases) in HL, even when working on non-microdissected FFPE tissue.

Tong Y, Qiao C, Wu RQ, et al.
[Detection of gene rearrangement in bone marrow of patients with non Hodgkin's lymphoma by BIOMED-2 protocols].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011; 19(6):1409-14 [PubMed] Related Publications
This study was purposed to explore the feasibility of BIOMED-2 protocols for detection of immunoglobin (IG) and T-cell receptor (TCR) gene clonal rearrangement in bone marrow of Non-Hodgkin's lymphoma(NHL) patients, and to evaluate its clinical value. Gene clonal rearrangment (IGH, IGK, IGL, TCRβ, TCRγ, TCRδ) was detected by using BIOMED-2 protocols in 73 bone marrow examples of NHL patients. The PCR results were compared with the cytomorphologic examination of bone marrow. The correlation between PCR detection results and clinical stage, pathological factors were also evaluated. The results showed that clonal IG or TCR gene rearrangements were found in 31 of 73 cases (42.5%), higher than the positive rate of cytological analysis (24.7%, 18/73, p < 0.05). IG/TCR clonality rates were 40.0% (22/55) for B-NHL and 50% (9/18) for T-NHL. IG/TCR clonality rates detected in patients with III/IV stage were higher than those with I/II stage (p < 0.05). It is concluded that BIOMED-2 protocols are effective methods for detection of abnormalities in bone marrow in patients with lymphoma, and are superior to cytomorphologic examination. The positive rate of PCR detection is correlated with Ann Arbor stage, but is not related with malignant degree, age, treatment status, B symptoms or the involvement of spleen.

Li WJ, Cui L, Gao C, et al.
[Gene rearrangement pattern of immunoglobulin and T-cell receptor (Ig/TR) and its clinical characteristics in children with SET-NUP214 fusion gene-positive leukemia/lymphoma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011; 19(6):1362-7 [PubMed] Related Publications
The purpose of this study was to analyze the gene rearrangement pattern of immunoglobulin and T-cell receptor (Ig/TR) and its clinical characteristics in three children with SET-NUP214 fusion gene positive leukemia/lymphoma. The transcript of SET-NUP214 fusion gene was detected by RT-nested PCR. The pattern of Ig/TR gene rearrangement was analyzed by using the BIOMED-2 multiplex PCR assays. Allelic-specific primers were designed for further monitoring the minimal residual disease (MRD). The results indicated that the fusion site located between exon 7 of SET and exon 18 of NUP214 at mRNA level in the three patients. The diagnoses were made as the mixed phenotype of acute leukemia (MPAL) for patients 1, acute T-lymphoblastic leukemia (T-ALL) for patients 2, and stage IV T-lymphoblastic lymphoma (T-LBL) for patients 3, respectively. Patient 1 responded to chemotherapy very poorly and relapsed at month 6 after hematopoietic stem cell transplantation. Patient 2 had high MRD (> 10(-2)) at the end of inducing remission therapy (day 33) which implied poor outcome, and died of toxic epidermal necrolysis and sequent serious infection. Patient 3 achieved hematological complete remission (CR) and MRD negative at day 15 and day 33 respectively. The duration of CR lasted for 30 months. Clonal TR gene rearrangements were detected in all the three patients. The rearrangements of TRD, TRG and TRB were found in patient 1 and 3. The rearrangements of TRD, TRB, IgH and IgK Kde were detected in patient 2. All the 6 TRB rearrangements detected were incomplete rearrangements, whereas 85.7% and 14.3% of the TRD, and TRG rearrangements were complete and incomplete, respectively. It is concluded that the transformation of SET-NUP214(+) leukemia/lymphoma cells may occur after the rearrangements of TRD and TRG and shortly after TRB rearrangement. The leukemia/lymphoma cells of patient 1 and 2 are more immature which may be related with poor outcome or response to chemotherapy.

Kroenlein H, Schwartz S, Reinhardt R, et al.
Molecular analysis of the t(2;8)/MYC-IGK translocation in high-grade lymphoma/leukemia by long-distance inverse PCR.
Genes Chromosomes Cancer. 2012; 51(3):290-9 [PubMed] Related Publications
Burkitt lymphoma and a subset of diffuse large B-cell lymphomas are characterized by chromosomal alterations affecting the MYC oncogene on 8q24. In most cases MYC is found juxtaposed to the immunoglobulin heavy chain (IGH) gene locus. Translocations to the immunoglobulin kappa (IGK) gene locus on 2p11 are observed in around 5-10% of cases. Little data exist on the molecular mechanisms leading to this aberration. The chromosomal breakpoints on chromosome 8 have been found dispersed over a large area 3' of MYC. In order to obtain a better understanding of this chromosomal translocation we developed a long-distance inverse (LDI) PCR method for the identification of chromosomal translocations affecting the IGK locus. We investigated a number of cytogenetically mostly uncharacterized high-grade lymphoma samples and identified a MYC-IGK juxtaposition in seven patients and three t(2;8)-positive cell lines. The chromosomal breakpoints were molecularly characterized and analyzed. The linear distance of the breakpoints on chromosome 8 to MYC ranged from some 100 bp to more than 0.5 MB. The reciprocal translocated allele could be characterized in the majority of cases. This study represents the largest series of t(2;8)-positive cases analyzed so far. The LDI PCR method developed here should also be useful for the analysis of chromosomal translocations affecting the IGK locus in general.

Zamò A, Bertolaso A, van Raaij AW, et al.
Application of microfluidic technology to the BIOMED-2 protocol for detection of B-cell clonality.
J Mol Diagn. 2012; 14(1):30-7 [PubMed] Related Publications
The BIOMED-2 protocol is widely used for detecting clonality in lymphoproliferative disorders. The protocol requires multiple PCR reactions, which are analyzed by either capillary electrophoresis (GeneScan analysis) or heteroduplex PAGE analysis. We tested a microfluidic chip-based electrophoresis device (Agilent 2100 Bioanalyzer) for the analysis of B-cell clonality using PCR for the three framework subregions (FR) of the Ig heavy chain gene (IGH) and PCR for two rearrangements occurring in the Ig κ chain gene (IGK-VJ and IGK-DE). We analyzed 62 B-cell lymphomas (33 follicular and 29 nonfollicular) and 16 reactive lymph nodes. Chip-based electrophoresis was conclusive for monoclonality in 59/62 samples; for 20 samples, it was compared with GeneScan analysis. Concordant results were obtained in 45/55 IGH (FR1, FR2, and FR3) gene rearrangements, and in 34/37 IGK gene rearrangements. However, when the chip device was used to analyze selected IGK gene rearrangements (biallelic IGK rearrangements or IGK rearrangements in a polyclonal background), its performance was not completely accurate. We conclude, therefore, that this microfluidic chip-based electrophoresis device is reliable for testing cases with dominant PCR products but is less sensitive than GeneScan in detecting clonal peaks in a polyclonal background for IGH PCR, or with complex IGK rearrangement patterns.

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