Detection of Immunoglobulin κ Light Chain Rearrangements by Polymerase Chain Reaction

The clonal determination of B-cell lymphoproliferative disorders by immunoglobulin heavy chain (IgH) rearrangement by polymerase chain reaction (PCR) is widely used. However, few attempts have been made to detect immunoglobulin κ light chain (Igκ) gene rearrangement using PCR. We studied 145 cases of B-cell neoplasms, along with 58 atypical and 18 reactive lymphoproliferative disorders, using newly designed degenerate oligoprimers recognizing the framework 3 (FR3κ) and the joint (Jκ. regions of the Igκ gene. PCR products were analyzed on nondenaturing polyacrylamide gel (ndPAGE). Clonal B-cell determination was further investigated using IgH rearrangement and t(11:14) or t(14:18). By combining these methods, we detected either clonality or translocation in 117 of 137 cases (85%) in mature B-cell neoplasms. The additional analysis of Igκ rearrangement improved sensitivity from 66% to 85%. To investigate whether the Ig gene configuration could be characterized using Igκ PCR in B-cell neoplasms showing severe breakdown of genomic DNA, 18 selected cases were analyzed. Successful amplification was detected in 72% of the cases using either FR3/2-JH and/or FR3Jκ oligoprimers. Finally, clonality was detected in 21 of 58 atypical B-cell proliferations, and among them, the atypical marginal cell (54%) and atypical large cell (50%) proliferations showed the highest frequency of clonal immunoglobulin gene products. We concluded that PCR/ndPAGE analysis of Igκ is a sensitive, rapid, and efficient method for assessing clonality in conjunction with IgH and specific translocation analysis. This approach is particularly useful in the characterization of B-cell lymphoproliferative disorders in archival material with poor preservation of the genomic DNA. The clonal determination of B-cell lymphoproliferative disorders by immunoglobulin heavy chain (IgH) rearrangement by polymerase chain reaction (PCR) is widely used. However, few attempts have been made to detect immunoglobulin κ light chain (Igκ) gene rearrangement using PCR. We studied 145 cases of B-cell neoplasms, along with 58 atypical and 18 reactive lymphoproliferative disorders, using newly designed degenerate oligoprimers recognizing the framework 3 (FR3κ) and the joint (Jκ. regions of the Igκ gene. PCR products were analyzed on nondenaturing polyacrylamide gel (ndPAGE). Clonal B-cell determination was further investigated using IgH rearrangement and t(11:14) or t(14:18). By combining these methods, we detected either clonality or translocation in 117 of 137 cases (85%) in mature B-cell neoplasms. The additional analysis of Igκ rearrangement improved sensitivity from 66% to 85%. To investigate whether the Ig gene configuration could be characterized using Igκ PCR in B-cell neoplasms showing severe breakdown of genomic DNA, 18 selected cases were analyzed. Successful amplification was detected in 72% of the cases using either FR3/2-JH and/or FR3Jκ oligoprimers. Finally, clonality was detected in 21 of 58 atypical B-cell proliferations, and among them, the atypical marginal cell (54%) and atypical large cell (50%) proliferations showed the highest frequency of clonal immunoglobulin gene products. We concluded that PCR/ndPAGE analysis of Igκ is a sensitive, rapid, and efficient method for assessing clonality in conjunction with IgH and specific translocation analysis. This approach is particularly useful in the characterization of B-cell lymphoproliferative disorders in archival material with poor preservation of the genomic DNA. The characterization of immunoglobulin (Ig) gene rearrangement has become an important and crucial step in the diagnosis of B-cell lymphoid malignancies. The clonal rearrangements of Ig heavy chains (IgH) and Ig light chains (IgL) in B-cell disorders provide excellent markers for molecular analysis.1Korsmeyer SJ B-lymphoid neoplasms: immunoglobulin genes as molecular determinants of clonality, lineage, differentiation, and translocation.Adv Intern Med. 1988; 33: 1-15PubMed Google Scholar, 2Medeiros LJ Bagg A Cossman J Application of molecular genetics to the diagnosis of hematopoietic neoplasms.in: Knowles DM Williams and Wilkins, Baltimore1992: 263-298Google Scholar For the past 10 years, Southern blotting has been widely used to detect clonality.3van Dongen JJ Wolvers-Tettero IL Analysis of immunoglobulin and T cell receptor genes. Part II. Possibilities and limitations in the diagnosis and management of lymphoproliferative diseases and related disorders.Clin Chim Acta. 1991; 198: 93-174Crossref PubMed Scopus (186) Google Scholar, 4Arnold A Cossman J Bakhshi A Jaffe ES Waldmann TA Korsmeyer SJ Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms.N Engl J Med. 1983; 309: 1593-1599Crossref PubMed Scopus (493) Google Scholar, 5Beishuizen A Verhoeven MA Mol EJ van Dongen JJ Detection of immunoglobulin κ light-chain gene rearrangement patterns by Southern blot analysis.Leukemia. 1994; 8 (discussion 2237–2239): 2228-2236PubMed Google Scholar Recently, however, polymerase chain reaction (PCR) has gradually replaced this approach and has become increasingly accepted as the primary method for detecting Ig clonality.6Sioutos N Bagg A Michaud GY et al.Polymerase chain reaction versus Southern blot hybridization. Detection of immunoglobulin heavy-chain gene rearrangements.Diagn Mol Pathol. 1995; 4: 8-13Crossref PubMed Scopus (97) Google Scholar, 7Lehman CM Sarago C Nasim S Comerford J Karcher DS Garrett CT Comparison of PCR with Southern hybridization for the routine detection of immunoglobulin heavy chain gene rearrangements.Am J Clin Pathol. 1995; 103: 171-176Crossref PubMed Scopus (53) Google Scholar As compared to Southern blotting, PCR has the advantage of high sensitivity, low cost, fast turnaround time, and technical simplicity. Furthermore, because small DNA fragments are the targets of PCR, this approach has been successfully applied in the study of formalin-fixed and paraffin-embedded tissue samples. Even in severely damaged archival material, PCR can still detect fragments smaller than 200 bp and identify clonal Ig gene products.8Trainor KJ Brisco MJ Story CJ Morley AA Monoclonality in B-lymphoproliferative disorders detected at the DNA level.Blood. 1990; 75: 2220-2222PubMed Google Scholar, 9Inghirami G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar Several groups have established PCR-based methodologies for the detection of IgH rearrangement.9Inghirami G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar, 10Yamada M Hudson S Tournay O et al.Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementarity-determining region (CDR-III)-specific probes.Proc Natl Acad Sci USA. 1989; 86: 5123-5127Crossref PubMed Scopus (283) Google Scholar, 11Deane M Norton JD Detection of immunoglobulin gene rearrangement in B lymphoid malignancies by polymerase chain reaction gene amplification.Br J Haematol. 1990; 74: 251-256Crossref PubMed Scopus (104) Google Scholar, 12Trainor KJ Brisco MJ Wan JH Neoh S Grist S Morley AA Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction.Blood. 1991; 78: 192-196PubMed Google Scholar, 13Segal GH T for clonality by polymerase chain reaction analysis. B-cell lymphoproliferative disorders of cell Pathol. 1994; PubMed Scopus Google Scholar, GH T M for clonality by polymerase chain reaction analysis. II. Pathol. 1994; PubMed Scopus Google Scholar, A GH for clonality by polymerase chain reaction analysis. and B-cell Pathol. PubMed Scopus Google Scholar of the were designed using recognizing and fragments of regions of the IgH and to the joint However, using the sensitivity and and at of neoplasms To this have used heavy chain oligoprimers that either or framework regions of Ig heavy and light chains to the M Norton JD heavy chain region is of cell in human B lineage J 1990; PubMed Scopus Google Scholar, M Detection of clonal B cell in paraffin-embedded by polymerase chain J Pathol. 1993; Google Scholar However, this method has fragments and is in formalin-fixed and paraffin-embedded Furthermore, of oligoprimers and Detection of clonal immunoglobulin gene rearrangements by polymerase chain reaction amplification and J Pathol. 1993; Google Scholar, A et analysis of detection for of PCR immunoglobulin heavy-chain gene rearrangements.Diagn Mol Pathol. PubMed Scopus Google Scholar because of these technical this approach is for routine has been used to study κ light chain Ig and light chain Ig gene However, of these have been on a small of and the were for whether this approach can be applied in patterns of κ gene of in cell and 1994; Google Scholar, G A et for the detection of in non-Hodgkin's to formalin-fixed, paraffin-embedded tissue and Mol Med. 1995; PubMed Scopus Google Scholar, Detection of clonal light chain gene rearrangements in and paraffin-embedded by polymerase chain J Pathol. 1995; Google Scholar Igκ gene rearrangement analysis is a for the clonal of B-cell B-cell differentiation, the Igκ gene rearrangement the in κ chain products are the SJ Waldmann TA P of immunoglobulin gene rearrangements in human Natl Acad Sci USA. 78: PubMed Scopus Google Scholar, Korsmeyer SJ genes and are in and the human immunoglobulin light-chain Natl Acad Sci USA. 1989; 86: PubMed Scopus Google Scholar, GH Korsmeyer SJ et and T cell receptor gene configuration in of Google Scholar have that in and in a large of B-cell either or Igκ products are Finally, a small of B-cell neoplasms of the Igκ region or Igκ in configuration A Verhoeven MA Mol EJ van Dongen JJ Detection of immunoglobulin κ light-chain gene rearrangement patterns by Southern blot analysis.Leukemia. 1994; 8 (discussion 2237–2239): 2228-2236PubMed Google Scholar, The frequency of at the human Ig κ chain 1990; Google Scholar the genomic products of Igκ an excellent for B-cell clonal analysis. We have designed and Ig κ light chain joint region that the region 3 of Igκ This of degenerate oligoprimers be to the large of Ig κ light chain region the of the κ gene. products from to using a the and patterns are The of Igκ analysis to the IgH and specific translocation the detection of than of mature B-cell neoplasms. A of of lymphomas and large cell lymphomas B-cell lymphomas marginal B-cell lymphomas and marginal B-cell large cell lymphomas B-cell leukemias 18 reactive lymphoid proliferations and 58 atypical lymphoid proliferations were in this of the were cases in the of the from to in the of of or in the of of were using and in with the Jaffe ES et of lymphoid neoplasms: a from the 1994; Google Scholar cases in and/or a a and a reactive The were to the cell or or to or cell was cases in the amplification of gene was were were used as a Several B- and or cell and cell were used as and The cell and cell G Knowles DM of by in human B 1990; PubMed Scopus Google large cell cell a from and cell with t(11:14) and were used as for and gene rearrangement DNA was from cell tissue or formalin-fixed and paraffin-embedded archival tissue The tissue were in the and in the of 200 of as G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar The was for 10 were at were and DNA was selected DNA was with and For DNA from archival formalin-fixed, paraffin-embedded to tissue were and in were with and with were as for tissue samples. 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Google Scholar, T van M Wolvers-Tettero IL van Dongen JJ PCR analysis of T cell receptor genes for clonality in T cell PubMed Scopus Google Scholar a of and of the PCR the DNA of products and a This is of a and as a on the the and of a with a of The the of DNA, and this as a on has compared with the To investigate the sensitivity of PCR/ndPAGE in detecting clonal Igκ genomic from of a with B-cell B were with the genomic DNA of a reactive A large of B in the and with T the of the reactive B B-cell clonal chain Ig gene rearrangement products were investigated using genomic DNA in the of specific recognizing the human IgH region or and joint region or G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar were in the of A or B as with The was with and to of 3 at by of at at or and at by a of at PCR products were on or by the detection of PCR fragments of bp or bp for and The of clonal IgH cases showed a with a This of oligoprimers was to successfully the products from the rearrangements of A was as a and was as The of the t(11:14) and was studied by PCR as CT et and polymerase chain reaction amplification of cell 1994; Google Scholar, M M Korsmeyer SJ DNA polymerase chain amplification of and detection of minimal Natl Acad Sci USA. 1988; PubMed Scopus Google Scholar The t(11:14) or products were of because of the translocation from bp and bp for and amplification was used as a to whether the DNA was for PCR analysis. The gene amplification of 8 and is bp than IgH or Igκ is to the of genomic DNA The genomic region was using and G P et in human lymphoid with and Natl Acad Sci USA. 1991; PubMed Scopus Google Scholar, P G et in non-Hodgkin's 1993; Google Scholar To the of detecting clonal immunoglobulin gene rearrangements in DNA an additional 18 B-cell neoplasms of with gene amplification were selected and to the of IgH IgH and Igκ of the of genomic DNA from B or reactive reactive and were as and a were as a to a analysis was to an of a G P et in human lymphoid with and Natl Acad Sci USA. 1991; PubMed Scopus Google Scholar were with of genomic DNA, 10 of and of 10 and in a of 10 of and were on an of reaction products was with an of the of and 10 and a gel the were and as G P et in human lymphoid with and Natl Acad Sci USA. 1991; PubMed Scopus Google Scholar Ig gene rearrangement analysis using PCR has become a in the characterization of human lymphoproliferative This approach is using recognizing a region of the that the amplification of small genomic fragments is in material and the analysis of is of Ig gene rearrangement we designed a of recognizing the region of of the Ig κ and the κ joint region of the small of the Igκ the of regions of these and small of of these gene the of κ is than that in the of of patterns of κ gene of in cell and 1994; Google Scholar, C of of of Scholar, P M κ gene rearrangement in lymphoproliferative an analysis of κ gene and 1994; Google Scholar routine gel clonal products and small and of as a the the products are by the and clonal products are The as a at than products. products are by a from to bp To the of clonal products using selected cases were characterized by analysis showed and this approach in the of mature B-cell Igκ clonal products could be detected in of the cases The highest was in and B-cell and The frequency of Igκ rearrangement was in This low frequency is to the of rearrangements in the of B-cell SJ Waldmann TA P of immunoglobulin gene rearrangements in human Natl Acad Sci USA. 78: PubMed Scopus Google Scholar Finally, Igκ was detected in of atypical B-cell clonal were in reactive Detection of Gene and in cases that at clonal gene rearrangement using Ig or B-cell neoplasms B-cell frequency of cases that at clonal gene rearrangement using Ig or in a frequency of The sensitivity of PCR/ndPAGE in detecting clonal Igκ rearrangement was analyzed by the gel a PCR could be in to of the DNA cases were by PCR analysis for clonality in the IgH the t(11:14) and translocation products of and were analyzed of oligoprimers the IgH and we detected clonality in 66% of mature B-cell neoplasms detected cases (50%) than of the highest of clonality was in and for and and in and for and study in mature B-cell neoplasms, the of Igκ and IgH rearrangement analysis the to as compared to IgH PCR using this PCR we have detected the highest of clonality, among mature B-cell neoplasms, in and routine molecular the of DNA is to and paraffin-embedded these tissue poor preservation of the genomic DNA and the amplification of large DNA fragments is To investigate whether PCR products the characterization of a of 18 archival of B-cell neoplasms, showed amplification of the gene were analyzed by IgH and Igκ cases showed Igκ and cases showed IgH showed amplification of IgH products. 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PubMed Scopus Google Scholar The high of of the region of Igκ is an for of and patterns of κ gene of in cell and 1994; Google Scholar, P M κ gene rearrangement in lymphoproliferative an analysis of κ gene and 1994; Google Scholar we designed a of degenerate oligoprimers the κ This has the advantage of a and is a and approach in As compared to the IgH Igκ a region in in κ than the heavy chain To the of the in detecting Igκ clonality, we used nondenaturing polyacrylamide gel to the FR3Jκ products. This approach the of a of DNA compared with high gel has the advantage of small of and the in is to the patterns of that used a gel M C Jaffe ES Analysis of T cell gene rearrangements by gel of polymerase chain reaction products. with J Pathol. 1995; Google Scholar, M B Analysis of receptor genes by polymerase chain reaction (PCR) DNA and high PCR 1995; 86: Google Scholar et E B J and gel as for the detection of in T cell receptor 1995; PubMed Scopus Google Scholar gene rearrangement by and that compared to was a and with high is excellent in the of FR3Jκ and products. PCR-based have been to light chain immunoglobulin gene rearrangements in and using either genomic G A et for the detection of in non-Hodgkin's to formalin-fixed, paraffin-embedded tissue and Mol Med. 1995; PubMed Scopus Google Scholar, Detection of clonal light chain gene rearrangements in and paraffin-embedded by polymerase chain J Pathol. 1995; Google Scholar or JD M A G for polymerase chain reaction amplification of human immunoglobulin genes and of J 1991; PubMed Scopus Google Scholar, et and of immunoglobulin κ light chains in with and in Clin Invest. 1995; PubMed Scopus Google Scholar, M P et PCR for amplification of human heavy and light chain immunoglobulin region 1995; PubMed Scopus Google Scholar, C T et immunoglobulin κ light chains are by the to a than heavy J Haematol. PubMed Scopus Google Scholar as and κ or in conjunction with or these the amplification of the products. However, oligoprimers to of the a routine in the be the of clonal light chain using be in cases in the a compared to the B-cell can in this the of oligoprimers and DNA be applied as in the of heavy chain Ig and receptor gene rearrangement B C M of DNA polymerase the PCR detection of immunoglobulin heavy chain 1995; Google Scholar, B A et high PCR analysis for of immunoglobulin heavy chain PubMed Scopus Google Scholar, M B Analysis of receptor genes by polymerase chain reaction (PCR) DNA and high PCR 1995; 86: Google Scholar, et lymphomas of and Google Scholar because the regions of light chain Ig are oligoprimers the region be and the of clonal B-cell The from et S J N of a B cell clonality analysis using of immunoglobulin light chain J Pathol. PubMed Scopus Google Scholar and the in this study that this approach can be in the analysis of clonal B-cell either Ig light S J N of a B cell clonality analysis using of immunoglobulin light chain J Pathol. PubMed Scopus Google Scholar or gene rearrangement products are We have studied a of B-cell lymphoproliferative by using Igκ and IgH 137 cases of mature B-cell using Igκ cases showed clonality, and of 18 cases of reactive B-cell proliferations the analysis of the clonal B-cell lymphoproliferative disorders by Igκ a of cases to that by IgH by combining the methods, the in of mature B-cell malignancies from 66% to 85%. the analysis IgH we to by showed a in IgH than G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar, GH CT of B-cell by polymerase chain A method for the detection of immunoglobulin gene rearrangements.Am J Pathol. Google Scholar, A A M et of polymerase chain reaction in the diagnosis of of B-cell lymphoid Mol Pathol. 1995; 4: PubMed Scopus Google Scholar As in the B-cell the of Igκ is This is to the lineage of the SJ Waldmann TA P of immunoglobulin gene rearrangements in human Natl Acad Sci USA. 78: PubMed Scopus Google Scholar, GH Korsmeyer SJ et and T cell receptor gene configuration in of Google Scholar this attempts have been made to the of detection of clonal B-cell lymphoproliferative the of and oligoprimers has the of clonal B-cell products in a of a of oligoprimers has been B C M of DNA polymerase the PCR detection of immunoglobulin heavy chain 1995; Google Scholar, B A et high PCR analysis for of immunoglobulin heavy chain PubMed Scopus Google Scholar the the of and a JH be for the sensitivity in that are from the analysis of analyzed cases were investigated on a molecular because a diagnosis could be by routine to small of with a large of The that cases were used in this study the sensitivity of oligoprimers However, we that these are of a The sensitivity of the Igκ was studied by a DNA We used tissue as a in is an and is to genomic DNA of G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar The cell of large of B as as T This the cell of this clonal Igκ can be detected in to of a sensitivity or to that of the This high sensitivity be to the that FR3Jκ products were characterized by the of the PCR as the primary method in gene rearrangement have been made of formalin-fixed and paraffin-embedded archival of these a frequency of in and archival by using PCR amplification fragments than 200 can be in by using a PCR G Szabolcs MJ Yee HT Corradini P Cesarman E Knowles DM Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin's lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction.Lab Invest. 1993; 68: 746-757PubMed Google Scholar, M Detection of clonal B cell in paraffin-embedded by polymerase chain J Pathol. 1993; Google Scholar, G A et for the detection of in non-Hodgkin's to formalin-fixed, paraffin-embedded tissue and Mol Med. 1995; PubMed Scopus Google Scholar, JH KJ Brisco MJ Morley AA Monoclonality in B cell detected in using the polymerase chain Clin Pathol. 1990; PubMed Scopus Google Scholar We the of Igκ amplification on tissue of the cases were formalin-fixed and paraffin-embedded that showed severe breakdown of genomic DNA. this in 72% of cases amplification of Ig products was combining Igκ and IgH gene we were to detect clonality in of This is than that in however, the detection of a of B-cell neoplasms, tissue is have that for clonality by PCR be to the highest unique of be used as a GH T for clonality by polymerase chain reaction analysis. B-cell lymphoproliferative disorders of cell Pathol. 1994; PubMed Scopus Google Scholar or to A GH for clonality by polymerase chain reaction analysis. and B-cell Pathol. PubMed Scopus Google Scholar lymphoproliferative disorders and in GH T M for clonality by polymerase chain reaction analysis. II. Pathol. 1994; PubMed Scopus Google Scholar oligoprimers recognizing and be applied as a However, with the of a of a large of clonal cases and are on these and we a be to the analysis of cases be characterized using PCR, by and Finally, the cases be studied using and/or oligoprimers. this can be a this the of Southern blot analysis can be to the small of cases and to further of unique among B-cell lymphoproliferative disorders in region in B-cell lymphoproliferative disorders a and is This in are to these to a B-cell To of these we studied a large of atypical disorders using was detected in a large of these clonal atypical marginal cell proliferations were the of by atypical large cell proliferations The of was further studied by IgH and Igκ clonality in at of these showed the of the The of Ig gene rearrangement in atypical marginal and large cell proliferations the high of in the diagnosis of these and the of gene rearrangement However, clonal PCR products in atypical the of clonal B-cell and are these the and/or clonal of these an be G lymphoproliferative Knowles DM Williams and Wilkins, Baltimore1992: Scholar the we be a in a be this the a of the is at to these a particularly important in of the that can be in the the of the be the in the a be study that the unique approach of IgH and Igκ gene rearrangement along with a is a useful in the routine of B-cell a of to detect κ light chain rearrangement on is a sensitive, and method as an to IgH analysis. to the amplification products in FR3Jκ is an for formalin-fixed and paraffin-embedded material, is in routine We for excellent technical We for of the