IGK

Gene Summary

Gene:IGK; immunoglobulin kappa locus
Aliases: IGK@
Location:2p11.2
Summary:-
Databases:HGNC, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 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.

  • Immunoglobulins
  • T-Lymphocyte Gene Rearrangement
  • Immunoglobulin Light Chains
  • Trisomy
  • Gene Rearrangement, B-Lymphocyte
  • Stromal Cells
  • B-Lymphocytes
  • B-Cell Lymphoma
  • FISH
  • MALT Lymphoma
  • Genes, Immunoglobulin
  • Acute Lymphocytic Leukaemia
  • Adolescents
  • RTPCR
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Skin Cancer
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Residual Disease
  • Infant
  • Ovarian Cancer
  • Twins, Monozygotic
  • Multiple Myeloma
  • Genetic Recombination
  • Childhood Cancer
  • Immunoglobulin kappa-Chains
  • Recurrence
  • Acute Myeloid Leukaemia
  • Clone Cells
  • Immunophenotyping
  • Reproducibility of Results
  • Chromosome 2
  • Immunohistochemistry
  • myc Genes
  • Translocation
  • Gene Rearrangement
  • Mutation
  • Polymerase Chain Reaction
  • Immunoglobulin Heavy Chains
  • Restriction Mapping
  • T-Cell Antigen Receptors
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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)

Yang CR, Hu YC, Zhou XG, Zhang D
[Clinicopathological features of follicular lymphoma in children].
Zhonghua Bing Li Xue Za Zhi. 2019; 48(2):132-136 [PubMed] Related Publications

Theunissen PMJ, de Bie M, van Zessen D, et al.
Next-generation antigen receptor sequencing of paired diagnosis and relapse samples of B-cell acute lymphoblastic leukemia: Clonal evolution and implications for minimal residual disease target selection.
Leuk Res. 2019; 76:98-104 [PubMed] Related Publications
Antigen receptor gene rearrangements are frequently applied as molecular targets for detection of minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukemia patients. Since such targets may be lost at relapse, appropriate selection of antigen receptor genes as MRD-PCR target is critical. Recently, next-generation sequencing (NGS) - much more sensitive and quantitative than classical PCR-heteroduplex approaches - has been introduced for identification of MRD-PCR targets. We evaluated 42 paired diagnosis-relapse samples by NGS (IGH, IGK, TRG, TRD, and TRB) to evaluate clonal evolution patterns and to design an algorithm for selection of antigen receptor gene rearrangements most likely to remain stable at relapse. Overall, only 393 out of 1446 (27%) clonal rearrangements were stable between diagnosis and relapse. If only index clones with a frequency >5% at diagnosis were taken into account, this number increased to 65%; including only index clones with an absolute read count >10,000, indicating truly major clones, further increased the stability to 84%. Over 90% of index clones at relapse were also present as index clone at diagnosis. Our data provide detailed information about the stability of antigen receptor gene rearrangements, based on which we propose an algorithm for selecting stable MRD-PCR targets, successful in >97% of patients.

Xu L, Song JC, Sun XH, et al.
Richter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia: A case report and literature review.
Medicine (Baltimore). 2018; 97(41):e12701 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Central nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.
PATIENT CONCERNS: A 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans' classification. The patient's leukocyte count was 12.1 × 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone.
DIAGNOSES: RS of the CNS diagnosed concurrently with CLL.
INTERVENTIONS: The patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone).
OUTCOMES: The patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms.
LESSONS: The survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes.

Yang LH, Ingersoll K, Zhao Y, et al.
CD3-positive diffuse large B-cell lymphoma relapses as CD3-negative large B-cell lymphoma: Loss of aberrant antigen expression in B-cell lymphoma after chemotherapy.
Pathol Res Pract. 2018; 214(10):1738-1744 [PubMed] Related Publications
Aberrant expression of CD3 on diffuse large B-cell lymphoma (DLBCL) is rare, and its mechanism and biological significance are currently unclear. Herein we report a case of Epstein-Barr virus-negative, CD3-positive DLBCL in a 53 year-old male, who had a remote history of renal transplantation. After standard chemotherapy, the patient was in clinical remission. He relapsed three years later, but at this time with apparent loss of CD3 expression. PCR-based IGK gene rearrangement studies demonstrated clonal amplicons with an identical nucleotide size between the primary and secondary DLBCL, confirming the clonal relationship despite their phenotypic differences. To our knowledge, this is the first case of CD3-positive DLBCL that demonstrated a loss of aberrant CD3 on relapse. The chronologic change in phenotype seen in this case suggests that the source of the patient's lymphoma relapse may arise from either a quiescent subclone without CD3 expression, or from an upstream neoplastic precursor cell.

Zhang Y, Yu D, Huang K, et al.
Evaluation of the diagnostic value of immunoglobulin clonal gene rearrangements in patients with parotid gland MALT lymphoma using BIOMED-2 protocol.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 126(2):165-173 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to evaluate the diagnostic value of immunoglobulin (Ig) clonal gene rearrangements for mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland.
STUDY DESIGN: We collected and retrospectively analyzed clinical data of 21 patients referred to our institution between 2009 and 2017. Eight patients had been primarily diagnosed MALT lymphoma of the parotid gland and the remaining patients with lymphoepithelial lesion. Paraffin-embedded tissues were chosen for extracting genomic DNA and multiplex primer polymerase chain reaction amplification by using BIOMED-2 primers. Polymerase chain reaction amplification products were analyzed by heteroduplex analysis.
RESULTS: Generally, 17 patients were identified to have parotid gland MALT lymphoma; 47.06% of them had Sjögren syndrome. The sensitivity of IGH VH-J
CONCLUSIONS: Ig clonal gene rearrangements assays using BIOMED-2 protocol can be a highly reliable diagnostic method for parotid gland MALT lymphoma. For patients with Sjögren syndrome along with histologically benign lymphoepithelial lesion, identification of Ig clonal gene rearrangements is important for routine differential diagnosis.

Nakayama S, Oda T, Minabe S, et al.
Primary Nonsecretory Plasma Cell Leukemia With Multiple Chromosomal Abnormalities: A Case Report.
Arch Iran Med. 2018; 21(1):41-43 [PubMed] Related Publications
Primary nonsecretory plasma cell leukemia (PCL) is an extremely rare type of multiple myeloma. Here, we report a case of nonsecretory PCL with no previous history of multiple myeloma. The case exhibited extremely low levels of serum immunoglobulin and light chain, no detectable serum M-protein or free light chain restriction, no urine BJP, and no cytoplasmic light chain expression in flow cytometry. In fluorescence in situ hybridization, tumor cells exhibited fusion genes for IgH/BCL1 and IgH/cMyc, disappearance of the p53 signal, and a split signal for IgK(2p11), but no split signal for IgL (22q11). Therefore, we diagnosed primary nonsecretory PCL with multiple chromosomal abnormalities.

Han S, Masaki A, Sakamoto Y, et al.
Improved clonality detection in Hodgkin lymphoma using a semi-nested modification of the BIOMED-2 PCR assay for IGH and IGK rearrangements: A paraffin-embedded tissue study.
Pathol Int. 2018; 68(5):287-293 [PubMed] Related Publications
The BIOMED-2 PCR protocols targeting IGH and IGK genes may be useful for detecting clonality in Hodgkin lymphoma (HL). The clonality detection rates, however, have not been very high with these methods using paraffin-embedded tumor sections. We previously described the usefulness of the semi-nested BIOMED-2 IGH assay in B-cell malignancies. In this study, we devised a novel semi-nested BIOMED-2 IGK assay. Employing 58 cases of classical HL, we carried out the standard BIOMED-2, BIOMED-2 followed by BIOMED-2 re-amplification, and BIOMED-2 followed by semi-nested BIOMED-2, all targeting IGH and IGK, using paraffin-embedded tissues. In both IGH and IGK assays, semi-nested assays yielded significantly higher clonality detection rates than the standard assays and re-amplification assays. Clonality was detected in 13/58 (22.4%) classical HL cases using the standard IGH/IGK assays while it was detected in 38/58 (65.5%) cases using semi-nested IGH/IGK assays. The detection rates were not associated with the HL subtypes, CD30-positive cell density, CD20-positive cell density, or Epstein-Barr virus (EBV) positivity. In conclusion, tumor clonality was detected in nearly two-thirds of classical HL cases using semi-nested BIOMED-2 IGH/IGK assays using paraffin tumor sections. These semi-nested assays may be useful when the standard IGH/IGK assays fail to detect clonality in histopathologically suspected HLs.

Wei P, Zhang YL, Xie JL, et al.
[Clinicopathologic characteristics of Burkitt-like lymphoma with chromosome 11q aberration].
Zhonghua Bing Li Xue Za Zhi. 2018; 47(3):176-179 [PubMed] Related Publications

Jiang S, Zhang Q, Su Y, Pan L
Network-Based Differential Analysis to Identify Molecular Features of Tumorigenesis for Esophageal Squamous Carcinoma.
Molecules. 2018; 23(1) [PubMed] Free Access to Full Article Related Publications
Esophageal cancer has a poor prognosis and high mortality rate across the world. The diagnosis and treatment of esophageal cancer are hindered by the limited knowledge about the pathogenesis mechanisms of esophageal cancer. Esophageal cancer has two major subtypes, squamous and adenocarcinoma. In this work, we proposed a method to select candidate biomarkers of esophageal squamous carcinoma based on the topological differential analysis between the gene-gene interaction networks for esophageal squamous carcinoma and normal cells. We established the gene-gene interaction networks for esophageal squamous carcinoma and normal based on the correlation of genes. For each gene, we firstly calculated and compared five centrality measures, which could reflect the topological property of a network. According to five centrality measures, the genes with large differences between the two networks were regarded as candidate biomarkers for esophageal squamous carcinoma. A total of 21 candidate biomarkers were identified for esophageal squamous carcinoma, and seven of them have been confirmed to be biomarkers of esophageal-12 squamous carcinoma by previous research. In addition, six genes (

Comfere N, Sundram U, Hurley MY, Swick B
Views of dermatopathologists about clonality assays in the diagnosis of cutaneous T-cell and B-cell lymphoproliferative disorders.
J Cutan Pathol. 2018; 45(1):39-47 [PubMed] Related Publications
BACKGROUND: Appropriate use criteria have been developed for many tests using expert judgment, evidence-based practice and clinical experience. In this context, we report the opinions of practitioners about clonality assays in various clinical scenarios where cutaneous lymphoma is suspected.
METHODS: An Appropriate Use Criteria Task Force sponsored by the American Society of Dermatopathology (ASDP) synthesized clinical scenarios for cutaneous lymphoproliferative disorders (LPDs). We conducted, summarized and presented a relevant literature search to an audience of 144 dermatopathologists with a variety of practice experiences at the 53rd Annual Meeting of the ASDP in Chicago, IL.
RESULTS: Twenty-seven clinical scenarios for LPDs (13 T-cell and 14 B-cell) were defined. Forty relevant studies for T-cell receptor gene clonality assays and 20 relevant studies for IgH/IgK clonality assays were identified. Audience response data from participating dermatopathologists reflected a wide variety of approaches to the application of clonality assays in the evaluation of LPDs, based on practice setting, personal experience and test availability.
CONCLUSIONS: Our clinical scenario analysis and literature review revealed well-supported clinical scenarios and identified opportunities for additional research to further define the utility of clonality assays in some clinical scenarios.

Ulvé R, Rault M, Bahin M, et al.
Discovery of Human-Similar Gene Fusions in Canine Cancers.
Cancer Res. 2017; 77(21):5721-5727 [PubMed] Related Publications
Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts:

Theunissen PMJ, van Zessen D, Stubbs AP, et al.
Antigen receptor sequencing of paired bone marrow samples shows homogeneous distribution of acute lymphoblastic leukemia subclones.
Haematologica. 2017; 102(11):1869-1877 [PubMed] Free Access to Full Article Related Publications
In B-cell precursor acute lymphoblastic leukemia, the initial leukemic cells share the same antigen receptor gene rearrangements. However, due to ongoing rearrangement processes, leukemic cells with different gene rearrangement patterns can develop, resulting in subclone formation. We studied leukemic subclones and their distribution in the bone marrow and peripheral blood at diagnosis. Antigen receptor gene rearrangements (IGH, IGK, TRG, TRD, TRB) were analyzed by next-generation sequencing in seven paired bone marrow samples and five paired bone marrow-peripheral blood samples. Background-thresholds were defined, which enabled identification of leukemic gene rearrangements down to very low levels. Paired bone marrow analysis showed oligoclonality in all 7 patients and up to 34 leukemic clones per patient. Additional analysis of evolutionary-related IGH gene rearrangements revealed up to 171 leukemic clones per patient. Interestingly, overall 86% of all leukemic gene rearrangements, including small subclones, were present in both bone marrow samples (range per patient: 72-100%). Paired bone marrow-peripheral blood analysis showed that 83% of all leukemic gene rearrangements in bone marrow were also found in peripheral blood (range per patient: 81-100%). Remarkably, in the paired bone marrow samples and paired bone marrow-peripheral blood samples the vast majority of leukemic gene rearrangements had a similar frequency (<5-fold frequency difference) (96% and 96% of leukemic rearrangements, respectively). Together, these results indicate that B-cell precursor acute lymphoblastic leukemia is generally highly oligoclonal. Nevertheless, the vast majority of leukemic clones, even the minor antigen receptor-defined subclones, are homogeneously distributed throughout the bone marrow and peripheral blood compartment.

Aukema SM, van Pel R, Nagel I, et al.
MYC expression and translocation analyses in low-grade and transformed follicular lymphoma.
Histopathology. 2017; 71(6):960-971 [PubMed] Related Publications
AIMS: Low-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of ≈3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.
METHODS AND RESULTS: We quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed ≥90% MYC expression), suggesting alternative mechanisms of MYC activation.
CONCLUSIONS: we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ≈40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.

Zhang Y, Xu N, Dong BJ, et al.
[Diagnostic Significance of BIOMED-2 Standardized Gene Rearran-gement System in Patients with Non-Hodgkin's Lymphoma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017; 25(1):115-119 [PubMed] Related Publications
OBJECTIVE: To detect the immunoglobulin(Ig) and T cell receptor(TCR) gene rearrangement in bone marrow of non-Hodgkin's lymphoma(NHL) patients by using BIOMED-2 standardized system, and to explore the potential clinical significance of Ig/TCR gene rearrangement.
METHODS: DNA was extracted in bone marrow and Formalin-fixed and Paraffin-embedded(FFPE) samples of NHL patients, the Ig/TCR gene rearrangements were analyzed by using BIOMED-2 multiple primers system and multiplex PCR assay.
RESULTS: Among 235 T-NHL cases, 71.9% showed TCR gene rearrangement. The positive rate of TCRγ and the TCRβ were 57.9% and 50.2%. Out of 583 B-NHL cases, 81.6% showed Ig gene rearrangement. The positive rate of IgH and the IgK were 70.7% and 69.3%. MCL patients showed 84.8% IgH rearrangement and 75.8% IgK rearrangement, as compared with FL(34.0%, 50.9%) and DLBCL(9.2%, 16.1%) patients, the difference was statistically significant (P<0.05). Out of Ig rearrangement positive B-NHL cases, 65 showed TCR gene rearrangement. None TCR rearrangement positive T-NHL cases showed Ig gene rearrangement, 25 cases(83.3%) showed Ig gene rearrangement in FFPE samples of 30 DLBCL patients, as compared to Ig rearrangement positive rate of bone marrow, the difference was statistically significant (P<0.001).
CONCLUSION: BIOMED-2 standardized Ig/TCR gene rearrangement system shows assistance for lymphoma diagnosis. The PCR sequencing analysis is much more sensitive and specific and has significance for clinical diagnosis.

Besbes S, Hamadou WS, Boulland ML, et al.
Minimal residual disease detection in Tunisian B-acute lymphoblastic leukemia based on immunoglobulin gene rearrangements.
Braz J Med Biol Res. 2017; 50(1):e5426 [PubMed] Free Access to Full Article Related Publications
IGH gene rearrangement and IGK-Kde gene deletion can be used as molecular markers for the assessment of B lineage acute lymphoblastic leukemia (B-ALL). Minimal residual disease detected based on those markers is currently the most reliable prognosis factor in B-ALL. The aim of this study was to use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde recombinations were mainly identified. These rearrangements were quantified to follow-up seven B-ALL after induction using patient-specific ASO. Four patients had an undetectable level of MRD with a sensitivity of up to 10-5. This molecular approach allowed identification of prognosis risk group and adequate therapeutic decision. The IGK-Kde and IGH gene rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced for the first time in Tunisian laboratories.

Besbes S, Hamadou WS, Boulland ML, et al.
Combined IKZF1 and IG markers as new tools for diagnosis and minimal residual disease assessment in Tunisian B-ALL.
Bull Cancer. 2016; 103(10):822-828 [PubMed] Related Publications
INTRODUCTION: The monitoring of minimal residual disease (MRD) approach in patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) allows an early detection of residual clones inducing relapses and therefore appropriate therapy strategy. The molecular markers may identify and quantify the residual blasts in B-ALL with normal cytology. In this study, we aimed to use combined IKZF1, IGH and IGK immunoglobulin genes for diagnosis and MRD monitoring in B-ALL sample using MLPA, multiplex PCR and real-time quantitative PCR.
MATERIAL: We showed that multiplex PCR and MLPA are necessary and complementary to detect IKZF1 deletions.
RESULTS: We have identified at the diagnosis clonal IGH rearrangement (VH3-JH5) and IKZF1 deletion (Δ4-7), which we have used it for MRD evaluation after induction chemotherapy. Despite the absence of chromosome abnormality, the patient may be classified in high-risk group with a relapse rate of residual blasts>10
CONCLUSION: The combined IKZF1 and immunoglobulin genes will be used as appropriate molecular tools for diagnosis and MRD assessment of B-lineage leukemias and introduced as a routine tests in Tunisian clinical laboratories. They will be useful to stratify patients into risk groups leading to better treatment strategy.

Zhao KX, Dai GZ, Zhu JF
Ascites as the initial characteristic manifestation in a patient with primary gastric CD8-positive diffuse large B-cell lymphoma.
Eur Rev Med Pharmacol Sci. 2016; 20(9):1707-11 [PubMed] Related Publications
CASE PRESENTATION: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and the most common type of non-Hodgkin's lymphomas, the stomach is the most common extranodal site. Gastric DLBCL is often characterized by epigastric pain and vomiting. We report a case of a 78-year-old female patient with gastric diffuse large B-cell lymphoma (DLBCL) with high CD8 level which was initially manifested with ascites of unknown origin. The patient was admitted with a chief complaint of abdominal distension and scanty urine over the last twenty days, while without anorexia and fatigue until 15 March. She had no history of viral hepatitis, tuberculosis, schistosomiasis.
RESULTS: Laboratory data revealed normal aminotransferases and bilirubin levels, but serum lactate dehydrogenase, CA125, ascitic fluid lactate dehydrogenase, ascitic fluid lymphocytes increased. The ascitic fluid was yellow-colored with 98.5% lymphocytes. Stool occult blood test was positive. Upper gastrointestinal endoscopy performed a few days later revealed multiple gastric crateriform ulcers, and Helicobacter pylori was detected in the biopsy specimen. Peripheral blood CD8+ was increased by 51%. Pathology test showed lymphocytes with atypical hyperplasia, and immunohistochemistry test resulted CD20+, CD10-, CD79α+, κ+, bcl-6+, Ki-67+ (approximately 95%), λ-, bcl-2-, CD3-, CD43-. Immunoglobulin gene (Ig) clonal rearrangement showed IgH: FR1 (+), FR2 (+), FR3(-), Igk: VJ(+), Vkde (+) in lymphoma tissue.
CONCLUSIONS: The features of histopathology and immunohistochemistry of the tissue confirmed diffuse large B-cell lymphoma (DLBL). The patient received an uncompleted CHOP program combined with H. pylori eradication. However, the patient deceased due to disease development sixteen days later after the diagnosis.

Roepman P, Boots CM, Scheidel KC, et al.
Molecular clonality assessment shows high performance to predict malignant B-cell non-Hodgkin's lymphoma using cytological smears.
J Clin Pathol. 2016; 69(12):1109-1115 [PubMed] Related Publications
AIMS: Molecular PCR-based clonality analysis is helpful for identification of monoclonal B-cell or T-cell populations and to distinguish malignant lymphoma from reactive lymphoid hyperplasia. Typically, clonality assessment on fine-needle aspiration cytology (FNAC) requires freshly obtained aspirates, but the collection and processing of these samples are often challenging in daily practice. In this study, we assessed the routine diagnostic value of the EuroClonality/BIOMED-2 assay for B-cell clonality on air-dried archived Giemsa-stained smears.
METHODS: This study comprised a retrospective analysis of a consecutive diagnostic cohort of 192 FNAC samples from 184 patients with at least 2-year follow-up. The results from the clonality assay were integrated with cytomorphological assessment and evaluated for their accuracy in detecting malignant disease. EuroClonality expert re-evaluation was performed for all cases with ambiguous results and for cases in which the diagnosis did not match the follow-up data.
RESULTS: The clonality assay showed a high accuracy of 93% for detection of malignancy, with a sensitivity of 93% and a specificity of 92%. All 64 cases with monoclonal Ig heavy chain (IGH)/Ig kappa chain (IGK) rearrangements were confirmed malignant by histology or clinical follow-up. Expert re-evaluation changed the definite diagnosis for five cases (3%), mainly because of low signals or no proper duplicate results. We discuss and elucidate all cases for which the clonality results did not match the disease follow-up.
CONCLUSIONS: This study showed that EuroClonality/BIOMED-2 assay can successfully be performed on cytological Giemsa-stained smears and inclusion in daily practice can assist in better identification of malignant lymphoma.

Ai XF, Zhang Y, Shi XR, et al.
[Application of Combined Detection of Fusion Gene and BIOMED-2 Standardized Ig Gene Rearrangement System in Childhood B-cell Acute Lymphoblastic Leukemia].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(2):352-7 [PubMed] Related Publications
OBJECTIVE: To explore the application of combined detection of fusion gene and BIOMED-2 standardized immunoglobulin (Ig) gene rearrangement system in diagnosis and treatment of children with acute lymphoblastic leukemia (ALL).
METHODS: Multiplex-PCR amplifications and RQ-PCR of RNA/DNA were performed using ALL fusion gene detection kit and BIOMED-2 primer. The Ig gene rearrangements were analyzed by using PCR fragment analysis system.
RESULTS: Out of 251 children with B-ALL, 77 cases were TEL-AML1(+) , 28 cases were E2A-PBX1(+) , 10 cases were MLL-AF4(+) , 11 cases were BCR-ABL(+) , the total positive rate was 50.2%, 82.5% showed IgH VH-JH rearrangement, 53.4% showed IgK rearrangement. The positive rate of combined detection of fusion gene and gene rearrangement was 99%. E2A-PBX1(+) and MLL-AF4(+) with IgK(+) gene rearrangement group was compared with negative control group, the difference was statistically significant (P < 0.001 or P = 0.005); 105 ALL fusion gene positive cases had been detected by fluorescence in situ hybridization (FISH) simultaneously, the accordance rate of fusion gene and FISH was more than 94%.
CONCLUSION: The combined detection of ALL fusion gene and BIOMED-2 standardized clonality analysis system can improve the positive detected rate of B-ALL dramatically, and make the grouping of disease prognosis more accurately; this combined detection is a more faster and sensitive method than FISH.

Ferret Y, Caillault A, Sebda S, et al.
Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.
Br J Haematol. 2016; 173(3):413-20 [PubMed] Related Publications
High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients.

Szablewski V, Ingen-Housz-Oro S, Baia M, et al.
Primary Cutaneous Follicle Center Lymphomas Expressing BCL2 Protein Frequently Harbor BCL2 Gene Break and May Present 1p36 Deletion: A Study of 20 Cases.
Am J Surg Pathol. 2016; 40(1):127-36 [PubMed] Related Publications
The classification of cutaneous follicular lymphoma (CFL) into primary cutaneous follicle center lymphoma (PCFCL) or secondary cutaneous follicular lymphoma (SCFL) is challenging. SCFL is suspected when tumor cells express BCL2 protein, reflecting a BCL2 translocation. However, BCL2 expression is difficult to assess in CFLs because of numerous BCL2+ reactive T cells. To investigate these issues and to further characterize PCFCL, we studied a series of 25 CFLs without any extracutaneous disease at diagnosis, selected on the basis of BCL2 protein expression using 2 BCL2 antibodies (clones 124 and E17) and BOB1/BCL2 double immunostaining. All cases were studied using interphase fluorescence in situ hybridization with BCL2, BCL6, IGH, IGK, IGL breakapart, IGH-BCL2 fusion, and 1p36/1q25 dual-color probes. Nineteen CFLs were BCL2 positive, and 6 were negative. After a medium follow-up of 24 (6 to 96) months, 5 cases were reclassified as SCFL and were excluded from a part of our analyses. Among BCL2+ PCFCLs, 60% (9/15) demonstrated a BCL2 break. BCL2-break-positive cases had a tendency to occur in the head and neck and showed the classical phenotype of nodal follicular lymphoma (CD10+, BCL6+, BCL2+, STMN+) compared with BCL2-break-negative PCFCLs. Del 1p36 was observed in 1 PCFCL. No significant clinical differences were observed between BCL2+ or BCL2- PCFCL. In conclusion, we show that a subset of PCFCLs harbor similar genetic alterations, as observed in nodal follicular lymphomas, including BCL2 breaks and 1p36 deletion. As BCL2 protein expression is usually associated with the presence of a BCL2 translocation, fluorescence in situ hybridization should be performed to confirm this hypothesis.

Ai X, Wang X, Wang B, et al.
[Application of BIOMED- 2 standardized Ig gene rearrangement system in multiple myeloma].
Zhonghua Xue Ye Xue Za Zhi. 2015; 36(11):918-21 [PubMed] Related Publications
OBJECTIVE: To explore the application of BIOMED- 2 standardized immunoglobulin (Ig) gene rearrangement system in the diagnosis of multiple myeloma (MM), and the significance of clonality analysis by multiplex-PCR amplifications.
METHODS: A total of 167 cases of MM bone marrow samples from 2009 to 2013, and 20 cases of reactive plasmacytosis used as the controls were included in this study. Multiplex-PCR amplifications were performed and the Ig gene rearrangements were analyzed using BIOMED-2 standardized clonality analysis system.
RESULTS: ① Of 167 MM cases, 107 showed IgH VH-JH rearrangement, 33 showed IgH DH-JH rearrangement, and 30% showed IgH DH-JH rearrangement in 60 IgH VH-JH rearrangement negative MM cases. The difference was statistically significant between IgH VH-JH rearrangement positive and negative cases (14.0% vs 30.0%, P=0.032). The total positive rate of IgH VH-JH, IgH DH-JH and IgK was 94.6%. The 20 reactive plasmacytosis (RP) cases showed negative Ig gene rearrangement. 2 of 167 MM cases, 9 (5.4%) showed clonal IgH rearrangement by agarose electrophoresis were confirmed as polyclonality by capillary electrophoresis. ③ Of 53 MM cases who have been detected by Ig gene rearrangement system and fluorescence in situ hybridization (FISH) for IgH simultaneously, 36 showed IgH rearrangement, 26 showed FISH IgH positive, and the difference was statistically significant (67.9% vs 49.1%, P=0.049).
CONCLUSION: Combined detection of IgH VH- JH, IgH DH- JH and IgK could improve the positive rate of MM clonality dramatically, and measurement of IgH DH-JH rearrangement was more important in the IgH VH- JH negative cases. Ig gene rearrangement system was a faster and more sensitive method than FISH IgH. Application of BIOMED- 2 standardized immunoglobulin (Ig) gene rearrangement system is of significance for MM diagnosis.

Wang C, Xia M, Sun X, et al.
IGK with conserved IGΚV/IGΚJ repertoire is expressed in acute myeloid leukemia and promotes leukemic cell migration.
Oncotarget. 2015; 6(36):39062-72 [PubMed] Free Access to Full Article Related Publications
We have previously reported that immunoglobulin heavy chain genes were expressed in myeloblasts and mature myeloid cells. In this study, we further demonstrated that rearranged Ig κ light chain was also frequently expressed in acute myeloid leukemia cell lines (6/6), primary myeloblasts from patients with acute myeloid leukemia (17/18), and mature monocytes (11/12) and neutrophils (3/12) from patients with non-hematopoietic neoplasms, but not or only rarely expressed in mature neutrophils (0/8) or monocytes (1/8) from healthy individuals. Interestingly, myeloblasts and mature monocytes/neutrophils shared several restricted IGKV and IGKJ gene usages but with different expression frequency. Surprisingly, almost all of the acute myeloid leukemia-derived IGKV showed somatic hypermutation; in contrast, mature myeloid cells-derived IGKV rarely had somatic hypermutation. More importantly, although IGK expression appeared not to affect cell proliferation, reduced IGK expression led to a decrease in cell migration in acute myeloid leukemia cell lines HL-60 and NB4, whereas increased IGK expression promoted their motility. In summary, IGK is expressed in myeloblasts and mature myeloid cells from patients with non-hematopoietic neoplasms, and is involved in cell migration. These results suggest that myeloid cells-derived IgK may have a role in leukemogenesis and may serve as a novel tumor marker for monitoring minimal residual disease and developing target therapy.

Copie-Bergman C, Cuillière-Dartigues P, Baia M, et al.
MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study.
Blood. 2015; 126(22):2466-74 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499.

Ghorbian S, Jahanzad I, Javadi GR, Sakhinia E
Evaluation of IGK and IGL molecular gene rearrangements according to the BIOMED-2 protocols for clinical diagnosis of Hodgkin lymphoma.
Hematology. 2016; 21(3):133-7 [PubMed] Related Publications
BACKGROUND: Although the analysis of molecular clonality rearrangements of the immunoglobulin light chains (IGK and IGL) is an alternative approach for diagnosis of B cell non-Hodgkin lymphomas (NHLs) using BIOMED-2 protocols, NHLs have not been extensively confirmed for Hodgkin lymphoma (HL) cases. We evaluated BIOMED-2 protocols in HL cases, which have been suggested previously as gold standard method for molecular clonality analysis on formalin fixed, paraffin-embedded (FFPE) tissue in NHL patients.
METHODS: We recruited 50 consecutive FFPE tissues of HL samples to evaluate IGK and IGL clonality gene rearrangements using BIOMED-2 and Heteroduplex methods.
RESULTS: Our findings revealed a total of 94% (47/50) positive clonality, which consisted of 70% (35/50) for IGK and 44% (22/50) for IGL. In three cases, clonality was not detected in any of the immunoglobulin gene segments.
CONCLUSIONS: Analysis of clonality gene rearrangements in IGK and IGL genes using BIOMED-2 protocols could be implemented as a valuable method for improving clonality detection rate in HL cases and sensitivity (94%) and accuracy of HL diagnosis similar to that of the NHL samples will be increased.

Montesinos-Rongen M, Purschke FG, Brunn A, et al.
Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.
J Immunol. 2015; 195(3):1312-9 [PubMed] Related Publications
Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS.

Caltharp SA, Qayed M, Park SI
Atypical Marginal Zone Hyperplasia Is a Mimic for Lymphoma in Pediatric Transplant Recipients: Report of Two Patients.
Pediatr Dev Pathol. 2015 Sep-Oct; 18(5):416-21 [PubMed] Related Publications
Atypical marginal zone hyperplasia (AMZH) of mucosa-associated lymphoid tissue (MALT) closely resembles lymphoma in that it shows expansion of the marginal zones with prominent intraepithelial B lymphocytes, is immunoglobulin light-chain restricted, and may show aberrant CD43 expression. However, unlike lymphoma, it does not show rearrangement of the immunoglobulin heavy chain gene (immunoglobulin H [IgH]) by polymerase chain reaction (PCR), and it behaves in a benign fashion. We identified AMZH in 2 pediatric solid organ transplant recipients who presented with adenotonsillar hypertrophy. To date, the patients have experienced a self-limited course in the absence of treatment or reduction of immunosuppression. Atypical marginal zone hyperplasia is a pitfall for posttransplant lymphoproliferative disorder and MALT lymphoma in the pediatric solid organ transplant population. In transplant patients with a lambda-restricted B-cell clone and marginal zone hyperplasia in native MALT sites, PCR for IgH and IgK gene rearrangement is essential to prevent misdiagnosis.

Kokovic I, Jezersek Novakovic B, Novakovic S
Diagnostic value of immunoglobulin κ light chain gene rearrangement analysis in B-cell lymphomas.
Int J Oncol. 2015; 46(3):953-62 [PubMed] Free Access to Full Article Related Publications
Analysis of the immunoglobulin κ light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis.

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.

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