Abstract
The identification and study of nonrandom recurrent chromosomal translocations has substantially increased our understanding of the non-Hodgkin lymphomas. Cytogenetic and molecular genetic data now form an integral part of current lymphoma classifications (1) and provide important information for diagnosis, tumor biology, and in some cases prognosis. The t(14;18)(q32;q21) abnormality is the most common translocation detected in B-lineage lymphoma and results in juxtaposition of the BCL-2 gene (18q21) and the JH locus of the immunoglobulin (Ig) heavy chain gene (14q32) (2–5). More specifically, in the North American population, alterations of the BCL-2 gene are detected in approx 75 to 85% of low-grade follicular lymphomas, 20–30% of aggressive large B-cell lymphomas, and rarely in other B-cell tumors (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia) (2,6–9). As a consequence of the BCL-2/JH fusion, deregulated overexpression of the antiapoptotic bcl-2 protein occurs owing to constitutive transcriptional activation of the BCL-2 gene by the Ig heavy chain gene enhancer. The unbridled expression of bcl-2 protein in lymphoid tumors confers resistance to programmed cell death (10,11) and is implicated in primary therapeutic failure and a less favorable prognosis (12–14). Although karyotypic detection of lymphoma-associated translocations such as the t(14;18) has proved to be useful in disease diagnosis and subcategorization, molecular genetic approaches including polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) have gained substantial popularity owing to their rapidity, relatively low cost, and increased sensitivity (6,15–22).
Keywords
- Polymerase Chain Reaction
- Polymerase Chain Reaction Product
- Chronic Lymphocytic Leukemia
- Follicular Lymphoma
- Minimal Residual Disease
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Harris, N. L., Jaffe, E. S., Stein, H., et al. (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84, 1361–1392.
Weiss, L. M., Warnke, R. A., Sklar, J., and Cleary, M. L. (1987) Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N. Engl. J.Med. 317, 1185.
Cleary, M. L. and Sklar, J. (1985) Nucleotide sequence of t(14;18) chromosomal translocation breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl. Acad. Sci. USA 82, 7439.
Bakhshi, A., Jensen, J. P., Goldman, P., Wright, J. J., McBride, O. W., Epstein, A. L., and Korsmeyer, S. J. (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899.
Tsujimoto, Y., Cossman, J., Jaffe, E., and Croce, C. M. (1985) Involvement of the bcl-2 gene in human follicular lymphomas. Science 228, 1440.
Horsman, D. E., Gascoyne, R. D., Coupland, R. W., Coldman, A. J., and Adomat, S. A. (1995) Comparison of cytogenetic analysis, Southern analysis, and poly-merase chain reaction for the detection of t(14; 18) in follicular lymphoma. Am. J. Clin. Pathol. 103, 472–478.
Yabumoto, K., Akasaka, T., Muramatsu, M., Kadowaki, N., Hayashi, T., Ohno, H., Fukuhara, S., and Okuma, M. (1996) Rearrangement of the’ 5 cluster region of the bcl-2 gene in lymphoid neoplasm: a summary of nine cases. Leukemia 10, 970–977.
Adachi, M., Cossman, J., Longo, D., Croce, C. M., and Tsujimoto, Y. (1989) Varian translocation of the bcl-2 gene to immunoglobulin light chain gene in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 86, 2771.
Kouides, P. A., Phatak, P. D., Wang, N., and Bennett, J. M. (1994) B-cell acute lymphoblastic leukemia with L1 morphology and coexistence of t(1;19) and t(14;18) chromosome translocations. Cancer Genet. Cytogenet. 78, 23–27.
Yang, E. and Korsmeyer, S. J. (1996) Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88, 386–401.
Hockenberry, D., Nunez, G., Milliman, C., Schreiber, R. D., and Korsmeyer, S. J. (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348,.
Gascoyne, R. D., Adomat, S. A., Krajewski, S., Krajewska, M., Horsman, D. E., Tolcher, A. W., O’Reilly, S. E., Hoskins, P., Coldman, A. J., Reed, J. C., and Connors, J. M.(1997) Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin’s lymphoma. Blood 90(1), 44-51.
Hill, M. E., MacLennan, K. A., Cunningham, D. C., et al. (1996) Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin’s lymphoma: a British National Lymphoma Investigation Study. Blood 88(3), 1046–1051.
Hermine, O., Haioun, C., Lepage, E., et al. (1996) Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’ s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 87(1), 265–272.
Liu, J., Johnson, R. M., and Traweek, S. T. (1993) Rearrangement of the BCL-2 gene in follicular lymphoma: detection by PCR in both fresh and fixed tissue samples. Diagn. Mol. Pathol. 2, 241–247.
Ladanyi, M. and Wang, S. (1992) Detection of rearrangements of the BCL2 major breakpoint region in follicular lymphomas: correlation of polymerase chain reaction results with southern blot analysis. Diagn. Mol. Pathol. 1, 31–35.
Shibata, D., Hu, E., Weiss, L. M., Brynes, R. K., and Nathwani, B. N. (1990) Detection of specific t(14;18) chromosomal translocations in fixed tissues. Hum. Pathol. 21, 199–203.
Pezella, F., Gatter, K. C., and Mason, D. Y. (1989) Detection of 14;18 chromosomal translocation in paraffinembedded lymphoma tissue. Lancet 1, 779,780.
Crescenzi, M., Seto, M., Herzig, G. P., et al. (1988) Thermostable DNA polymerase chain amplification of t(14; 18) chromosome breakpoints and detection of minimal residual disease. Proc. Natl. Acad. Sci. USA 85, 4869–4873.
Lee, M., Chang, K., Cabanillas, F., et al. (1987) Detection of minimal residual cells carrying the t(14; 18) by DNA sequence amplification. Science 230, 1350–1354.
Poetsch, M., Weber-Matthieson, K., Plendl, J. J., Grote, W., and Schlegelberger, B. (1996) Detection of the t(14;18) chromosomal translocation by interphase cytogenetics with yeast-artificial-chromosome probes in follicular lymphoma and nonneoplastic lymphoproliferation. J. Clin. Oncol. 14, 963–969.
Taniwaki, M., Silverman, G. A., Nishida, K., Horike, S., Misawa, S., Shimazaki, C., Miura, I., Nagai, M., Abe, M., Fukuhara, S., and Kashima, K. (1995) Translo-cations and amplification of the BCL2 gene are detected in interphase nuclei of non-Hodgkin’s lymphoma by in situ hybridization with yeast artificial chromosome clones. Blood 86, 1481–1486.
Ngan, B., Nourse J., and Cleary, M. L. (1989) Detection of chromosomal translocation t(14;18) within the minor cluster region of bcl-2 by polymerase chain reaction and direct genomic sequencing of the enzymatically amplified DNA in follicular lymphomas. Blood 73, 1759–1762.
Cleary, M. L., Galili, N., and Sklar, J. (1986) Detection of a second t(14;18) breakpoint cluster region in follicular lymphomas. J. Exp. Med. 164, 315.
Dyer, M. J. S., Zani, V. J, Lu, W. Z., et al. (1994) BCL2 Translocations in leuke-mias of mature B cells. Blood 83, 3682–3688.
Adachi, M., Tefferi, A., Greipp, P. R., Kipps, T. J., and Tsujimoto, Y. (1990) Preferential linkage of BCL-2 to immunoglobulin light chain gene in chronic lym-phocytic leukemia. J. Exp. Med. 171, 559.
Segal, G. H., Jorgensen, T., Scott, M., and Braylan, R. C. (1994) Optimal primer selection for clonality assessment by polymerase chain reaction analysis: II. Follicular lymphomas. Hum. Pathol. 25, 1276–1282.
Akasaka, T., Akasaka, H., Yonetani, N., Ohno, H., Yamabe, H., Fukuhara, S., and Okuma, M. (1998) Refinement of the BCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets. Genes Chromosomes Cancer 21, 17–29.
Pezzella, F., Ralfkiaer, E., Gatter, K. C., and Mason, D. Y. (1990) The 14;18 translocation in European cases of follicular lymphoma: comparison of Southern blotting and the polymerase chain reaction. Br. J. Haematol. 76, 58.
Lopez-Guillermo, A., Cabanillas, F., McLaughlin, P., et al. (1998) The clinical significance of molecular response in indolent follicular lymphomas. Blood 91, 2955–2960.
Corradini, P., Astolfi, M., Cherasco, C., Ladetto, M., Voena, C., Caracciolo, D., Pileri, A., and Tarella, C. (1997) Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin’s lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting. Blood 89, 724–731.
Freedman, A. S., Gribben, J. G., Neuberg, D., et al. (1996) High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 88, 2780–2786.
Gribben, J. G., Neuberg, D., Freedman, A. S., et al. (1993) Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantion for B-cell lymphoma. Blood 81, 3449–3457.
Gribben, J. G., Saprito, L., Barber, M., Blake, K. W., Edwards, R. M., Griffin, J. D., Freedman, A. S., and Nadler, L. M. (1992) Bone marrows of non-Hodgkin’s lymphoma patients with a bcl-2 translocation can be purged of polymerase chain reaction-detectable lymphoma cells using monoclonal antibodies and immunomagnetic bead depletion. Blood 80, 1083–1089.
Luthra, R., McBride, J. A., Cabanillas, F., and Sarris, A. (1998) Novel’ 5 exonu-clease-based real-time PCR assay for the detection of t(14;18)(q32;q21) in patients with follicular lymphoma. Am. J. Pathol. 153, 63–68.
Heid, C. A., Stevens, J., Kivak, K. J., and Williams, P. M. (1996) Real time quantitative PCR. Genome Res. 6, 986–994.
Rauzy, O., Galoin, S., Chale, J. J., Adoue, D., Albarede, J. L., Delsol, G., and al Saati, T. (1998) Detection of t(14;18) carrying cells in bone marrow and peripheral blood from patients affected by non-lymphoid diseases. Mol. Pathol. 51, 333–338.
Dolken, G., Illerhaus, G., Hirt, C., and Mertelsmann, R. (1996) BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with non-malignant diseases. J. Clin. Oncol. 14, 1333–1344.
Limpens, J., Stad, R., Vos, C., de Vlaam, C., de Jong, D., van Ommen, G. B., Schuuring, E., and Kluin, P. M. (1995) Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 85, 2528–2536.
Corbally, N., Grogan, L., Keane, M. M., Devaney, D. M., Dervan, P. A., and Carney, D. N. (1994) Bcl-2 rearrangement in Hodgkin’s disease and reactive lymph nodes. Am. J. Clin. Pathol. 101, 756–760.
Aster, J. C., Kobayashi, Y., Shiota, M., Mori, S., and Sklar, J. (1992) Detection of the t(14;18) at similar frequencies in hyperplastic lymphoid tissues from American and Japanese patients. Am. J. Pathol. 141, 291–299.
Limpens, J., de Jong, D., van Krieken, J. H., Price, C. G., Young, B. D., van Ommen, G. J., and Kluin, P. M. (1991) Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene 6, 2271–2276.
Segal, G. H., Scott, M., Jorgensen, T., and Braylan, R. C. (1994) Standard polymerase chain reaction analysis does not detect t(14;18) in reactive lymphoid hyperplasia. Arch. Pathol. Lab. Med. 118, 791–794.
Berinstein, N. L, Reis, M. D., Ngan, B. Y., Sawka, C. A., Jamal, H. H., and Kuzniar, B. (1993) Detection of occult lymphoma in the peripheral blood and bone marrow of patients with untreated early-stage and advanced-stage follicular lymphoma. J. Clin. Oncol. 11, 1344–1352.
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Viswanatha, D.S. (2001). Detection of t(14; 18)(q32;q21)-Associated BCL-2/JH Gene Fusion in Non-Hodgkin Lymphoma. In: Killeen, A.A. (eds) Molecular Pathology Protocols. Methods in Molecular Medicine™, vol 49. Humana Press. https://doi.org/10.1385/1-59259-081-0:147
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DOI: https://doi.org/10.1385/1-59259-081-0:147
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