Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;10(1):73–84. doi: 10.1111/j.1750-3639.2000.tb00244.x

Characteristic Chromosomal Imbalances in Primary Central Nervous System Lymphomas of the Diffuse Large B‐Cell Type

Tillmann Weber 1,2, Ruthild G Weber 1,4, Kerstin Kaulich 3, Bertrand Actor 1, Birgit Meyer‐Puttlitz 3, Stefan Lampel 1, Rainer Büschges 3, Ralf Weigel 2, Martina Deckert‐Schlüter 3, Peter Schmiedek 2, Guido Reifenberger 3, Peter Lichter 1,✉
PMCID: PMC8098171  PMID: 10668897

Abstract

We performed a genome wide screening for genomic alterations on a series of 19 sporadic primary central nervous system lymphomas (PCNSL) of the diffuse large B‐cell type by comparative genomic hybridization (CGH). The tumors were additionally analyzed for amplification and rearrangement of the BCL2 gene at 18q21 as well as for mutation of the recently cloned BCL10 gene at 1p22. Eighteen tumors showed genomic imbalances on CGH analysis. On average, 2.1 losses and 4.7 gains were detected per tumor. The chromosome arm most frequently affected by losses of genomic material was 6q (47%) with a commonly deleted region mapping to 6q21‐q22. The most frequent gains involved chromosome arms 12q (63%), 18q and 22q (37% each), as well as 1q, 9q, 11q, 12p, 16p and 17q (26% each). High‐level amplifications were mapped to 9p23‐p24 (1 tumor) and to 18q21‐q23 (2 tumors). However, PCR‐based analysis, Southern blot analysis and high‐resolution matrix‐CGH of the BCL2 gene revealed neither evidence for amplification nor for genetic rearrangement. Mutational analysis of BCL10 in 16 PCNSL identified four distinct sequence polymorphisms but no mutation. Taken together, our data do not support a role of BCL2 rearrangement/ amplification and BCL10 mutation in PCNSL but indicate a number of novel chromosomal regions that likely carry yet unknown tumor suppressor genes or proto‐oncogenes involved in the pathogenesis of these tumors.

Full Text

The Full Text of this article is available as a PDF (232.4 KB).

References

  • 1. Antinori A, Larocca LM, Fassone L, Cattani P, Capello D, Cingolani A, Saglio G, Fadda G, Gaidano G, Ortona L (1999) HHV‐8/KSHV is not associated with AIDS‐related primary central nervous system lymphoma. Brain Pathol 9:199–208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Avet‐Loiseau H, Vigier M, Moreau A, Mellerin MP, Gaillard F, Harousseau JL, Bataille R, Milpied N (1997) Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas. Br J Haematol 97: 119–122. [DOI] [PubMed] [Google Scholar]
  • 3. Barth TF, Döhner H, Werner CA, Stilgenbauer S, Schlotter M, Pawlita M, Lichter P, Möller P, Bentz M (1998) Characteristic pattern of chromosomal gains and losses in primary large B‐cell lymphomas of the gastrointestinal tract. Blood 91: 4321–4330. [PubMed] [Google Scholar]
  • 4. Bentz M, Plesch A, Stilgenbauer S, Döhner H, Lichter P (1998) Minimal size of deletions detected by comparative genomic hybridization. Genes Chromosom Cancer 21: 172–175. [PubMed] [Google Scholar]
  • 5. Bentz M, Werner CA, Döhner H, Joos S, Barth TFE, Siebert R, Schröder M, Stilgenbauer S, Fischer K, Möller P, Lichter P (1996) High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma. Blood 88: 1437–1444. [PubMed] [Google Scholar]
  • 6. Chan WY, Wong N, Chan AB, Chow JH, Lee JC (1998) Consistent copy number gain in chromosome 12 in primary diffuse large cell lymphomas of the stomach. Am J Pathol 152: 11–16. [PMC free article] [PubMed] [Google Scholar]
  • 7. Cobbers JM, Wolter M, Reifenberger J, Ring GU, Jessen F, An HX, Niederacher D, Schmidt EE, Ichimura K, Floeth F, Kirsch L, Borchard F, Louis DN, Collins VP, Reifenberger G (1998) Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL. Brain Pathol 8: 263–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Corboy JR, Garl PJ, Kleinschmidt‐DeMasters BK (1998) Human herpesvirus 8 DNA in CNS lymphomas from patients with and without AIDS. Neurology 50: 335–340. [DOI] [PubMed] [Google Scholar]
  • 9. Cote TR, Manns A, Hardy CR, Yellin FJ, Hartge P (1996) Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group. J Natl Cancer Inst 88: 675–679. [DOI] [PubMed] [Google Scholar]
  • 10. DeAngelis LM (1991) Primary central nervous system lymphoma: a new clinical challenge. Neurology 41: 619–621. [DOI] [PubMed] [Google Scholar]
  • 11. Deckert‐Schluter M, Rang A, Wiestler OD (1998) Apoptosis and apoptosis‐related gene products in primary non‐Hodgkin's lymphoma of the central nervous system. Acta Neuropathol (Berl) 96: 157–162. [DOI] [PubMed] [Google Scholar]
  • 12. Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L, Dehaen M, Verhoef G, Thomas J, De Kelver W, Bakker‐Schut T, Cassiman JJ, Raap AK, De Wolf‐Peeters C, Van den Berghe H, Hagemeijer A (1997) Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 11: 747–758. [DOI] [PubMed] [Google Scholar]
  • 13. Du Manoir S, Schröck E, Bentz M, Speicher MR, Joos S, Ried T, Lichter P, Cremer T (1995) Quantitative analysis of comparative genomic hybridization. Cytometry 19: 27–41. [DOI] [PubMed] [Google Scholar]
  • 14. Du Manoir S, Speicher MR, Joos S, Schröck E, Popp S, Döhner H, Kovacs G, Robert‐Nicoud M, Lichter P, Cremer T (1993) Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum Genet 90: 590–610. [DOI] [PubMed] [Google Scholar]
  • 15. Eby NL, Grufferman S, Flannelly CM, Schold SCJ, Vogel FS, Burger PC (1988) Increasing incidence of primary brain lymphoma in the US. Cancer 62: 2461–2465. [DOI] [PubMed] [Google Scholar]
  • 16. Gaidano G, Capello D, Pastore C, Antinori A, Gloghini A, Carbone A, Larocca LM, Saglio G (1997) Analysis of human herpesvirus type 8 infection in AIDS‐related and AIDS‐unrelated primary central nervous system lymphoma. J Infect Dis 175: 1193–1197. [DOI] [PubMed] [Google Scholar]
  • 17. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf‐Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Müller‐Hermelink H‐K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA (1994) A revised European‐American classification of lymphoid neoplasms: A proposal from the international lymphoma study group. Blood 84: 1361–1392. [PubMed] [Google Scholar]
  • 18. Hatta Y, Yamada Y, Tomonaga M, Miyoshi I, Said JW, Koeffler HP (1999) Detailed deletion mapping of the long arm of chromosome 6 in adult T‐cell leukemia. Blood 93: 613‐. [PubMed] [Google Scholar]
  • 19. Ichimura K, Schmidt EE, Goike HM, Collins VP (1996) Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13: 1065–1072. [PubMed] [Google Scholar]
  • 20. Itoyama T, Sadamori N, Tsutsumi K, Tokunaga Y, Soda H, Tomonaga M, Yamamori S, Masuda Y, Oshima K, Kikuchi M (1994) Primary central nervous system lymphomas. Immunophenotypic, virologic, and cytogenetic findings of three patients without immune defects. Cancer 73: 455–463. [DOI] [PubMed] [Google Scholar]
  • 21. Jellinger KA, Paulus W (1995) Primary central nervous system lymphomas—new pathological developments. J Neurooncol 24: 33–36. [DOI] [PubMed] [Google Scholar]
  • 22. Joos S, Otano‐Joos MI, Ziegler S, Brüderlein S, du Manoir S, Bentz M, Möller P, Lichter P (1996) Primary mediastinal (thymic) B‐cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87: 1571–1578. [PubMed] [Google Scholar]
  • 23. Joos S, Scherthan H, Speicher MR, Schlegel J, Cremer T, Lichter P (1993) Detection of amplified genomic sequences by reverse chromosome painting using genomic tumor DNA as probe. Hum Genet 90: 584–589. [DOI] [PubMed] [Google Scholar]
  • 24. Kallioniemi A, Kallioniemi O‐P, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258: 818–821. [DOI] [PubMed] [Google Scholar]
  • 25. Kallioniemi O‐P, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW, Pinkel D (1994) Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosom. Cancer 10: 231–243. [DOI] [PubMed] [Google Scholar]
  • 26. Kramer MHH, Hermans E, Wijburg K, Philippo E, Geelen E, Van Krieken JHJM, De Jong D, Maartense E, Schuuring E, Kluin PM (1998) Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B‐cell lymphoma. Blood 9: 3152–3162. [PubMed] [Google Scholar]
  • 27. Kuukasjarvi T, Tanner M, Pennanen S, Karhu R, Kallioniemi O‐P, Isola J (1997) Genetic changes in intra‐ductal breast cancer detected by comparative genomic hybridization. Am J Pathol 150: 1465–1471. [PMC free article] [PubMed] [Google Scholar]
  • 28. Larocca LM, Capello D, Rinelli A, Nori S, Antinori A, Gloghini A, Cingolani A, Migliazza A, Saglio G, Cammilleri‐Broet S, Raphael M, Carbone A, Gaidano G (1998) The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center‐related B cells. Blood 92: 1011–1019. [PubMed] [Google Scholar]
  • 29. Levine EG, Arthur DC, Machnicki J, Frizzera G, Hurd D, Peterson B, Gajl‐Peczalska KJ, Bloomfield C (1989) Four new recurring translocations in non‐Hodgkin lymphoma. Blood 74: 1796–1800. [PubMed] [Google Scholar]
  • 30. Lichter P, Bentz M, Joos S (1995) Detection of chromosomal aberrations by means of molecular cytogenetics: Painting of chromosomes and chromosomal subregions and comparative genomic hybridization. Methods Enzym 254: 334–359. [DOI] [PubMed] [Google Scholar]
  • 31. Liu J, Johnson RM, Traweek ST (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. [PubMed] [Google Scholar]
  • 32. Merup M, Moreno TC, Heyman M, Ronnberg K, Grander D, Detlofsson R, Rasool O, Liu Y, Soderhall S, Juliusson G, Gahrton G, Einhorn S (1998) 6q deletions in acute lymphoblastic leukemia and non‐Hodgkin's lymphomas. Blood 91: 3397–3400. [PubMed] [Google Scholar]
  • 33. Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H (1994) Pathology with clinical correlations of primary central nervous system non‐Hodgkin's lymphoma. The Massachusetts General Hospital experience 1958–1989. Cancer 74: 1383–1397. [DOI] [PubMed] [Google Scholar]
  • 34. Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S (1997) BCL2 overexpression associated with chromosomal amplification in diffuse large B‐cell lymphoma. Blood 90: 1168–1174. [PubMed] [Google Scholar]
  • 35. Monni O, Joensuu H, Franssila K, Knuutila S (1996) DNA copy number changes in diffuse large B‐cell lymphoma ‐comparative genomic hybridization study. Blood 87: 5269–5278. [PubMed] [Google Scholar]
  • 36. Morgello S (1995) Pathogenesis and classification of primary central nervous system lymphoma: an update. Brain Pathol 5: 383–393. [DOI] [PubMed] [Google Scholar]
  • 37. Morgello S, Tagliati M, Ewart MR (1997) HHV‐8 and AIDS‐related CNS lymphoma. Neurology 48: 1333–1335. [DOI] [PubMed] [Google Scholar]
  • 38. Offit K, Parsa NZ, Gaidano G, Filippa DA, Louie D, Pan D, Jhanwar SC, Dalla‐Favera R, Chaganti RSK (1993) 6q deletions define distinct clinico‐pathologic subsets of non‐Hodgkin's lymphoma. Blood 82: 2157–2162. [PubMed] [Google Scholar]
  • 39. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Müller‐Hermelink HK (1997) The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low‐grade but not high‐grade malignant non‐Hodgkin's lymphomas of the mucosa‐associated lymphoid tissue (MALT‐) type. Cancer Res 57: 3944–3948. [PubMed] [Google Scholar]
  • 40. Paietta E, Van‐Ness B, Le Beau MM, Bennett J, Cassileth P, Wiernik PH (1992) Translocation (2;9)(p12;p23) in a case of acute leukemia with t(4;11)(q21;q23). Lack of rearrangement of the kappa and interferon gene loci. Cancer Genet Cytogenet 60: 82–85. [DOI] [PubMed] [Google Scholar]
  • 41. Pinkel D, Straume T, Gray JW (1986) Cytogenetic analysis using quantitative, high sensitivity, fluorescence hybridization. Proc Natl Acad Sci USA 83: 2934–2938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Piper J, Rutovitz D, Sudar D, Kallioniemi A, Kallioniemi O‐P, Waldman FM, Gray JW, Pinkel D (1995) Computer image analysis of comparative genomic hybridization. Cytometry 19: 10–26. [DOI] [PubMed] [Google Scholar]
  • 43. Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L, Offit K, Jhanwar SC, Chaganti RS (1998) Chromosomal and gene amplification in diffuse large B‐cell lymphoma. Blood 92: 234–240. [PubMed] [Google Scholar]
  • 44. Reifenberger J, Ring GU, Gies U, Cobbers JMJL, Oberstraß J, An H‐X, Niederacher D, Wechsler W, Reifenberger G (1996) Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. J Neuropathol Exp Neurol 55:822–831. [DOI] [PubMed] [Google Scholar]
  • 45. Rimokh R, Gadoux M, Bertheas M‐F, Berger F, Garoscio M, Deleage G, Germain D, Magaud J‐P (1993) FVT‐1, a novel human transcription unit affected by variant translocation t(2;18)(p11;q21) of follicular lymphoma. Blood 81: 136–142. [PubMed] [Google Scholar]
  • 46. Schouten HC, Sanger WG, Weisenburger DD, Armitage JO (1990) Abnormalities involving chromosome 6 in newly diagnosed patients with non‐Hodgkin's lymphoma. Nebraska Lymphoma Study Group. Cancer Genet Cytogenet 47: 73–82. [DOI] [PubMed] [Google Scholar]
  • 47. Schütz BR, Scheurlen W, Krauss J, du Manoir S, Joos S, Bentz M, Lichter P (1996) Mapping of chromosomal gains and losses in primitive neuroectodermal tumors by comparative genomic hybridization. Genes Chromosom Cancer 16: 196–203. [DOI] [PubMed] [Google Scholar]
  • 48. Solinas‐Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Döhner H, Cremer T, Lichter P (1997) Matrix‐based comparative genomic hybridization: Biochips to screen for genomic imbalances. Genes Chromosom Cancer 20: 399–407. [PubMed] [Google Scholar]
  • 49. Speicher MR, Jauch A, Walt H, du Manoir S, Ried T, Jochum W, Sulser T, Cremer T (1995) Correlation of microscopic phenotype with genotype in a formalin‐fixed, paraffin‐embedded testicular germ cell tumor with universal DNA amplification, comparative genomic hybridization, and interphase cytogenetics. Am J Pathol 146:1332–1340. [PMC free article] [PubMed] [Google Scholar]
  • 50. Tanaka S, Louie DC, Kant JA, Reed JC (1992) Frequent incidence of somatic hypermutations in translocated BCL2 oncogenes of non‐Hodgkin's lymphomas. Blood 79: 229–237. [PubMed] [Google Scholar]
  • 51. Telenius H, Carter NP, Bebb CE, Nordenskjöld M, Ponder BAJ, Tunnacliffe A (1992) Degenerate oligonucleotide‐primed PCR: General amplification of target DNA by a single degenerate primer. Genomics 13: 718–725. [DOI] [PubMed] [Google Scholar]
  • 52. Volpe G, Vitolo U, Carbone A, Pastore C, Bertini M, Botto B, Audisio E, Freilone R, Novero D, Cappia S, De Giuli P, Mazza U, Resegotti L, Palestro G, Saglio G, Gaidano G (1996) Molecular Heterogeneity of B‐lineage diffuse large cell lymphoma. Genes Chromosom Cancer 16: 21–30. [DOI] [PubMed] [Google Scholar]
  • 53. Weber RG, Boström J, Wolter M, Baudis M, Collins VP, Reifenberger G, Lichter P (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: Toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94: 14719–14724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Weber RG, Scheer M, Born IA, Joos S, Cobbers JM, Hofele C, Reifenberger G, Zöller JE, Lichter P (1998) Recurrent chromosomal imbalances detected in biopsy material from oral premalignant and malignant lesions by combined tissue microdissection, universal DNA amplification, and comparative genomic hybridization. Am J Pathol 153: 295–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Werner CA, Döhner H, Barth TF, Stilgenbauer S, Plesch A, Lichter P, Bentz M (1998) Molecular cytogenetic analysis of low‐grade B‐cell neoplasias: a comparative genomic hybridization study. Recent Results Cancer Res 144: 53–60. [DOI] [PubMed] [Google Scholar]
  • 56. Werner CA, Döhner H, Joos S, Trümper LH, Baudis M, Barth TFE, Ott G, Möller P, Lichter P, Bentz M (1997) High‐level DNA amplifications are common genetic aberrations in B‐cell neoplasms. Am J Pathol 151: 335–342. [PMC free article] [PubMed] [Google Scholar]
  • 57. Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul‐Rauf M, Price H, Karran L, Majekodunmi O, Wlodarska I, Pan L, Crook T, Hamoudi R, Isaacson PG, Dyer MJ (1999) Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96: 35–45. [DOI] [PubMed] [Google Scholar]
  • 58. Wiltshire RN, Duray P, Bittner ML, Visakorpi T, Meltzer PS, Tuthill RJ, Liotta LA, Trent JM (1995) Direct visualization of the clonal progression of primary cutaneous melanoma: Application of tissue microdissection and comparative genomic hybridization. Cancer Res 55: 3954–3957. [PubMed] [Google Scholar]
  • 59. Younes A, Pugh W, Goodacre A, Katz R, Rodriguez MA, Hill D, Cabanillas F, Andreeff M (1994) Polysomy of chromosome 12 in 60 patients with non‐Hodgkin's lymphoma assessed by fluorescence in situ hybridization: differences between follicular and diffuse large cell lymphoma. Genes Chromosom Cancer 9: 161–167. [DOI] [PubMed] [Google Scholar]
  • 60. Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L, Rakestraw KM, Naeve CW, Beckmann G, Weisenburger DD, Sanger WG, Nowotny H, Vesely M, Callet‐Bauchu E, Salles G, Dixit VM, Rosenthal A, Schlegelberger B, Morris SW (1999) Inactivating mutations and overexpression of BCL10, a caspase recruitment domain‐containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 22: 63–68. [DOI] [PubMed] [Google Scholar]
  • 61. Zhang SJ, Endo S, Ichikawa T, Washiyama K, Kumanishi T (1998) Frequent deletion and 5′ CpG island methylation of the p16 gene in primary malignant lymphoma of the brain. Cancer Res 58: 1231–1237. [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES