Abstract
Primary central nervous system lymphomas (PCNSL) constitute diffuse large B‐cell lymphomas arising in and remaining confined to the brain. Little information is available on cytogenetic changes in PCNSL, and recurrent chromosomal translocations have not yet been identified. Fluorescence in situ hybridization (FISH) of a series of 13 PCNSL from immunocompetent patients revealed 3 cases with signal patterns of a BCL6‐specific probe suggesting a breakpoint in this oncogene locus in chromosome band 3q27. Here, we describe cloning of the translocation breakpoints by long‐distance inverse polymerase chain reaction (LDI‐PCR) in 2 of these tumors. Both breakpoints affected the first intron of BCL6. In one PCNSL, the HSPCA (HSP90A) gene in 14q32.31 was identified as BCL6 partner. In the second lymphoma, the gene encoding glyceraldehyde‐3‐phosphate dehydrogenase (GAPD) on 12p13.31 was detected as a hitherto unknown partner of BCL6. Our results suggest translocation‐mediated BCL6 oncogene activation as a so far unknown pathogenetically relevant mechanism in PCNSL.
Full Text
The Full Text of this article is available as a PDF (235.1 KB).
References
- 1. Akasaka H, Akasaka T, Kurata M, Ueda C, Shimizu A, Uchiyama T, Ohno H (2000) Molecular anatomy of BCL6 translocations revealed by long‐distance polymerase chain reaction‐based assays. Cancer Res 60:2335–2341. [PubMed] [Google Scholar]
- 2. Akasaka T, Ueda C, Kurata M, Akasaka H, Yamabe H, Uchiyama T, Ohno H (2000) Nonimmunoglobulin (non‐Ig)/BCL6 gene fusion in diffuse large B‐cell lymphoma results in worse prognosis than Ig/BCL6. Blood 96:2907–2909. [PubMed] [Google Scholar]
- 3. Akasaka T, Lossos IS, Levy R (2003) BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood 102:1443–1448. [DOI] [PubMed] [Google Scholar]
- 4. Allman D, Jain A, Dent A, Maile R, Selvaggi T, Kehry M, Staudt L (1996) BCL‐6 expression during B‐cell activation. Blood 87:5257–5268. [PubMed] [Google Scholar]
- 5. Braaten KM, Betensky RA, De Leval L, Okada Y, Hochberg FH, Louis DN, Harris NL, Batchelor TT (2003) BCL‐6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clin Cancer Res 9:1063–1069. [PubMed] [Google Scholar]
- 6. Chen W, Butler M, Rao PH, Chaganti SR, Louie DC, Dalla‐Favera R, Chaganti RS (1998) The t(2;3)(q21;q27) translocation in non‐Hodgkin's lymphoma displays BCL6 mutations in the 5′ regulatory region and chromosomal breakpoints distant from the gene. Oncogene 17:1717–1722. [DOI] [PubMed] [Google Scholar]
- 7. Gatter KC, Warnke RA (2001) Diffuse large cell lymphoma, In: Pathology and genetics of tumors of haematopoietic and lymphoid tissues, Jaffe ES, Harris NL, Stein H. W. VJ (eds): p 171–174, vol., IARC Press: Lyon . [Google Scholar]
- 8. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf‐Peeters C, Falini B, Gatter KC (1994) A revised European‐American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361–1392. [PubMed] [Google Scholar]
- 9. Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, Van Krieken JH, 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 92:3152–3162. [PubMed] [Google Scholar]
- 10. 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]
- 11. Lossos IS, Warnke R, Levy R (2002) BCL‐6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5′ regulatory region of the BCL‐6 gene. Leukemia 16:1857–1862. [DOI] [PubMed] [Google Scholar]
- 12. Montesinos‐Rongen M, Küppers R, Schlüter D, Spieker T, Van Roost D, Schaller C, Reifenberger G, Wiestler OD, Deckert‐Schlüter M (1999) Primary central nervous system lymphomas are derived from germinal‐center B cells and show a preferential usage of the V4‐34 gene segment. Am J Pathol 155:2077–2086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Montesinos‐Rongen M, Zühlke‐Jenisch R, Gesk S, MartinSubero JI, Schaller C, Van Roost D, Wiestler OD, Deckert M, Siebert R (2002) Interphase cytogenetic analysis of lymphoma‐associated chromosomal breakpoints in primary diffuse large B‐cell lymphomas of the central ne rvous system. J Neuropathol Exp Neurol 61:926–933. [DOI] [PubMed] [Google Scholar]
- 14. Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C, Ye BH, Lista F, Filippa DA, Rosenbaum A, et al. (1994) Rearrangement of the bcl‐6 gene as a prognostic marker in diffuse large‐cell lymphoma. N Engl J Med 331:74–80. [DOI] [PubMed] [Google Scholar]
- 15. Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RSK, Dalla‐Favera R (2002) Mutations of the BCL‐6 proto‐oncogene disrupt its negative autoregulation in diffuse large B‐cell lymphoma. Blood 2002–2011–3387. [DOI] [PubMed]
- 16. Thompsett AR, Ellison DW, Stevenson FK, Zhu D (1999) V (H) gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cells with ongoing mutational activity. Blood 94:1738–1746. [PubMed] [Google Scholar]
- 17. Wang X, Li Z, Naganuma A, Ye BH (2002) Negative autoregulation of BCL‐6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci U S A 99:15018–15023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Xu WS, Liang RH, Srivastava G (2000) Identification and characterization of BCL6 translocation partner genes in primary gastric high‐grade B‐cell lymphoma: heat shock protein 89 alpha is a novel fusion partner gene of BCL6. Genes Chromosomes Cancer 27:69–75. [DOI] [PubMed] [Google Scholar]