Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lymphoma

Loss of heterozygosity on chromosome 6q14–q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma

Abstract

Deletions of chromosome 6q have been reported in several hematological malignancies, but data are not conclusive regarding their biological and prognostic impact. Therefore, we focused on pediatric patients diagnosed with T-cell lymphoblastic lymphoma (T-LBL) treated uniformly according to the NHL-BFM95 protocol. We used loss-of-heterozygosity (LOH) analysis of 25 microsatellite markers located on chromosome 6q14–q24. Fragment-length analysis was performed on ABI-PRISM3100 Genetic-Analyzer. Eligibility criterion was 3 informative markers. Between April 1995 and March 2003, 185 T-LBL patients were treated according to the NHL-BFM95 protocol. Five-year event-free (EFS) and disease-free survival (DFS) were 79±3 and 87±3% (median follow-up 4.7 [1.2–10.1] years). Sixty-one patients were evaluable for LOH analysis, including 18 out of 23 patients with relapse. EFS and DFS were 67±6 and 69±6% for these 61 patients. Testing of 853 markers in the 61 patients identified the presence of LOH in 19 patients (31%): 13 of the 18 relapse patients and five of the 41 in complete remission (odds ratio 18.7, 95% confidence interval 4.7–75.3). One LOH-positive patient died from treatment-related toxicity. We conclude that LOH on chromosome 6q14–q24 may have conferred a high risk of relapse on our group of children with T-LBL treated according to the NHL-BFM95 protocol.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    Article  CAS  PubMed  Google Scholar 

  2. Greaves MF, Wiemels J . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3: 639–649.

    Article  CAS  PubMed  Google Scholar 

  3. Mancini M, Vegna ML, Castoldi GL, Mecucci C, Spirito F, Elia L et al. Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia. Leukemia 2002; 16: 2055–2061.

    Article  CAS  PubMed  Google Scholar 

  4. Schop RF, Kuehl WM, Van Wier SA, Ahmann GJ, Price-Troska T, Bailey RJ et al. Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100: 2996–3001.

    Article  CAS  PubMed  Google Scholar 

  5. Cave H, Guidal C, Elion J, Vilmer E, Grandchamp B . A low rate of loss of heterozygosity is found at many different loci in childhood B-lineage acute lymphocytic leukemia. Leukemia 1996; 10: 1486–1491.

    CAS  PubMed  Google Scholar 

  6. Schouten HC, Sanger WG, Weisenburger DD, Armitage JO . Abnormalities involving chromosome 6 in newly diagnosed patients with non-Hodgkin's lymphoma. Nebraska Lymphoma Study Group. Cancer Genet Cytogenet 1990; 47: 73–82.

    Article  CAS  PubMed  Google Scholar 

  7. Rutherford S, Yu Y, Rumpel CA, Frierson Jr HF, Moskaluk CA . Chromosome 6 deletion and candidate tumor suppressor genes in adenoid cystic carcinoma. Cancer Lett 2005; July 28;[E-pub ahead of print].

  8. Abe T, Makino N, Furukawa T, Ouyang H, Kimura M, Yatsuoka T et al. Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. Genes Chromosomes Cancer 1999; 25: 60–64.

    Article  CAS  PubMed  Google Scholar 

  9. Cooney KA, Wetzel JC, Consolino CM, Wojno KJ . Identification and characterization of proximal 6q deletions in prostate cancer. Cancer Res 1996; 56: 4150–4153.

    CAS  PubMed  Google Scholar 

  10. Cuneo A, Rigolin GM, Bigoni R, de Angeli C, Veronese A, Cavazzini F et al. Chronic lymphocytic leukemia with 6q− shows distinct hematological features and intermediate prognosis. Leukemia 2004; 18: 476–483.

    Article  CAS  PubMed  Google Scholar 

  11. Jackson A, Carrara P, Duke V, Sinclair P, Papaioannou M, Harrison CJ et al. Deletion of 6q16–q21 in human lymphoid malignancies: a mapping and deletion analysis. Cancer Res 2000; 60: 2775–2779.

    CAS  PubMed  Google Scholar 

  12. Offit K, Parsa NZ, Gaidano G, Filippa DA, Louie D, Pan D et al. 6q deletions define distinct clinico-pathologic subsets of non-Hodgkin's lymphoma. Blood 1993; 82: 2157–2162.

    CAS  PubMed  Google Scholar 

  13. Gaidano G, Hauptschein RS, Parsa NZ, Offit K, Rao PH, Lenoir G et al. Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma. Blood 1992; 80: 1781–1787.

    CAS  PubMed  Google Scholar 

  14. Menasce LP, Orphanos V, Santibanez-Koref M, Boyle JM, Harrison CJ . Deletion of a common region on the long arm of chromosome 6 in acute lymphoblastic leukaemia. Genes Chromosomes Cancer 1994; 10: 26–29.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Matthiesen P, Harder S, Siebert R, Castoldi G, Calasanz MJ et al. A 3-cM commonly deleted region in 6q21 in leukemias and lymphomas delineated by fluorescence in situ hybridization. Genes Chromosomes Cancer 2000; 27: 52–58.

    Article  CAS  PubMed  Google Scholar 

  16. Sherratt T, Morelli C, Boyle JM, Harrison CJ . Analysis of chromosome 6 deletions in lymphoid malignancies provides evidence for a region of minimal deletion within a 2-megabase segment of 6q21. Chromosome Res 1997; 5: 118–124.

    Article  CAS  PubMed  Google Scholar 

  17. Starostik P, Greiner A, Schultz A, Zettl A, Peters K, Rosenwald A et al. Genetic aberrations common in gastric high-grade large B-cell lymphoma. Blood 2000; 95: 1180–1187.

    CAS  PubMed  Google Scholar 

  18. Sinclair PB, Sorour A, Martineau M, Harrison CJ, Mitchell WA, O'Neill E et al. A fluorescence in situ hybridization map of 6q deletions in acute lymphocytic leukemia: identification and analysis of a candidate tumor suppressor gene. Cancer Res 2004; 64: 4089–4098.

    Article  CAS  PubMed  Google Scholar 

  19. Steinemann D, Gesk S, Zhang Y, Harder L, Pilarsky C, Hinzmann B et al. Identification of candidate tumor-suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms. Genes Chromosomes Cancer 2003; 37: 421–426.

    Article  CAS  PubMed  Google Scholar 

  20. Hayashi Y, Raimondi SC, Look AT, Behm FG, Kitchingman GR, Pui CH et al. Abnormalities of the long arm of chromosome 6 in childhood acute lymphoblastic leukemia. Blood 1990; 76: 1626–1630.

    CAS  PubMed  Google Scholar 

  21. Heerema NA, Sather HN, Sensel MG, Lee MK, Hutchinson R, Lange BJ et al. Clinical significance of deletions of chromosome arm 6q in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. Leuk Lymphoma 2000; 36: 467–478.

    Article  CAS  PubMed  Google Scholar 

  22. Heerema NA, Sather HN, Sensel MG, Kraft P, Nachman JB, Steinherz PG et al. Frequency and clinical significance of cytogenetic abnormalities in pediatric T-lineage acute lymphoblastic leukemia: a report from the Children's Cancer Group. J Clin Oncol 1998; 16: 1270–1278.

    Article  CAS  PubMed  Google Scholar 

  23. Takeuchi S, Koike M, Seriu T, Bartram CR, Schrappe M, Reiter A et al. Frequent loss of heterozygosity on the long arm of chromosome 6: identification of two distinct regions of deletion in childhood acute lymphoblastic leukemia. Cancer Res 1998; 58: 2618–2623.

    CAS  PubMed  Google Scholar 

  24. Offit K, Louie DC, Parsa NZ, Filippa D, Gangi M, Siebert R et al. Clinical and morphologic features of B-cell small lymphocytic lymphoma with del(6)(q21q23). Blood 1994; 83: 2611–2618.

    CAS  PubMed  Google Scholar 

  25. Whang-Peng J, Knutsen T, Jaffe ES, Steinberg SM, Raffeld M, Zhao WP et al. Sequential analysis of 43 patients with non-Hodgkin's lymphoma: clinical correlations with cytogenetic, histologic, immunophenotyping, and molecular studies. Blood 1995; 85: 203–216.

    CAS  PubMed  Google Scholar 

  26. Mansoor A, Medeiros LJ, Weber DM, Alexanian R, Hayes K, Jones D et al. Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course. Am J Clin Pathol 2001; 116: 543–549.

    Article  CAS  PubMed  Google Scholar 

  27. Walters R, Kantarjian HM, Keating MJ, Estey EH, Trujillo J, Cork A et al. The importance of cytogenetic studies in adult acute lymphocytic leukemia. Am J Med 1990; 89: 579–587.

    Article  CAS  PubMed  Google Scholar 

  28. Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen M . Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med 1987; 316: 79–84.

    Article  CAS  PubMed  Google Scholar 

  29. Foroni L, Sorour A, Sinclair P DV . Loss of heterozygosity (LOH) and microsatellite instability (MSI) of chromosme 6q16–21 identifies a prognostically poor group of childhood and adult T Cell acute lymphoblastic leukemia (ALL) patients. Blood 2003; 102: 606 (abstract).

    Google Scholar 

  30. Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A et al. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood 1994; 84: 1043–1049.

    CAS  PubMed  Google Scholar 

  31. Burkhardt B, Woessmann W, Zimmermann M, Kontny U, Vormoor J, Doerffel W et al. Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 2006; 24: 491–499.

    Article  PubMed  Google Scholar 

  32. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the acute leukaemias: French–American–British (FAB) cooperative group. Br J Haematol 1976; 33: 451–458.

    Article  CAS  PubMed  Google Scholar 

  33. Ludwig WD, Rieder H, Bartram CR, Heinze B, Schwartz S, Gassmann W et al. Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of the German multicenter trials GMALL 03/87 and 04/89. Blood 1998; 92: 1898–1909.

    CAS  PubMed  Google Scholar 

  34. Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelenyi G et al. Updated Kiel classification for lymphomas. Lancet 1988; 1: 292–293.

    Article  CAS  PubMed  Google Scholar 

  35. Jaffe ES, Harris NL, Stein H, Vardiman J . WHO Classification, Tumours of Haematopoietic and Lymphoid Tissue. IARC Press: Lyon, 2001.

    Google Scholar 

  36. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.

    CAS  PubMed  Google Scholar 

  37. Murphy SB . Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980; 7: 332–339.

    CAS  PubMed  Google Scholar 

  38. Hatta Y, Yamada Y, Tomonaga M, Miyoshi I, Said JW, Koeffler HP . Detailed deletion mapping of the long arm of chromosome 6 in adult T-cell leukemia. Blood 1999; 93: 613–616.

    CAS  PubMed  Google Scholar 

  39. Merup M, Moreno TC, Heyman M, Ronnberg K, Grander D, Detlofsson R et al. 6q deletions in acute lymphoblastic leukemia and non-Hodgkin's lymphomas. Blood 1998; 91: 3397–3400.

    CAS  PubMed  Google Scholar 

  40. Gerard B, Cave H, Guidal C, Dastugue N, Vilmer E, Grandchamp B . Delineation of a 6 cM commonly deleted region in childhood acute lymphoblastic leukemia on the 6q chromosomal arm. Leukemia 1997; 11: 228–232.

    Article  CAS  PubMed  Google Scholar 

  41. Li CY, Chow C, Chan WY . Allelic imbalance mapped to 6q14.1 is associated with loss of expression of 5-HT receptor 1B in non-Hodgkin lymphomas. Diagn Mol Pathol 2004; 13: 69–74.

    Article  PubMed  Google Scholar 

  42. Kaplan EL, Meier P . Non-parametric estimation from incomplete observations. J Am Stat Assos 1958; 53: 457–481.

    Article  Google Scholar 

  43. Mantel E . Evaluation of survival data and tow new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  44. Breslow NE, Day NE . Statistical Methods in Cancer Research. 1 – The Analysis of Case–Control Studies. IARC Scientific Publications: Lyon, 2005.

    Google Scholar 

  45. Burger B, Zimmermann M, Mann G, Kuhl J, Loning L, Riehm H et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 2003; 21: 184–188.

    Article  PubMed  Google Scholar 

  46. Andreasson P, Hoglund M, Bekassy AN, Garwicz S, Heldrup J, Mitelman F et al. Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias. Eur J Haematol 2000; 65: 40–51.

    Article  CAS  PubMed  Google Scholar 

  47. Reiter A, Schrappe M, Ludwig WD, Tiemann M, Parwaresch R, Zimmermann M et al. Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 2000; 95: 416–421.

    CAS  PubMed  Google Scholar 

  48. Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G, Parwaresch R et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 2005; 131: 39–49.

    Article  PubMed  Google Scholar 

  49. Wang J, Kataoka H, Suzuki M, Sato N, Nakamura R, Tao H et al. Downregulation of EphA7 by hypermethylation in colorectal cancer. Oncogene 2005; 24: 5637–5647.

    Article  CAS  PubMed  Google Scholar 

  50. Eisen T, Easty DJ, Bennett DC, Goding CR . The POU domain transcription factor Brn-2: elevated expression in malignant melanoma and regulation of melanocyte-specific gene expression. Oncogene 1995; 11: 2157–2164.

    CAS  PubMed  Google Scholar 

  51. Akoulitchev S, Chuikov S, Reinberg D . TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 2000; 407: 102–106.

    Article  CAS  PubMed  Google Scholar 

  52. Liu ZJ, Tanaka Y, Mine S, Morinobu A, Yagita H, Okumura K et al. Functional cooperation of cyclin C and c-Myc in mediating homotypic cell adhesion via very late antigen-4 activation and vascular cell adhesion molecule-1 induction. Blood 1998; 92: 4700–4711.

    CAS  PubMed  Google Scholar 

  53. Attarbaschi A, Dworzak M, Steiner M, Urban C, Fink FM, Reiter A et al. Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 2005; 44: 70–76.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the expert work of Ulrike Meyer, Bettina Paul, Nora Mühlegger (data management) and Edelgard Odenwald and Gabriele Buck (cytomorphology). Central histopathology and immunophenotyping of tissue samples was supported by the Kinder Krebs Initiative (KKI), Buchholz-Holm-Seppensen, Germany. The LOH analysis was performed with the support of the start-up research program of the medical faculty of the Justus-Liebig University, Giessen, Germany.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B Burkhardt.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burkhardt, B., Bruch, J., Zimmermann, M. et al. Loss of heterozygosity on chromosome 6q14–q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma. Leukemia 20, 1422–1429 (2006). https://doi.org/10.1038/sj.leu.2404275

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404275

Keywords

This article is cited by

Search

Quick links