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Ten-year Experiences on Initial Genetic Examination in Childhood Acute Lymphoblastic Leukaemia in Hungary (1993–2002). Technical Approaches and Clinical Implementation

  • Published:
Pathology & Oncology Research

Abstract

A nationwide study was started in 1993 to provide genetic diagnosis for all newly diagnosed childhood ALL cases in Hungary using cytogenetic examination, DNA-index determination, FISH (aneuploidy, ABL/BCR, TEL/AML1) and molecular genetic tests (ABL/BCR, MLL/AF4, TEL/AML1). Aim of the study was to assess the usefullness of different genetic methods, to study the frequency of various aberrations and their prognostic significance. Results were synthesized for genetic subgrouping of patients. To assess the prognostic value of genetic aberrations overall and event-free survival of genetic subgroups were compared using Kaplan-Meier method. Prognostic role of aberrations was investigated by multivariate analysis (Cox’s regression) as well in comparison with other factors (age, sex, major congenital abnormalities, initial WBC, therapy, immunophenotype). Five hundred eighty-eight ALL cases were diagnosed between 1993–2002. Cytogenetic examination was performed in 537 (91%) (success rate 73%), DNA-index in 265 (45%), FISH in 74 (13%), TEL/AML1 RT-PCR in 219 (37%) cases producing genetic diagnosis in 457 patients (78%). Proportion of subgroups with good prognosis in prae-B-cell ALL was lower than expected: hyperdiploidB 18% (73/400), TEL/AML1+ 9% (36/400). Univariate analysis showed significantly better 5-year EFS in TEL/AML1+ (82%) and hyperdiploidB cases (78%) than in tetraploid (44%) or pseudodiploid (52%) subgroups. By multivariate analysis main negative prognostic factors were: congenital abnormalities, high WBC, delay in therapy, specific translocations. Conclusion: Complementary use of each of genetic methods used is necessary for reliable genetic diagnosis according to the algorythm presented. Specific genetic alterations proved to be of prognostic significance.

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Abbreviations

ALL:

acute lymphocytic leukaemia

EFS:

event free survival

FISH:

fluorescens in situ hybridization

MLL:

mixed linear leukaemia gene

PCR:

plymerase chain reaction

WBC:

white blood cell

References

  1. Anastasi J (1993) in situ hybridization in leukemia. Applications in diagnosis, subclassification, and monitoring the response to therapy. Ann N Y Acad Sci 677:214–224

    Article  PubMed  CAS  Google Scholar 

  2. Andreasson P, Hoglund M, Bekassy AN, Garwicz S, Heldrup J, Mitelman F, Johansson B (2000) Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukaemias. Eur J Haematol 65(1):40–51

    Article  PubMed  CAS  Google Scholar 

  3. Armstrong SA, Look AT (2005) Molecular genetics of acute lymphoblastic leukaemia. J Clin Oncol 23(26):6306–6315

    Article  PubMed  CAS  Google Scholar 

  4. Berger A, Strehl S, Hekele A, Ambros PF, Haas OA, Gadner H (1994) Interphase cytogenetic study of childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 23(5):413–421

    Article  PubMed  CAS  Google Scholar 

  5. Chessels JM, Bailey C, Richards SM (1995) Intensification of treatment and survival in all children with lymphoblastic leukaemia: Results of UK Medical Research Council trial UKALL X. Lancet 345:143

    Article  Google Scholar 

  6. Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM (1997) Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia. Br J Haematol 99(1):3–100

    Article  Google Scholar 

  7. Gray JW, Kallioniemi A, Kallioniemi O, Pallavicini M, Waldman F, Pinkel D (1992) Molecular cytogenetics: diagnosis and prognostic assessment. Curr Opin Biotechnol 3(6):623–631

    Article  PubMed  CAS  Google Scholar 

  8. Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3(9):639–649

    Article  PubMed  CAS  Google Scholar 

  9. Harbott J, Ritterbach J, Ludwig WD, Bartram CR, Reiter A, Lampert F (1993) Clinical significance of cytogenetic studies in childhood acute lymphoblastic leukaemia: experience of the BFM trials. Recent Results Cancer Res 131:123–132

    PubMed  CAS  Google Scholar 

  10. Heim S, Mitelman F (1992) Cytogenetic analysis in the diagnosis of acute leukaemia. Cancer 70(6 Suppl):1701–1709

    Article  PubMed  CAS  Google Scholar 

  11. Huh YO, Andreeff M (1994) Flow cytometry. Clinical and research applications in haematologic malignancies. Hematol Oncol Clin North Am 8(4):703–723

    PubMed  CAS  Google Scholar 

  12. ISCN (1995) An international system for human cytogenetic nomenclature. Karger, Basel

    Google Scholar 

  13. Johansson B, Mertens F, Mitelman F (2004) Clinical and biological importance of cytogenetic abnormalities in childhood and adult acute lymphoblastic leukaemia. Ann Med 36(7):492–503

    Article  PubMed  CAS  Google Scholar 

  14. Kersey JH (1997) Fifty years of studies of the biology and therapy of childhood leukaemia. Blood 90(11):4243–4251

    PubMed  CAS  Google Scholar 

  15. Márkász L, Kis LL, Stuber G, Flaberg E, Otvos R, Eksborg S, Skribek H, Olah E, Szekely L (2007) Hodgkin-lymhoma-derived cells show high sensitivity to dactinomycin and paclitaxel. Leuk Lymphoma 48(9):1835–1845

    Article  PubMed  Google Scholar 

  16. Márkász L, Stuber G, Flaberg E, Gustafsson Jernberg A, Eksborg S, Oláh E, Skribek H, Székely L (2006) Cytotoxic drug sensitivity of Epstein-Barr virus transformed lymphoblastoid B cells. BMC Cancer 6(1):265

    Article  PubMed  Google Scholar 

  17. Márkász L, Stuber G, Vanherberghen B, Flaberg E, Oláh É, Carbone E, Eksborg S, Klein E, Skribek H, Székely L (2007) Effect of frequently used chemotherapeutic drugs on the cytotoxic activity of human natural killer cells. Mol Cancer Ther 6:644–654

    Article  PubMed  Google Scholar 

  18. Márkász L, Hajas G, Kiss A, Lontay B, Rajnavölgyi É, Erdődi F, Oláh É (2007) Granulocyte colony stimulating factor increases drug resistance to daunorubicin and induces proliferation of leukaemic blast cells. Pathol Oncol Res (in press)

  19. Mitelman F (1986) Geographic heterogeneity of chromosome aberrations in haematologic disorders. Cancer Genet Cytogenet 20(3–4):203–208

    Article  PubMed  CAS  Google Scholar 

  20. Mitelman F, Heim S (1992) Quantitative acute leukaemia cytogenetics. Genes Chromosomes Cancer 5(1):57–66

    Article  PubMed  CAS  Google Scholar 

  21. Moricke A, Zimmermann M, Reiter A, Gadner H, Odenwald E, Harbott J, Ludwig WD, Riehm H, Schrappe M (2005) Prognostic impact of age in children and adolescents with acute lymphoblastic leukaemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 6:310–320

    Article  Google Scholar 

  22. Pinkel D (1987) Curing children of leukaemia. Cancer 59(10):1683–1691

    Article  PubMed  CAS  Google Scholar 

  23. Pinkel D (1989) Species-specific therapy of acute lymphoid leukaemia. Haematol Blood Transfus 32:27–36

    PubMed  CAS  Google Scholar 

  24. Pui CH, Crist WM (1992) Cytogenetic abnormalities in childhood acute lymphoblastic leukaemia correlates with clinical features and treatment outcome. Leuk Lymphoma 7(4):259–274

    Article  PubMed  CAS  Google Scholar 

  25. Pui CH, Evans WE (1998) Acute lymphoblastic leukaemia. N Engl J Med 339:605–615

    Article  PubMed  CAS  Google Scholar 

  26. Raimondi SC (1993) Current status of cytogenetic research in childhood acute lymphoblastic leukaemia. Blood 81(9):2237–2251

    PubMed  CAS  Google Scholar 

  27. Ritterbach J, Hiddemann W, Beck JD, Schrappe M, Janka-Schaub G, Ludwig WD, Harbott J, Lampert F (1998) Detection of hyperdiploid karyotypes (>50 chromosomes) in childhood acute lymphoblastic leukaemia (ALL) using fluorescence in situ hybridization (FISH). Leukaemia 12(3):427–433

    Article  CAS  Google Scholar 

  28. Rowley JD (1999) The role of chromosome translocations in leukaemogenesis. Semin Hematol 4(Suppl 7):59–72

    Google Scholar 

  29. Schrappe M, Camitta B, Pui CH, Eden T, Gaynon P, Gustafsson G, Janka-Schaub GE, Kamps W, Masera G, Sallan S, Tsuchida M, Vilmer E (2000) Long-term results of large prospective trials in childhood acute lymphoblastic leukaemia. Leukaemia 12:2193–2194

    Article  Google Scholar 

  30. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, Gadner H, Odenwald E, Riehm H (2000) Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukaemia 12:2205–2222

    Article  Google Scholar 

  31. Schuler D (1999) Systemizing childhood cancer care in Hungary: twenty-five years of progress. Med Pediatr Oncol 32(1):68–70

    Article  PubMed  CAS  Google Scholar 

  32. Secker-Walker LM (1990) Prognostic and biological importance of chromosome findings in acute lymphoblastic leukaemia. Cancer Genet Cytogenet 49(1):1–13

    Article  PubMed  CAS  Google Scholar 

  33. Trueworthy R, Shuster J, Look T, Crist W, Borowitz M, Carroll A, Frankel L, Harris M, Wagner H, Haggard M et al (1992) Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukaemia of childhood: a Pediatric Oncology Group study. J Clin Oncol 10(4):606–613

    PubMed  CAS  Google Scholar 

  34. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR (2002) Classification, subtype discovery, and prediction of outcome in paediatric acute lymphoblastic leukaemia by gene expression profiling. Cancer Cell 2:133–143

    Article  Google Scholar 

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Acknowledgement

This work was supported by national grants: OTKA T020642, T038307, M045500, ETT T/07028, ETT 341/2003. We are grateful to contributing laboratories for cooperation: Cytogenetic Laboratory of St. Laszlo Hospital, Budapest; 2nd.Dept. of Paediatrics, Semmelweis University, Budapest; Institute of Pathology, University of Pécs, Department of Paediatrics, University of Debrecen, Markusovszky Hospital, Szombathely.

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Authors and Affiliations

  1. Clinical Genetic Center, Department of Pediatrics, University of Debrecen, 98 Nagyerdei krt, 4012, Debrecen, Hungary

    Eva Olah & Erzsebet Balogh

  2. Institute of Pathology, University of Pécs, Pécs, Hungary

    Laszlo Pajor

  3. Hungarian Pediatric Cancer Registry, II. Department of Paediatrics, Semmelweis University, Budapest, Hungary

    Zsuzsanna Jakab

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  1. Eva Olah
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  2. Erzsebet Balogh
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  4. Zsuzsanna Jakab
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the Hungarian Pediatric Oncology Network

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Correspondence to Eva Olah.

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Members of the Hungarian Paediatric Oncology Network1

Gabor Kovacs, IInd Department of Paediatrics Semmelweis University, Budapest; Imre Rényi, Ist Department of Paediatrics Semmelweis University, Budapest; Andrea Békési, Bethesda, Magyarosi Edina, Heim Pal, Ilona Galantai, Madarasz Children’s Hospitals, Budapest; Csongor Kiss, Department of Paediatrics of University of Debrecen, Pal Kajtar, Department of Paediatrics, Univ. of Pécs, Katalin Bartyik, Dept. of Paediatrics, Szeged; Kalman Nagy Children’s Health Centre of Miskolc; Peter Masat, Department of Paediatrics, Markusovszky Hospital, Szombathely. President: Csongor Kiss, MD DSc.

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Olah, E., Balogh, E., Pajor, L. et al. Ten-year Experiences on Initial Genetic Examination in Childhood Acute Lymphoblastic Leukaemia in Hungary (1993–2002). Technical Approaches and Clinical Implementation. Pathol. Oncol. Res. 17, 81–90 (2011). https://doi.org/10.1007/s12253-010-9286-2

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