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Five Most Common Prognostically Important Fusion Oncogenes are Detected in the Majority of Pakistani Pediatric Acute Lymphoblastic Leukemia Patients and are Strongly Associated with Disease Biology and Treatment Outcome

  • Awan, Tashfeen (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Iqbal, Zafar (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Aleem, Aamer (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Sabir, Noreen (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Absar, Muhammad (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Rasool, Mahmood (Centre of Excellence in Genomic Medicine Research, King Abdulaziz University) ;
  • Tahir, Ammara H. (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Basit, Sulman (Biochemistry Research Section, Department of Anatomy, College of Medicine and King Khalid University Hospital, King Saud University) ;
  • Khalid, Ahmad Mukhtar (School of Biological Sciences, University of Sargodha) ;
  • Sabar, Muhammad Farooq (Centre for Advanced Molecular Biology & National Centre of Excellence in Molecular Biology) ;
  • Asad, Sultan (Centre for Advanced Molecular Biology & National Centre of Excellence in Molecular Biology) ;
  • Ali, Agha Shabbir (Post Graduate Medical Institute & Institute of Child Health) ;
  • Mahmood, Amer (Embryonic Stem Cell Unit, Department of Anatomy, College of Medicine and King Khalid University Hospital, King Saud University) ;
  • Akram, Muhammad (Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital) ;
  • Saeed, Tariq (Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital) ;
  • Saleem, Arsalan (University of Health Sciences) ;
  • Mohsin, Danish (University of Health Sciences) ;
  • Shah, Ijaz Hussain (Department of Oncology, Punjab Medical College and Allied Hospital) ;
  • Khalid, Muhammad (Department of Oncology, Punjab Medical College and Allied Hospital) ;
  • Asif, Muhammad (Department of Biotechnology and Informatics, (BUITEMS)) ;
  • Haq, Riazul (Health Centre, University of Texas San Antonio) ;
  • Iqbal, Mudassar (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab) ;
  • Akhtar, Tanveer (Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab)
  • 발행 : 2012.11.30

초록

Background and Objectives: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome. Method: We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. Results: Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival ($43.7{\pm}4.24$ weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). Conclusions: This is the first study from Pakistan correlating molecular markers with disease biology and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival. Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the development of facilities for stem cell transplantation.

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참고문헌

  1. Andersen MK, Autio K, Barbany G, et al (2011). Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19) (q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols. Br J Haematol, 155, 235-43. https://doi.org/10.1111/j.1365-2141.2011.08824.x
  2. Ariffin H, Chen SP, Kwok CS, et al (2007). Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: results of the Malaysia-Singapore Leukemia Study Group. J Pediatr Hematol Oncol, 29, 27-31. https://doi.org/10.1097/MPH.0b013e318030ac4c
  3. Ashraf MS (2012) Pediatric Oncology in Pakistan. J Pediatr Hematol Oncol, 34, 23-5. https://doi.org/10.1097/MPH.0b013e318249abf9
  4. Bhojwani D, Pei D, Sandlund JT, et al (2012). ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia, 26, 265-70. https://doi.org/10.1038/leu.2011.227
  5. Bowman WP, Larsen EL, Devidas M, et al (2011). Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906. Pediatr Blood Cancer, 57, 569-77. https://doi.org/10.1002/pbc.22944
  6. Burmeister T, Nicola G, Stefan S, et al (2010). Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia. Haematologic, 5, 241-6.
  7. Cheok MH, Evans WE (2006). Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer Therapy. Nat Rev Cancer, 6, 117-29. https://doi.org/10.1038/nrc1800
  8. DeBraekeleer E, Basinko A, Douet-Guilbert N, et al (2010). Cytogenetics in pre-B and B-cell acute lymphoblastic leukemia: a study of 208 patients diagnosed between 1981 and 2008. Cancer Genetics and Cytogenetics, 200, 8-15. https://doi.org/10.1016/j.cancergencyto.2010.03.004
  9. El-Sissy A, El-Mashari M, Bassuni W, et al (2006). A molecular detection of BCR/ABL fusion gene in Saudi acute lymphoblastic leukemia patients. J Egypt Natl Canc Inst, 18, 109-16.
  10. Faiz M, Qureshi AM, Qazi JI (2011). Molecular characterization of different fusion oncogenes associated with childhood Acute Lymphoblastic leukaemia from Pakistan. IJAVMS, 5, 497-507. https://doi.org/10.5455/ijavms.20110905093504
  11. Gaynon PS, Crotty ML, Sather HN, et al (1997). Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children's Cancer Group initiative. Leuk Lymphoma, 26, 57-65. https://doi.org/10.3109/10428199709109158
  12. Hunger SP, Lu X, Devidas M, et al (2012). Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol, 30, 1663-9. https://doi.org/10.1200/JCO.2011.37.8018
  13. Iacobucci I, Papayannidis C, Lonetti A, et al (2012). Cytogenetic and molecular predictors of outcome in acute lymphocytic leukemia: recent developments. Curr Hematol Malig Rep, 7, 133-43. https://doi.org/10.1007/s11899-012-0122-5
  14. Iqbal Z, Tanveer A (2006). Incidence of different fusion oncogenes in acute Lymphoblastic Leukemia (ALL) patients from Pakistan: possible implications in differential diagnosis, prognosis, treatment and management of ALL. Haematologica, 91, 64.
  15. Iqbal Z, Iqbal M, Akhter T (2007). Frequency of BCR-ABL fusion oncogene in Pakistani childhood acute lymphoid leukemia (ALL) patients reflects ethnic differences in molecular genetics of ALL. J Pediatr Hematol Oncol, 29, 585. https://doi.org/10.1097/MPH.0b013e3180f61bcf
  16. Iqbal Z, Awan T, Iqbal M, et al (2012). High frequency of BCRABL oncogene in pediatric acute lymphoblastic leukemia (ALL) patients as revealed by RT-PCR and interphase FISH: association with disease biology and treatment outcome. J Clin Oncol, 30, 444.
  17. Jimenez-Morales S, Miranda-Peralta E, Saldana-Alvarez Y, et al (2008). BCR-ABL, ETV6-RUNX1 and E2A-PBX1: prevalence of the most common acute lymphoblastic leukemia fusion genes in Mexican patients. Leuk Res, 32, 1518-22. https://doi.org/10.1016/j.leukres.2008.03.021
  18. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, et al (2007). High resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia, 21, 1258-66. https://doi.org/10.1038/sj.leu.2404691
  19. Lazic J, Tosic N, Dokmanovic L, et al (2010). Clinical features of the most common fusion genes in childhood acute lymphoblastic leukemia. Med Oncol, 27, 449-53. https://doi.org/10.1007/s12032-009-9232-x
  20. Leung W, Campana D, Yang J, et al (2011). High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood, 118, 223-30. https://doi.org/10.1182/blood-2011-01-333070
  21. McGregor S, McNeer J, Gurbuxani S (2012). Beyond the 2008 World Health Organization classification: the role of the hematopathology laboratory in the diagnosis and management of acute lymphoblastic leukemia. Semin Diagn Pathol, 29, 2-11. https://doi.org/10.1053/j.semdp.2011.07.004
  22. Mesquita DR, Cordoba JC, Magalhaes IQ, et al (2009). Molecular and chromosomal mutations among children with B-lineage lymphoblastic leukemia in Brazil's federal district. Genet Mol Res, 8, 345-53. https://doi.org/10.4238/vol8-1gmr582
  23. Pui CH, Carroll WL, Meshinchi S, et al (2011). Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol, 29, 551-65. https://doi.org/10.1200/JCO.2010.30.7405
  24. Pui CH, Robison LL, Look AT (2008). Acute Lymphoblastic Leukaemia. Lancet, 371, 1030-43. https://doi.org/10.1016/S0140-6736(08)60457-2
  25. Pui CH, Sandlund JT, Pei D, et al (2004). Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood, 104, 2690-6. https://doi.org/10.1182/blood-2004-04-1616
  26. Pui CH, Sandlund JT, Pei D, et al (2003). Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA, 290, 2001-7. https://doi.org/10.1001/jama.290.15.2001
  27. Pulsipher MA, Peters C, Pui CH (2011). High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant? Biol Blood Marrow Transplant, 17, 137-48. https://doi.org/10.1016/j.bbmt.2010.10.005
  28. Raimondi SC, Pui CH, Hancock ML, et al (1996). Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia. Leukemia, 10, 213-24.
  29. Reichard KK, Kang H, Robinett S (2011). Pediatric B-lymphoblastic leukemia with RUNX1 amplification: clinicopathologic study of eight cases. Mod Pathol, 24, 1606-11. https://doi.org/10.1038/modpathol.2011.118
  30. Rives S, Estella J, Gomez P, et al (2011). Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005. Br J Haematol, 154, 600-11. https://doi.org/10.1111/j.1365-2141.2011.08783.x
  31. Romana SP, Poirel H, Leconiat M, et al (1995). High frequency of t(12; 21) in childhood B-lineage acute lymphoblastic leukemia. Blood, 86, 4263-9.
  32. Sabir N, Iqbal Z, Aleem A, et al (2012). Prognostically Significant Fusion Oncogenes in Pakistani Patients with Adult Acute Lymphoblastic Leukemia and their Association with Disease Biology and Outcome. Asian Pac J Cancer Prev, 13, 3349-55. https://doi.org/10.7314/APJCP.2012.13.7.3349
  33. Schmiegelow K, Lausten TU, Baruchel A, et al (2012). High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia. Leukemia, 26, 675-81. https://doi.org/10.1038/leu.2011.274
  34. Schultz KR, Bowman WP, Aledo A, et al (2009). Improved early EFS with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol, 27, 5175-81. https://doi.org/10.1200/JCO.2008.21.2514
  35. Siddiqui R, Nancy N, Naing WP, et al (2010). Distribution of common genetic subgroups in childhood acute lymphoblasticleukemia in four developing countries. Cancer Genet Cytogenet, 200, 149-53. https://doi.org/10.1016/j.cancergencyto.2010.04.010
  36. Siraj AK, Ozbek U, Sazawal S, et al (2002). Preclinical validation of a monochrome real-time multiplex assay for translocations in childhood acute lymphoblastic leukemia. Clin Cancer Res, 8, 3832-40.
  37. Trevino LR, Yang W, French D, et al (2009). Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet, 41, 1001-5. https://doi.org/10.1038/ng.432
  38. van Dongen JJ, Macintyre EA, Gabert JA, et al (1999). Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia, 13, 1901-28. https://doi.org/10.1038/sj.leu.2401592
  39. Xu H, Cheng C, Devidas M, et al (2012). ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol, 30, 751-7. https://doi.org/10.1200/JCO.2011.38.0345
  40. Zhang J, Mullighan CG, Harvey RC, et al (2011). Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood, 118, 3080-7. https://doi.org/10.1182/blood-2011-03-341412

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