Title: FISH Analysis of 9p21 Deletion in Egyptian Childhood Acute Lymphoblastic Leukemia Patients: Relation to Prognosis and Disease Outcome

Authors: Hoda Mohamed El Gendi, Dina Aziz Khattab, Gehan Mostafa Hamed, Mona Fathey Abdel Fattah

 DOI:  https://dx.doi.org/10.18535/jmscr/v5i1.14

Abstract

Background: Identification of specific abnormal genes involved in the process of leukemogenesis often suggests possible prognostic markers that may be applied into risk stratification and treatment protocol in leukemia. Inactivation of the 9p21 region has been reported in acute lymphoblastic leukemia (ALL) but its prognostic importance in childhood ALL has been debated for a long time. The aim of this work was to detect deletion of 9p21 in pediatric ALL patients to evaluate its impact on patients response to therapy and to correlate it to standard prognostic factors.

Patients and Methods: Fluorescence in situ hybridization (FISH) technique was used to detect deletion of 9p21 in 45 newly diagnosed pediatric ALL patients, with follow- up for 12 months to assess their response to chemotherapy and for detection of relapse.

Result: 9p21 deletion was detected in twelve (26.7%) out of the forty five pediatric ALL patients, and it was significantly associated with poor prognostic criteria; age<1or >10 years, splenomegaly, hepatomegaly, high risk score and bad patient outcome.

Conclusion: The incidence of 9p21 deletion is higher in high risk group of pediatric ALL and conveys an inferior outcome.

Keywords: del (9p21), childhood ALL, prognosis, outcome.

References

1.   1.      Meshinchi S, Arceci RJ. Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. Oncologist. 2007;12: 341–355.

2.      Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethe-sda, MD: National Institute of Health, 1999.

3.      Carroll WL, Bhojwani D, Min DJ, Moskowitz N, Raetz E. Childhood acute lymphoblastic leukemia in the age of genomics. pediatr Blood Cancer. 2006;46: 570-578.

4.      Schiffman JD, Wang Y, McPherson LA, Welch K, Zhang N, Davis R, Lacayo NJ, Dahl GV, Faham M, Ford JM, Ji HP. Molecular inversion probes reveal patterns of 9p21 deletion and copy number aberrations in childhood leukemia. Cancer Genetics and Cytogenetics. 2009;193:9-18.

5.      Greaves M. A Natural History for Pedia-tric Acute Leukemia. Blood. 1993;82 (4):1043-1051

6.      Pui CH, Relling MV, Pharm D, Downing JR. Acute lymphoblastic leukemia. N Eng1 J Med. 2004;350:1535-48.

7.      Lee L, Livak K, Mullah B. Seven colour, homogenous detection of six PCR products. Biotechniques. 1999;27:342.

8.      Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene. 2002;21:3475-3495.

9.      Bertin R, Acquaviva C, Mirebeau D, Guidal-Giroux C, Vilmer E, Cave H. CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono- and biallelic 9p21 deletions in childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2003;37:44–57.

10.  Sulong S, Moorman AV, Irving JAE, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart ARM, Bailey S, Bown NP, Hall AG, Harrison CJ. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups BLOOD. 2009;113 (1):100-107.

11.  Chim CS, Wong AS, Kwong YL. Epigenetic inactivation of INK4/CDK/RB cell cycle pathway in acute leukemias. Ann of Hematol. 2003;82(12):738–742.

12.  Kuchinskaya E, Heyman M, Nordgren A, Soderha S, Forestier E, Wehner P, Vettenranta K, Jonsson O, Wesenberg F, Sahle´n S, Nordenskjo M, Blennow E. Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphob-lastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol. British Journal of Haematology. 2011;152:615–622.

13.  Lin YC, Diccianni MB, Kim Y, Lin H, Lee CH, Lin RJ, et al. Human p16c, a novel transcriptional variant of p16INK4a, coexpresses with p16INK4a in cancer cells and inhibits cell-cycle progression. Oncogene. 2007;26:7017–7027.

14.  Calero Moreno TM, Gustafsson G, Garwicz S, Grander D, Jonmundsson GK, Frost BM, Makipernaa A, Rasool O, Savolainen ER, Schmiegelow K, Soderhall S, Vettenranta K, Wesenberg F, Einhorn S, Heyman M. Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92. Leukemia. 2002;16:2037–2045.

15.  Dohner H, Estey EH, AmadoriS, Appelbaum FR, Buhner T, Burnett A, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lo Wenberg B, Bloomfield CD. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia Net. Blood. 2010;115:453-474.

16.  Einsiedel HG, Von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G, et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemiarelapse study of the Berlin-Frankfurt-Mu¨ nster Group 87. J Clin Oncol 2005;23:7942–7950.

17.  Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14:18–24.

18.  Woo HY, Kim, DW, Park, H, Seong, KW, Koo HH, Kim SH. Molecular cytogenetic analysis of gene rearrangements in childhood acute lymphoblastic leukemia. Journal of  Korean Medical Science. 2005;20:36–41.

19.  Karkucak M, Gorukmez O, Yakut T, Baytan B, Gorukmez O, Gunes A. Molecular Cytogenetic Findings in Cases with Childhood Acute Lymphoblastic Leukemia. International Journal of Hemat-ology and Oncology. 2012;22 (2):67-70.

20.  Mirebeau D, Acquaviva C, Suciu S, Bertin R, Dastugue N, Robert A, et al. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica. 2006;91:881–885.

21.  Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–764.

22.  Perez-Vera P, Salas C, Montero-Ruiz O, Frias S, Dehesa G, Jarquin B, et al. Analysis of gene rearrangements using a fluorescence in situ hybridization method in Mexican patients with acute lymphoblastic leukemia: experience at a single institution. Cancer Genetics and Cytogenetics. 2008;184:94–98.

23.  Ramakers-van Woerden NL, Pieters R, Slater RM, Loonen AH, Beverloo HB, van Drunen E, et al. In vitro drug resistance and prognostic impact of p16INK4a/ P15INK4b deletions in childhood T-cell acute lymphoblastic leukaemia. British Journal of Haematology. 2001;112:680–690.

24.  Kees UR, Burton PR, Lu C and Baker DL. Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood. 1997;89:4161–4166.

25.  Carter TL, Watt PM, Kumar R, Burton PR, Reaman GH, Sather HN, et al. Hemizygous p16(INK4A) deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse. Blood. 2001;97:572–574.

26.  Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K, et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood. 2008;112:4178–4183.

27.  Kim HJ, Woo HY, Koo HH, Tak EY, Kim SH. ABL oncogene amplification with p16(INK4a) gene deletion in precursor T-cell acute lymphoblastic leukemia/ lymphoma: report of the first case. Am J Hematol. 2004;76(4):360–336.

Corresponding Author

Mona Fathey Abdel Fattah

4 Eletreby Basha Abo Elezz, Heliopolis, Cairo, Egypt

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