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Chromosome Imbalances and Alterations of AURKA and MYCN Genes in Children with Neuroblastoma

  • Inandiklioglu, Nihal (Department of Medical Biology and Genetics, Faculty of Medicine, Cukurova University) ;
  • Yilmaz, Sema (Department of Pediatric Oncology, Faculty of Medicine, Cukurova University) ;
  • Demirhan, Osman (Department of Medical Biology and Genetics, Faculty of Medicine, Cukurova University) ;
  • Erdogan, seyda (Department of Pathology, Faculty of Medicine, Cukurova University) ;
  • Tanyeli, Atila (Department of Pediatric Oncology, Faculty of Medicine, Cukurova University)
  • 발행 : 2012.11.30

초록

Background: Neuroblastoma (NB), like most human cancers, is characterized by genomic instability, manifested at the chromosomal level as allelic gain, loss or rearrangement. Genetics methods, as well as conventional and molecular cytogenetics may provide valuable clues for the identification of target loci and successful search for major genes in neuroblastoma. We aimed to investigate AURKA and MYCN gene rearrangements and the chromosomal aberrations (CAs) to determine the prognosis of neuroblastoma. Methods: We performed cytogenetic analysis by G-banding in 25 cases [11 girls (44%) and 14 boys (66%)] and in 25 controls. Fluorescence in situ hybridization (FISH) with AURKA and MYCN gene probes was also used on interphase nuclei to screen for alterations. Results: Some 18.4% of patient cells exhibited CAs., with a significant difference between patient and control groups in the frequencies (P<0.0001). Some 72% of the cells had structural aberrations, and only 28% had numerical chnages in patients. Structural aberrations consisted of deletions, translocations, breaks and fragility in various chromosomes, 84% and 52% of the patients having deletions and translocations, respectively. Among these expressed CAs, there was a higher frequency at 1q21, 1q32, 2q21, 2q31, 2p24, 4q31, 9q11, 9q22, 13q14, 14q11.2, 14q24, and 15q22 in patients. 32% of the patients had chromosome breaks, most frequently in chromosomes 1, 2, 3, 4, 5, 8, 9, 11, 12, 19 and X. The number of cells with breaks and the genomic damage frequencies were higher in patients (p<0.001). Aneuploidies in chromosomes X, 22, 3, 17 and 18 were most frequently observed. Numerical chromosome abnormalities were distinctive in 10.7% of sex chromosomes. Fragile sites were observed in 16% of our patients. Conclusion: Our data confirmed that there is a close correlation between amplification of the two genes, amplification of MYCN possibly contributing significantly to the oncogenic properties of AURKA. The high frequencies of chromosomal aberrations and amplifications of AURKA and MYCN genes indicate prognostic value in children with neuroblastomas and may point to contributing factors in their development.

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참고문헌

  1. Ambros IM, Zellner A, Roald B, et al (1996). Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. The New England J Med, 334, 1505-11. https://doi.org/10.1056/NEJM199606063342304
  2. Berwanger B, Hartmann O, Bergmann E, et al (2002). Loss of a Fyn-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma. Cancer Cell, 2, 377-86. https://doi.org/10.1016/S1535-6108(02)00179-4
  3. Brodeur GM, Sekhon GS, Goldstein MN, (1977). Chromosomal aberrations in human neuroblastomas. Cancer, 40, 2256-63. https://doi.org/10.1002/1097-0142(197711)40:5<2256::AID-CNCR2820400536>3.0.CO;2-1
  4. Brodeur GM, Green AA, Hayes FA, et al (1981). Cytogenetic features of human neuroblastomas and cell lines. Cancer Res, 41, 4678-86.
  5. Brodeur G (2003). Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer, 3, 203-16. https://doi.org/10.1038/nrc1014
  6. Capasso M, Diskin SJ, (2010). Genetics and genomics of neuroblastoma. Cancer Treat Res, 155, 65-84. https://doi.org/10.1007/978-1-4419-6033-7_4
  7. Caron H, van Sluis P, Buschman R, et al (1996). Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus. Hum Genet, 97, 834-37. https://doi.org/10.1007/BF02346199
  8. Carvajal RD, Tse A, Schwartz GK, (2006). Aurora kinases: new targets for cancer therapy. Clin Cancer Res, 12, 6869-75. https://doi.org/10.1158/1078-0432.CCR-06-1405
  9. Dumanski JP (1996). The human chromosome 22-located genes and malignancies of the central nervous system. Neuropathol Appl Neurobiol, 22, 412-7. https://doi.org/10.1111/j.1365-2990.1996.tb00912.x
  10. Ejeskar K, Aburatani H, Abrahamsson J, et al (1998). Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumoursuppressor locus distal to the FHIT gene. Br J Cancer, 77, 1787-91. https://doi.org/10.1038/bjc.1998.297
  11. Fearon ER, Cho KR, Nigro JM, et al (1990). Identification of a chromosome 18q gene that is altered in colorectal cancers. Sci, 247, 49-56. https://doi.org/10.1126/science.2294591
  12. Fong CT, White PS, Peterson K, et al (1992). Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas. Cancer Res, 52, 1780-5.
  13. Fundia AF, Larripa IB, (1989). Coincidence in Fragile Site Expression with Fluorodeoxyuridine and Bromodeoxyuridine. Cancer Genet Cytogenet, 41, 41-8. https://doi.org/10.1016/0165-4608(89)90106-4
  14. Gilbert F, Balaban G, Moorhead P, et al (1982). Abnormalities of chromosome 1p in neuroblastoma tumours and cell lines. Cancer Genet Cytogenet, 7, 33-42. https://doi.org/10.1016/0165-4608(82)90105-4
  15. Guled M, Myllykangas S, Frierson HF Jr, et al (2008). Array comparative genomic hybridization analysis of olfactory neuroblastoma. Mod Pathol, 21, 770-8. https://doi.org/10.1038/modpathol.2008.57
  16. Guo C, White PS, Weiss MJ, et al (1999). Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene, 18, 4948-57. https://doi.org/10.1038/sj.onc.1202887
  17. Hahn SA, Schutte M, Hoque AT, et al (1996). DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science (Wash. DC), 271, 350-3. https://doi.org/10.1126/science.271.5247.350
  18. Karauzum SB, Luleci G, Ozbilim G, et al (1998). Cytogenetic findings in thirty lung carcinoma patients. Cancer Genet Cytogenet, 100, 114-23. https://doi.org/10.1016/S0165-4608(96)00422-0
  19. Kohl NE, Kanda N, Schreck RR, et al (1983). Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell, 35, 359-67. https://doi.org/10.1016/0092-8674(83)90169-1
  20. Krona C, Caren H, Sjoberg RM, et al (2008). Analysis of neuroblastoma tumour progression; loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumourigenesis. Int J of Oncol, 32, 575-83.
  21. Maris JM, Matthay KK, (1999). Molecular biology of neuroblastoma. J Clin Oncol, 17, 2264-79. https://doi.org/10.1200/JCO.1999.17.7.2264
  22. Marshall B, Isidro G, Martins AG, Boavida MG (1997). Loss of heterozygosity at chromosome 9p21 in primary neuroblastomas: evidence for two deleted regions. Cancer Genet Cytogenet, 96, 134-9. https://doi.org/10.1016/S0165-4608(96)00300-7
  23. McAlpine PJ, Shows TB, Boucheli C, Huebner M, Anderson WA (1991). The 1991 catalog of mapped genes and report of the nomenclature committee, human gene mapping 11. Cytogenet Cell Genet, 58, 5-102. https://doi.org/10.1159/000133160
  24. Mitelman F (ed.), Skarger, (1995). ISCN: An international system for humn cytogenetics nomenclature. Basel.
  25. Mora J, Cheung NK, Chen L, et al (2001). Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin Cancer Res, 7, 1358-61.
  26. Nanashima A, Tagawa Y, Yasutake T, et al (1997). Aneusomy of chromosome 18 is associated with the development of colorectal carcinoma. J Gastroenterology, 32, 487-91. https://doi.org/10.1007/BF02934087
  27. Otto T, Horn S, Brockmann M, et al (2009). Stabilization of N-Myc is a critical function of aurora a in human neuroblastoma. Cancer Cell, 15, 67-78. https://doi.org/10.1016/j.ccr.2008.12.005
  28. Pandis N, Jin Y, Gorunova L, et al (1995). Chromosome analysis of 97 primary carcinomas of the breast: Identification of eight karyotypic subgroups. Genes Chrom Cancer, 12, 173-85. https://doi.org/10.1002/gcc.2870120304
  29. Petkovic I, Cepulic M (1991). Cytogenetic analysis of primary neuroblastoma with del(1), del(14), hsr, and dmin chromosomes. Cancer Genet Cytogenet, 55, 231-4. https://doi.org/10.1016/0165-4608(91)90082-6
  30. Rubie H, Hartmann O, Michon J, et al (1997). N-myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL90 study. J Clin Oncol, 15, 1171-82. https://doi.org/10.1200/JCO.1997.15.3.1171
  31. Spitz R, Hero B, Ernestus K, Berthold F, (2003). Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4 s neuroblastoma. Clin Cancer Res, 9, 52-8.
  32. Spitz R, Hero B, Skowron M, Ernestus K, Berthold F, (2004). MYCN status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. Eur J Cancer, 40, 2753-9. https://doi.org/10.1016/j.ejca.2004.05.002
  33. Sreekantaiah C, Bhargava MK, Shetty NJ, (1988). Chromosome 1 abnormalities in cervical carcinoma. Cancer, 62, 1317-24. https://doi.org/10.1002/1097-0142(19881001)62:7<1317::AID-CNCR2820620713>3.0.CO;2-K
  34. Sumegi J, Nishio J, Nelson M, et al (2011). A novel t(4;22) (q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. Mod Pathol, 24, 333-42. https://doi.org/10.1038/modpathol.2010.201
  35. Suzuki T, Yokota J, Mugishima H, et al (1989). Frequent loss of heterozygosity on chromosome 14q in neuroblastoma. Cancer Res, 49, 1095-8.
  36. Thompson PM, Seifried BA, Kyemba SK, et al (2001). Loss of heterozygosity for chromosome 14q in neuroblastoma. Med Pediatr Oncol, 36, 28-31. https://doi.org/10.1002/1096-911X(20010101)36:1<28::AID-MPO1008>3.0.CO;2-0
  37. Weiss MJ, Guo C, Shusterman S, et al (2000). Localization of a hereditary neuroblastoma predisposition gene to 16p12- p13. Med Pediatr Oncol, 35, 526-30. https://doi.org/10.1002/1096-911X(20001201)35:6<526::AID-MPO5>3.0.CO;2-S
  38. Young RP, Whittington CF, Hopkins RJ, et al (2010). Chromosome 4q31 locus in COPD is also associated with lung cancer. Eur Respir J, 36, 1375-82. https://doi.org/10.1183/09031936.00033310
  39. Zhou H, Kuang J, Zhong L, et al (1998). Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet, 20, 89-193.

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