Abstract
Purpose
The biological heterogeneity of neuroblastoma results in a varied outcome ranging from spontaneous regression to fatal tumor progression. Microarray expression profiling and genetic polymorphism arrays may help identify key genes that differ in aggressive neuroblastomas from those observed in tumors associated with a favorable outcome.
Methods
Total RNA was extracted from 16 neuroblastomas obtained from patients who subsequently died of the disease and from 16 favorable neuroblastomas and analyzed using a human whole genome oligomicroarray (55K CodeLink). Genes overexpressed in favorable tumors were subsequently analyzed in 121 neuroblastoma tumors obtained before chemotherapy using real-time RT-PCR. And among these cases, expression levels of these genes were also analyzed in 20 tumors obtained after chemotherapy.
Results
Oligomicroarray analysis revealed the overexpression of 283 genes in favorable tumors that were associated with either regressing or maturing tumors. Three candidate genes, including DHRS3, NROB1, and CYP26A1, were selected that were significantly overexpressed in favorable tumors by quantitative real-time RT-PCR (P < 0.01). No cases with overexpression of all three genes showed poor outcomes. In 20 post-chemotherapeutic tumors, the expression levels of these genes increased in the cases where patients survived but decreased in the fatal cases.
Conclusions
Using microarray expression profiling, we identified genes that exhibit altered gene expression in neuroblastoma tumors associated with a favorable outcome. These candidates warrant further study for use in risk assessment and/or as therapeutic targets in neuroblastoma.
Similar content being viewed by others
References
Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3(3):203–216
Westermann F, Schwab M (2002) Genetic parameters of neuroblastomas. Cancer Lett 184(2):127–147
Hiyama E, Hiyama K, Nishiyama M, Reynolds CP, Shay JW, Yokoyama T (2003) Differential gene expression profiles between neuroblastomas with high telomerase activity and low telomerase activity. J Pediatr Surg 38(12):1730–1734
Hiyama E, Hiyama K, Yamaoka H, Sueda T, Reynolds CP, Yokoyama T (2004) Expression profiling of favorable and unfavorable neuroblastomas. Pediatr Surg Int 20(1):33–38
Hiyama E, Hiyama K (2002) Clinical application of microarrays as a tool of understanding cancer biology. In: Cancro MP (ed) Recent Res Develop Cancer, vol 4. Transworld Research Network, Kerala, India, pp 675–692
Takita J, Ishii M, Tsutsumi S, Tanaka Y, Kato K, Toyoda Y, Hanada R, Yamamoto K, Hayashi Y, Aburatani H (2004) Gene expression profiling and identification of novel prognostic marker genes in neuroblastoma. Genes Chromosomes Cancer 40(2):120–132
Komatsu M, Hiyama K, Tanimoto K, Yunokawa M, Otani K, Ohtaki M, Hiyama E, Kigawa J, Ohwada M, Suzuki M, Nagai N, Kudo Y, Nishiyama M (2006) Prediction of individual response to platinum/paclitaxel combination using novel marker genes in ovarian cancers. Mol Cancer Ther 5(3):767–775
Hiyama K, Otani K, Ohtaki M, Satoh K, Kumazaki T, Takahashi T, Mitsui Y, Okazaki Y, Hayashizaki Y, Omatsu H, Noguchi T, Tanimoto K, Nishiyama M (2005) Differentially expressed genes throughout the cellular immortalization processes are quite different between normal human fibroblasts and endothelial cells. Int J Oncol 27(1):87–95
Brodeur GM, Seeger RC, Barrett A, Berthold F, Castleberry RP, D’Angio G, De Bernardi B, Evans AE, Favrot M, Freeman AI et al (1988) International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6(12):1874–1881
Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B, Stram DO, Gerbing RB, Lukens JN, Matthay KK, Castleberry RP (1999) The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86(2):364–372
Sawaguchi S, Kaneko M, Uchino J, Takeda T, Iwafuchi M, Matsuyama S, Takahashi H et al (1990) Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy: a report from the Study Group of Japan. Cancer 66:1879–1887
Abu-Abed S, Dolle P, Metzger D, Wood C, MacLean G, Chambon P, Petkovich M (2003) Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1. Development 130(7):1449–1459
Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dolle P (2002) Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet 31(1):84–88
De Marco P, Merello E, Mascelli S, Raso A, Santamaria A, Ottaviano C, Calevo MG, Cama A, Capra V (2006) Mutational screening of the CYP26A1 gene in patients with caudal regression syndrome. Birth Defects Res A Clin Mol Teratol 76(2):86–95
Acknowledgments
We thank Ikuko Fukuba and Emi Fukuda for their technical assistance. This research was partially supported by a Grant-in-Aid for Scientific Research (B) (No. 19390449) from the Ministry of Education, Culture, Sports, Science, and Technology and those (H16-KODOMO-IPPAN-012, for cancer 16-16) from the Ministry of Health, Labour, and Welfare of the Government of Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kamei, N., Hiyama, K., Yamaoka, H. et al. Evaluation of genes identified by microarray analysis in favorable neuroblastoma. Pediatr Surg Int 25, 931–937 (2009). https://doi.org/10.1007/s00383-009-2448-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00383-009-2448-1