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Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas

Abstract

Neuroblastomas are characterized by 1p deletions, suggesting that a tumor suppressor gene (TSG) resides in this region. We have mapped the smallest region of deletion (SRD) to a 2 Mb region of 1p36.31 using microsatellite and single nucleotide polymorphisms. We have identified 23 genes in this region, and we have analysed these genes for mutations and RNA expression patterns to identify candidate TSGs. We sequenced the coding exons of these genes in 30 neuroblastoma cell lines. Although rare mutations were found in 10 of the 23 genes, none showed a pattern of genetic change consistent with homozygous inactivation. We examined the expression of these 23 genes in 20 neuroblastoma cell lines, and most showed readily detectable expression, and no correlation with 1p deletion. However, 7 genes showed uniformly low expression in the lines, and 2 genes (CHD5, RNF207) had virtually absent expression, consistent with the expected pattern for a TSG. Our mutation and expression analysis in neuroblastoma cell lines, combined with expression analysis in normal tissues, putative function and prior implication in neuroblastoma pathogenesis, suggests that the most promising TSG deleted from the 1p36 SRD is CHD5, but TNFRSF25, CAMTA1 and AJAP1 are also viable candidates.

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References

  • Attiyeh EF, London WB, Mosse YP, Wang Q, Winter C, Khazi D et al. (2005). Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353: 2243–2253.

    Article  CAS  PubMed  Google Scholar 

  • Bader SA, Fasching C, Brodeur GM, Stanbridge EJ . (1991). Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells. Cell Growth Differ 2: 245–255.

    CAS  PubMed  Google Scholar 

  • Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D et al. (2007). CHD5 is a tumor suppressor at human 1p36. Cell 128: 459–475.

    Article  CAS  PubMed  Google Scholar 

  • Bauer A, Savelyeva L, Claas A, Praml C, Berthold F, Schwab M . (2001). Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig. Genes Chromosomes Cancer 31: 228–239.

    Article  CAS  PubMed  Google Scholar 

  • Bergo MO, Gavino BJ, Hong C, Beigneux AP, McMahon M, Casey PJ et al. (2004). Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest 113: 539–550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodeur GM . (2003). Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3: 203–216.

    Article  CAS  PubMed  Google Scholar 

  • Brodeur GM, Green AA, Hayes FA, Williams KJ, Williams DL, Tsiatis AA . (1981). Cytogenetic features of human neuroblastomas and cell lines. Cancer Res 41: 4678–4686.

    CAS  PubMed  Google Scholar 

  • Brodeur GM, Maris JM . (2006). Neuroblastoma. In: Pizzo Pa, Poplack Dg (eds). Principles and Practice of Pediatric Oncology. Lippincott Williams & Wilkins: Philadelphia, pp 933–970.

    Google Scholar 

  • Brodeur GM, Sekhon G, Goldstein MN . (1977). Chromosomal aberrations in human neuroblastomas. Cancer 40: 2256–2263.

    Article  CAS  PubMed  Google Scholar 

  • Buetow KH, Edmonson MN, Cassidy AB . (1999). Reliable identification of large numbers of candidate SNPs from public EST data. Nat Genet 21: 323–325.

    Article  CAS  PubMed  Google Scholar 

  • Caron H, Peter M, van Sluis P, Speleman F, de Kraker J, Laureys G et al. (1995). Evidence for two tumour suppressor loci on chromosomal bands 1p35–36 involved in neuroblastoma: one probably imprinted, another associated with N-myc amplification. Hum Mol Genet 4: 535–539.

    Article  CAS  PubMed  Google Scholar 

  • Caron H, Spieker N, Godfried M, Veenstra M, van Sluis P, de Kraker J et al. (2001). Chromosome bands 1p35–36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted. Genes Chromosomes Cancer 30: 168–174.

    Article  CAS  PubMed  Google Scholar 

  • Chen YZ, Soeda E, Yang HW, Takita J, Chai L, Horii A et al. (2001). Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36. Genes Chromosomes Cancer 31: 326–332.

    Article  CAS  PubMed  Google Scholar 

  • Cheng NC, Van Roy N, Chan A, Beitsma M, Westerveld A, Speleman F et al. (1995). Deletion mapping in neuroblastoma cell lines suggests two distinct tumor suppressor genes in the 1p35–36 region, only one of which is associated with N-myc amplification. Oncogene 10: 291–297.

    CAS  PubMed  Google Scholar 

  • Eggert A, Grotzer MA, Zuzak TJ, Ikegaki N, Zhao H, Brodeur GM . (2002). Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system. Eur J Cancer 38: 92–98.

    Article  CAS  PubMed  Google Scholar 

  • Elia A, Vyas J, Laing KG, Clemens MJ . (2004). Ribosomal protein L22 inhibits regulation of cellular activities by the Epstein–Barr virus small RNA EBER-1. Eur J Biochem 271: 1895–1905.

    Article  CAS  PubMed  Google Scholar 

  • Fok V, Mitton-Fry RM, Grech A, Steitz JA . (2006). Multiple domains of EBER 1, an Epstein–Barr virus noncoding RNA, recruit human ribosomal protein L22. RNA 12: 872–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gehring M, Berthold F, Edler L, Schwab M, Amler LC . (1995). The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. Cancer Res 55: 5366–5369.

    CAS  PubMed  Google Scholar 

  • Grenet J, Valentine VA, Kitson J, Li H, Farrow SN, Kidd VJ . (1998). Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma. Genomics 49: 385–393.

    Article  CAS  PubMed  Google Scholar 

  • Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS . (2005). A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet 37: 549–554.

    Article  CAS  PubMed  Google Scholar 

  • Henrich KO, Claas A, Praml C, Benner A, Mollenhauer J, Poustka A et al. (2007). Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma. Eur J Cancer 43: 607–616.

    Article  CAS  PubMed  Google Scholar 

  • Henrich KO, Fischer M, Mertens D, Benner A, Wiedemeyer R, Brors B et al. (2006). Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients. Clin Cancer Res 12: 131–138.

    Article  CAS  PubMed  Google Scholar 

  • Ho R, Minturn JE, Hishiki T, Zhao H, Wang Q, Cnaan A et al. (2005). Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Cancer Res 65: 9868–9875.

    Article  CAS  PubMed  Google Scholar 

  • Katoh M, Katoh M . (2003). Identification and characterization of FLJ10737 and CAMTA1 genes on the commonly deleted region of neuroblastoma at human chromosome 1p36.31-p36.23. Int J Oncol 23: 1219–1224.

    CAS  PubMed  Google Scholar 

  • Maris JM, Jensen J, Sulman EP, Beltinger CP, Allen C, Biegel JA et al. (1997). Human Kruppel-related 3 (HKR3): a candidate for the 1p36 neuroblastoma tumour suppressor gene? Eur J Cancer 33: 1991–1996.

    Article  CAS  PubMed  Google Scholar 

  • Martinsson T, Sjoberg RM, Hallstensson K, Nordling M, Hedborg F, Kogner P . (1997). Delimitation of a critical tumour suppressor region at distal 1p in neuroblastoma tumours. Eur J Cancer 33: 1997–2001.

    Article  CAS  PubMed  Google Scholar 

  • Martinsson T, Sjoberg RM, Hedborg F, Kogner P . (1995). Deletion of chromosome 1p loci and microsatellite instability in neuroblastomas analyzed with short-tandem repeat polymorphisms. Cancer Res 55: 5681–5686.

    CAS  PubMed  Google Scholar 

  • McDonald JM, Dunmire V, Taylor E, Sawaya R, Bruner J, Fuller GN et al. (2005). Attenuated expression of DFFB is a hallmark of oligodendrogliomas with 1p-allelic loss. Mol Cancer 4: 35.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohira M, Kageyama H, Mihara M, Furuta S, Machida T, Shishikura T et al. (2000). Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line. Oncogene 19: 4302–4307.

    Article  CAS  PubMed  Google Scholar 

  • Oliphant A, Barker DL, Stuelpnagel JR, Chee MS . (2002). BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 56–58 (Suppl): 60–61.

    Google Scholar 

  • Rozen S, Skaletsky H . (2000). Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132: 365–386.

    CAS  PubMed  Google Scholar 

  • Schleiermacher G, Peter M, Michon J, Hugot JP, Vielh P, Zucker JM et al. (1994). Two distinct deleted regions on the short arm of chromosome 1 in neuroblastoma. Genes Chromosomes Cancer 10: 275–281.

    Article  CAS  PubMed  Google Scholar 

  • Steemers FJ, Chang W, Lee G, Barker DL, Shen R, Gunderson KL . (2006). Whole-genome genotyping with the single-base extension assay. Nat Methods 3: 31–33.

    Article  CAS  PubMed  Google Scholar 

  • Takeda O, Homma C, Maseki N, Sakurai M, Kanda N, Schwab M et al. (1994). There may be two tumor suppressor genes on chromosome arm 1p closely associated with biologically distinct subtypes of neuroblastoma. Genes Chromosomes Cancer 10: 30–39.

    Article  CAS  PubMed  Google Scholar 

  • Thompson PM, Gotoh T, Kok M, White PS, Brodeur GM . (2003). CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene 22: 1002–1011.

    Article  CAS  PubMed  Google Scholar 

  • Thompson PM, Maris JM, Hogarty MD, Seeger RC, Reynolds CP, Brodeur GM et al. (2001). Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res 61: 679–686.

    CAS  PubMed  Google Scholar 

  • Wang Q, Diskin S, Rappaport E, Attiyeh E, Mosse Y, Shue D et al. (2006). Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Cancer Res 66: 6050–6062.

    Article  CAS  PubMed  Google Scholar 

  • White PS, Maris JM, Beltinger C, Sulman E, Marshall HN, Fujimori M et al. (1995). A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci USA 92: 5520–5524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok M et al. (2005). Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 24: 2684–2694.

    Article  CAS  PubMed  Google Scholar 

  • Winter-Vann AM, Baron RA, Wong W, dela Cruz J, York JD, Gooden DM et al. (2005). A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc Natl Acad Sci USA 102: 4336–4341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the NIH (R01-CA039771; GMB) and the Audrey E Evans Endowed Chair in Molecular Oncology (GMB). We are grateful to Juan Perin from the Bioinformatics Core for assistance in the sequence analysis of candidate TSGs.

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Correspondence to G M Brodeur.

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Okawa, E., Gotoh, T., Manne, J. et al. Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas. Oncogene 27, 803–810 (2008). https://doi.org/10.1038/sj.onc.1210675

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