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TERT promotor region rearrangements analyzed in high-risk neuroblastomas by FISH method and whole genome sequencing

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Abstract

Background

Unfavorable neuroblastomas (NBLs) achieve telomere stabilization via telomerase activation through MYCN amplification, TERT promoter region (TERT-PR) rearrangements, or alternative telomere lengthening of telomeres. No well-established methods are available for investigating TERT-PR rearrangements. We examined the relationship between and prognosis by fluorescence in situ hybridization (FISH) upstream and downstream of TERT to establish a simple analysis method.

Procedure

TERT-PR rearrangements were analyzed in 3 M MYCN amplified cases and, 11MYCN non-amplified cases (1 MS case, 1 L2 case and 2 M cases less than 18 months, and 1 L2 case and  6 M cases over 18 months old at diagnosis) to determine if MYCN and TERT-PR rearrangement were independent prognostic factors. In total, 14 patients (11 males, 3 females; median age 36.4 months, range 1–122 months) with NBLs were evaluated at Hiroshima University. We identified MYCN amplification, TERT expression, and TERT-PR rearrangements. TERT-PR rearrangement was detected by FISH upstream and downstream of TERT on Chr5.p15.33. For TERT-PR rearranged cases, we characterized the fusion partners by whole genome sequencing.

Results

We detected TERT-PR rearrangements in two NBL samples. Both samples were high-risk NBLs and MYCN single NBLs, and their TERT expression levels were extremely higher than in the other samples. Genomic translocation occurred at chromosome 5p15.33 according to whole genome sequencing, agreeing with the FISH results. One case showed translocation of the chr5.p15.33 SLCA6A19 gene to 22q12.3, and another case showed chr5p15.33 to chr5q33.3.

Conclusions

FISH is a useful diagnostic tool for evaluating high-risk NBLs in which TERT-PR rearrangements have occurred.

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References

  1. Gurney JG, Ross JA, Wall DA et al (1997) Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol 19:428–432

    Article  CAS  Google Scholar 

  2. Molenaar JJ, Koster J, Zwijnenburg DA et al (2012) Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483(7391):589–593

    Article  CAS  Google Scholar 

  3. Caron H, van Sluis P, de Kraker J et al (1996) Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 334(4):225–230

    Article  CAS  Google Scholar 

  4. Hiyama E, Hiyama K, Yokoyama T et al (1995) Correlating telomerase activity levels with human neuroblastoma outcomes. Natr Med 1:249–255

    Article  CAS  Google Scholar 

  5. Poremba C, Hero B, Heine B et al (2000) Telomerase is a strong indicator for assessing the proneness to progression in neuroblastomas. Med Pediatr Oncol 35:651–655

    Article  CAS  Google Scholar 

  6. Onitake Y, Hiyama E, Kamei N et al (2009) Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres. J Pediatr Surg 44:2258–2266

    Article  Google Scholar 

  7. Kurihara S, Hiyama E, Onitake Y et al (2014) Clinical features of ATRX or DAXX mutated neuroblastoma. J Pediatr Surg 49:1835–1838

    Article  Google Scholar 

  8. Hiyama E, Hiyama K (2009) Diagnostic and prognostic molecular markers in neuroblastoma. Transworld research Network, Kerala

    Google Scholar 

  9. Hiyama E, Iehara T, Sugimoto T et al (2008) Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study. Lancet 371:1173–1180

    Article  Google Scholar 

  10. Valentijn LJ, Koster J, Zwijnenburg DA et al (2015) TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet 47:1411–1414

    Article  CAS  Google Scholar 

  11. Kawashima M, Kojima M, Ueda Y et al (2016) Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments. J Pediatr Surg 51(12):2080–2085

    Article  Google Scholar 

  12. Peifer M, Hertwig F, Roels F et al (2015) Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526(7575):700–704

    Article  CAS  Google Scholar 

  13. Brisse HJ, McCarville MB, Granata C et al (2011) International neuroblastoma risk group project: guideline for imaging and staging of neuroblastic tumors: consensus report from the international neuroblastoma risk group project. Radiology 261:243–257

    Article  Google Scholar 

  14. Sawaguchi S, Kaneko M, Uchino J 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

    Article  CAS  Google Scholar 

  15. Fan et al (2014) 2014 BreakDancer—identification of genomic structural variation from paired-end read mapping. Curr Protocol Bioinform 45:1561–15611

    Article  Google Scholar 

  16. Lindner S, Bachmann HS, Odersky A et al (2015) Absence of telomerase reverse transcriptase promoter mutations in neuroblastoma. Biomed Rep 3(4):443–446

    Article  CAS  Google Scholar 

  17. Mac SM, D'Cunha CA, Farnham PJ (2000) Direct recruitment of N-myc to target gene promoters. Mol Carcinog 29(2):76–86

    Article  CAS  Google Scholar 

  18. Huang M, Yan C, Xiao J et al (2019) Relevance and clinicopathologic relationship of BRAF V600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in Northwest China. Diagn Pathol 14(1):74

    Article  Google Scholar 

  19. Stenman A, Hysek M, Jatta K et al (2019) TERT promoter mutation spatial heterogeneity in a metastatic follicular thyroid carcinoma: implications for clinical work-up. Endocr Pathol 30(3):246–248

    Article  CAS  Google Scholar 

  20. Giorgenon TMV, Carrijo FT, Arruda MA et al (2019) Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules. Arch Endocrinol Metab 63(2):107–112

    PubMed  Google Scholar 

  21. Lu VM, Goyal A, Lee A et al (2019) The prognostic significance of TERT promoter mutations in meningioma: a systematic review and meta-analysis. J Neurooncol 142(1):1–10

    Article  CAS  Google Scholar 

  22. Amisaki M, Tsuchiya H, Sakabe T et al (2019) Identification of genes involved in the regulation of TERT in hepatocellular carcinoma. Cancer Sci 110(2):550–560

    Article  CAS  Google Scholar 

  23. Gay-Bellile M, Véronèse L, Combes P et al (2017) TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer. Oncotarget 8(44):77540–77551

    Article  Google Scholar 

  24. Horn S, Figl A, Rachakonda PS et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961

    Article  CAS  Google Scholar 

  25. Griewank KG, Murali R, Schilling B et al (2013) TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours. Br J Cancer 109:497–501

    Article  CAS  Google Scholar 

  26. Huang FW, Hodis E, Xu MJ et al (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959

    Article  CAS  Google Scholar 

  27. Reynolds CP, Zuo JJ, Hong CM et al (1996) Telomerase RNA expression in neuroblastoma correlates with high stage and clinical outcome. Proc Am Assoc Cancer Res 37:199

    Google Scholar 

  28. Hiyama E, Hiyama K, Ohtsu K et al (1997) Telomerase activity in neuroblastoma: is it prognostic indicator of clinical behavior? Eur J Cancer 33:1932–1936

    Article  CAS  Google Scholar 

  29. Greenberg RA, O’Hagan RC, Deng H et al (1999) Telomerase reverse transcriptase gene is a direct target of c-myc but is not functionally equivalent in cellular transformation. Oncogene 18:1219–1226

    Article  CAS  Google Scholar 

  30. Kyo S, Takakura M, Taira T et al (2000) Sp1 cooperates with c-myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res 28:669–677

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all staff of the institutes that submitted NBL samples in this study. We thank Mr. S. Kimra, Mrs. N. Morihara, Mrs. S. Hirano, Ms. I. Fukuba, and Mrs. F. Irisuna for the technical assistance. We also thank the Analysis Center of Life Science, Natural Science Center of Basic Research and Development, and Research Center for Molecular Center, Graduate School of Biomedical Science, Hiroshima University for the use of their facilities. This research was partially supported by a Grant-in-Aid for Scientific Research (A) (No. 15H02567 & 19H010561) from the Ministry of Education, Culture, Sports, Science, and Technology and those (No. 18ck0106332h & 20ck0106609h) from the AMED (Japan Agency for Medical Research and Development)..

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Authors and Affiliations

  1. Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan

    Masumi Kawashima, Yuka Ueda, Sho Kurihara & Eiso Hiyama

  2. Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Masumi Kawashima, Yuka Ueda, Sho Kurihara & Eiso Hiyama

  3. Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Eiso Hiyama

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  1. Masumi Kawashima
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  2. Yuka Ueda
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  4. Eiso Hiyama
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Correspondence to Eiso Hiyama.

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Kawashima, M., Ueda, Y., Kurihara, S. et al. TERT promotor region rearrangements analyzed in high-risk neuroblastomas by FISH method and whole genome sequencing. Int J Clin Oncol 25, 2166–2174 (2020). https://doi.org/10.1007/s10147-020-01773-z

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  • DOI: https://doi.org/10.1007/s10147-020-01773-z

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