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Mutated SON putatively causes a cancer syndrome comprising high-risk medulloblastoma combined with café-au-lait spots

  • Celine Chiu
  • Stefanie Loth
  • Michaela Kuhlen
  • Sebastian Ginzel
  • Jörg Schaper
  • Thorsten Rosenbaum
  • Torsten Pietsch
  • Arndt Borkhardt
  • Jessica I. HoellEmail author
Short Communication

Abstract

Medulloblastoma is the most frequent malignant brain tumor in childhood. This highly malignant neoplasm occurs usually before 10 years of age and more frequently in boys. The 5-year event-free survival rate for high-risk medulloblastoma is low at 62% despite a multimodal therapy including surgical resection, radiation therapy and chemotherapy. We report the case of a boy, who was born to consanguineous parents. Prominently, he had multiple café-au-lait spots. At the age of 3 years he was diagnosed with a high-risk metastatic medulloblastoma. The patient died only 11 months after diagnosis of a fulminant relapse presenting as meningeal and spinal dissemination. Whole-exome sequencing of germline DNA was employed to detect the underlying mutation for this putative cancer syndrome presenting with the combination of medulloblastoma and skin alterations. After screening all possible homozygous gene SNVs, we identified a mutation of SON, an essential protein in cell cycle regulation and cell proliferation, as the most likely genetic cause.

Keywords

Medulloblastoma Skin alteration Cancer syndrome SON mutation 

Notes

Acknowledgements

The authors thank Michael Gombert for sequencing.

Funding

Celine Chiu was funded by the Düsseldorf School of Oncology (funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Düsseldorf) and Jessica I. Hoell by Deutsche Forschungsgemeinschaft (DFG, HO 5456/3-1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Muller K, Goschzik T, Zur Muhlen A, Gerber N, Warmuth-Metz M, Soerensen N, Deinlein F, Benesch M, Zwiener I, Kwiecien R, Faldum A, Bode U, Fleischhack G, Hovestadt V, Kool M, Jones D, Northcott P, Kuehl J, Pfister S, Pietsch T, Rutkowski S (2016) Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters. J Clin Oncol 34(34):4151–4160.  https://doi.org/10.1200/JCO.2016.67.2428 CrossRefGoogle Scholar
  2. 2.
    Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, Debatin KM, Deubzer H, Dirksen U, Eckert C, Eggert A, Erlacher M, Fleischhack G, Fruhwald MC, Gnekow A, Goehring G, Graf N, Hanenberg H, Hauer J, Hero B, Hettmer S, von Hoff K, Horstmann M, Hoyer J, Illig T, Kaatsch P, Kappler R, Kerl K, Klingebiel T, Kontny U, Kordes U, Korholz D, Koscielniak E, Kramm CM, Kuhlen M, Kulozik AE, Lamottke B, Leuschner I, Lohmann DR, Meinhardt A, Metzler M, Meyer LH, Moser O, Nathrath M, Niemeyer CM, Nustede R, Pajtler KW, Paret C, Rasche M, Reinhardt D, Riess O, Russo A, Rutkowski S, Schlegelberger B, Schneider D, Schneppenheim R, Schrappe M, Schroeder C, von Schweinitz D, Simon T, Sparber-Sauer M, Spix C, Stanulla M, Steinemann D, Strahm B, Temming P, Thomay K, von Bueren AO, Vorwerk P, Witt O, Wlodarski M, Wossmann W, Zenker M, Zimmermann S, Pfister SM, Kratz CP (2017) Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A 173(4):1017–1037.  https://doi.org/10.1002/ajmg.a.38142 CrossRefGoogle Scholar
  3. 3.
    Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. New Engl J Med 369(16):1502–1511.  https://doi.org/10.1056/NEJMoa1306555 CrossRefGoogle Scholar
  4. 4.
    Hoell JI, Gombert M, Ginzel S, Loth S, Landgraf P, Kafer V, Streiter M, Prokop A, Weiss M, Thiele R, Borkhardt A (2014) Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect. Klin Padiatr 226(6–7):357–361.  https://doi.org/10.1055/s-0034-1389905 Google Scholar
  5. 5.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079CrossRefGoogle Scholar
  6. 6.
    Duraku LS, Hossaini M, Schuttenhelm BN, Holstege JC, Baas M, Ruigrok TJ, Walbeehm ET (2013) Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2 × 3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain. Exp Neurol 241:13–24.  https://doi.org/10.1016/j.expneurol.2012.11.029 CrossRefGoogle Scholar
  7. 7.
    DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43(5):491–498.  https://doi.org/10.1038/ng.806 CrossRefGoogle Scholar
  8. 8.
    McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26(16):2069–2070.  https://doi.org/10.1093/bioinformatics/btq330 CrossRefGoogle Scholar
  9. 9.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249.  https://doi.org/10.1038/nmeth0410-248 CrossRefGoogle Scholar
  10. 10.
    Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081CrossRefGoogle Scholar
  11. 11.
    Mercimek-Mahmutoglu S, Ndika J, Kanhai W, de Villemeur TB, Cheillan D, Christensen E, Dorison N, Hannig V, Hendriks Y, Hofstede FC, Lion-Francois L, Lund AM, Mundy H, Pitelet G, Raspall-Chaure M, Scott-Schwoerer JA, Szakszon K, Valayannopoulos V, Williams M, Salomons GS (2014) Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat 35(4):462–469.  https://doi.org/10.1002/humu.22511 CrossRefGoogle Scholar
  12. 12.
    Kinzel D, Boldt K, Davis EE, Burtscher I, Trumbach D, Diplas B, Attie-Bitach T, Wurst W, Katsanis N, Ueffing M, Lickert H (2010) Pitchfork regulates primary cilia disassembly and left-right asymmetry. Dev Cell 19(1):66–77.  https://doi.org/10.1016/j.devcel.2010.06.005 CrossRefGoogle Scholar
  13. 13.
    McIntyre JC, Williams CL, Martens JR (2013) Smelling the roses and seeing the light: gene therapy for ciliopathies. Trends Biotechnol 31(6):355–363.  https://doi.org/10.1016/j.tibtech.2013.03.005 CrossRefGoogle Scholar
  14. 14.
    Conduit SE, Ramaswamy V, Remke M, Watkins DN, Wainwright BJ, Taylor MD, Mitchell CA, Dyson JM (2017) A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma. Oncogene 36(43):5969–5984.  https://doi.org/10.1038/onc.2017.208 CrossRefGoogle Scholar
  15. 15.
    Hickey CJ, Kim JH, Ahn EY (2014) New discoveries of old SON: a link between RNA splicing and cancer. J Cell Biochem 115(2):224–231.  https://doi.org/10.1002/jcb.24672 CrossRefGoogle Scholar
  16. 16.
    Sharma A, Takata H, Shibahara K, Bubulya A, Bubulya PA (2010) Son is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell 21(4):650–663.  https://doi.org/10.1091/mbc.E09-02-0126 CrossRefGoogle Scholar
  17. 17.
    Furukawa T, Tanji E, Kuboki Y, Hatori T, Yamamoto M, Shimizu K, Shibata N, Shiratori K (2012) Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells. Mol cancer 11:88.  https://doi.org/10.1186/1476-4598-11-88 CrossRefGoogle Scholar
  18. 18.
    Kim JH, Baddoo MC, Park EY, Stone JK, Park H, Butler TW, Huang G, Yan X, Pauli-Behn F, Myers RM, Tan M, Flemington EK, Lim ST, Ahn EY (2016) SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes. Mol cell 61(6):859–873.  https://doi.org/10.1016/j.molcel.2016.02.024 CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Children’s HospitalHeinrich-Heine UniversityDüsseldorfGermany
  2. 2.Department of Diagnostic and Interventional Radiology, Medical FacultyUniversity of DuesseldorfDüsseldorfGermany
  3. 3.Department of PediatricsSana Kliniken DuisburgDuisburgGermany
  4. 4.Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of BonnDZNE German Center for Neurodegenerative DiseasesBonnGermany

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