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Virchows Archiv

, Volume 475, Issue 5, pp 625–636 | Cite as

IDH1 immunohistochemistry reactivity and mosaic IDH1 or IDH2 somatic mutations in pediatric sporadic enchondroma and enchondromatosis

  • Essia Saiji
  • Fabienne Gumy Pause
  • Pierre Lascombes
  • Christelle Cerato Biderbost
  • Nathalie Lin Marq
  • Margaret Berczy
  • Laura Merlini
  • Anne-Laure RougemontEmail author
Original Article
  • 265 Downloads

Abstract

Mosaic somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes have been identified in most enchondromas by targeted mutation analysis. Next-generation sequencing (NGS), that may detect even low-level mosaic mutation rates, has not previously been applied to enchondromas. Immunohistochemistry using the H09 clone is routinely used as a surrogate for the common R132H IDH1 mutation in gliomas. We compared immunohistochemistry and NGS results in a series of 13 enchondromas from 8 pediatric patients. NGS identified a heterozygous IDH mutation in all enchondromas, showing identical mutation status in patients with multiple tumors assessed, thereby confirming somatic mosaicism. A majority of the tumors harbored an IDH1 mutation (p.R132H in 3 tumors; p.R132C in 4 tumors from 2 patients; p.R132L and p.R132G in one tumor each). A p.R172S IDH2 mutation was identified in 4 enchondromas, but not in the ependymoma from one patient with Ollier disease, who further displayed a heterozygous STK11 missense mutation. IDH mutation rates varied between 14% (indicative of mutations in 28% of the cells and of intratumoral mosaicism) and 45% (tumor content was close to 100%). Cytoplasmic H09 reactivity was observed as expected in tumors with an IDH1 p.R132H mutation; cross-reactivity was seen with the p.R132L variant. This first NGS study of pediatric enchondromas confirms that IDH mutations may occur in a mosaic fashion. STK11 gene mutations may provide insights in the development of multiple cartilaginous tumors in enchondromatosis, this tumor suppressor gene having been shown in animal models to regulate both chondrocyte maturation and growth plate organization during development.

Keywords

IDH mutation Immunohistochemistry Next-generation sequencing NGS Ollier FFPE Children 

Notes

Acknowledgments

The authors thank Mrs. P. Bordignon for the immunohistochemistry techniques and Dr. L. Ho and Dr. S. Clement-Leboube for the OncoScan analysis.

Authors’ contributions

• Have substantially contributed to the conception or design of the work (Anne-Laure Rougemont and Essia Saiji) or the acquisition, analysis, or interpretation of data for the work (Essia Saiji, Fabienne Gumy Pause, Pierre Lascombes, Christelle Cerato Biderbost, Nathalie Lin Marq, Margaret Berczy, Laura Merlini, and Anne-Laure Rougemont).

• Have drafted the work (Anne-Laure Rougemont and Essia Saiji) or revised it critically for important intellectual content (Fabienne Gumy Pause, Pierre Lascombes, Christelle Cerato Biderbost, Margaret Berczy, Nathalie Lin Marq, and Laura Merlini).

• Gave final approval of the version to be published (Essia Saiji, Fabienne Gumy Pause, Pierre Lascombes, Christelle Cerato Biderbost, Nathalie Lin Marq, Margaret Berczy, Laura Merlini, and Anne-Laure Rougemont).

• Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (Essia Saiji, Fabienne Gumy Pause, Pierre Lascombes, Christelle Cerato Biderbost, Nathalie Lin Marq, Margaret Berczy, Laura Merlini, and Anne-Laure Rougemont).

Compliance with ethical standards

The authors/coauthors declare that the study has complied with the ethical standards. This study was approved by the Commission Cantonale d’Ethique de la Recherche (CCER Review Board, approval number GE 14-229).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    (2012 ) World Health Organization Classification of Tumors. Pathology and genetics. IARC Press, LyonGoogle Scholar
  2. 2.
    Eefting D, Schrage YM, Geirnaerdt MJ, Le Cessie S, Taminiau AH, Bovee JV, Hogendoorn PC, Tc EBN (2009) Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol 33:50–57.  https://doi.org/10.1097/PAS.0b013e31817eec2b CrossRefPubMedGoogle Scholar
  3. 3.
    Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343.  https://doi.org/10.1002/path.2913 CrossRefPubMedGoogle Scholar
  4. 4.
    Damato S, Alorjani M, Bonar F, McCarthy SW, Cannon SR, O'Donnell P, Tirabosco R, Amary MF, Flanagan AM (2012) IDH1 mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas. Histopathology 60:363–365.  https://doi.org/10.1111/j.1365-2559.2011.04010.x CrossRefPubMedGoogle Scholar
  5. 5.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773.  https://doi.org/10.1056/NEJMoa0808710 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Arai M, Nobusawa S, Ikota H, Takemura S, Nakazato Y (2012) Frequent IDH1/2 mutations in intracranial chondrosarcoma: a possible diagnostic clue for its differentiation from chordoma. Brain Tumor Pathol 29:201–206.  https://doi.org/10.1007/s10014-012-0085-1 CrossRefPubMedGoogle Scholar
  7. 7.
    Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovee JV (2011) Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256–1261.  https://doi.org/10.1038/ng.1004 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM (2011) Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 43:1262–1265.  https://doi.org/10.1038/ng.994 CrossRefPubMedGoogle Scholar
  9. 9.
    Foster JM, Oumie A, Togneri FS, Vasques FR, Hau D, Taylor M, Tinkler-Hundal E, Southward K, Medlow P, McGreeghan-Crosby K, Halfpenny I, McMullan DJ, Quirke P, Keating KE, Griffiths M, Spink KG, Brew F (2015) Cross-laboratory validation of the OncoScan(R) FFPE assay, a multiplex tool for whole genome tumour profiling. BMC Med Genet 8:5.  https://doi.org/10.1186/s12920-015-0079-z CrossRefGoogle Scholar
  10. 10.
    Herget GW, Strohm P, Rottenburger C, Kontny U, Krauss T, Bohm J, Sudkamp N, Uhl M (2014) Insights into enchondroma, enchondromatosis and the risk of secondary chondrosarcoma. Review of the literature with an emphasis on the clinical behaviour, radiology, malignant transformation and the follow up. Neoplasma 61:365–378.  https://doi.org/10.4149/neo_2014_046 CrossRefPubMedGoogle Scholar
  11. 11.
    Hirata M, Sasaki M, Cairns RA, Inoue S, Puviindran V, Li WY, Snow BE, Jones LD, Wei Q, Sato S, Tang YJ, Nadesan P, Rockel J, Whetstone H, Poon R, Weng A, Gross S, Straley K, Gliser C, Xu Y, Wunder J, Mak TW, Alman BA (2015) Mutant IDH is sufficient to initiate enchondromatosis in mice. Proc Natl Acad Sci U S A 112:2829–2834.  https://doi.org/10.1073/pnas.1424400112 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Moriya K, Kaneko MK, Liu X, Hosaka M, Fujishima F, Sakuma J, Ogasawara S, Watanabe M, Sasahara Y, Kure S, Kato Y (2014) IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome. Cancer Sci 105:359–362.  https://doi.org/10.1111/cas.12337 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Schaap FG, French PJ, Bovee JV (2013) Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in tumors. Adv Anat Pathol 20:32–38.  https://doi.org/10.1097/PAP.0b013e31827b654d CrossRefPubMedGoogle Scholar
  14. 14.
    Suijker J, Baelde HJ, Roelofs H, Cleton-Jansen AM, Bovee JV (2015) The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or -2 blocks osteoblast differentiation in vitro and in vivo. Oncotarget 6:14832–14842.  https://doi.org/10.18632/oncotarget.4024 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Suijker J, Oosting J, Koornneef A, Struys EA, Salomons GS, Schaap FG, Waaijer CJ, Wijers-Koster PM, Briaire-de Bruijn IH, Haazen L, Riester SM, Dudakovic A, Danen E, Cleton-Jansen AM, van Wijnen AJ, Bovee JV (2015) Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget 6:12505–12519.  https://doi.org/10.18632/oncotarget.3723 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cleven AHG, Suijker J, Agrogiannis G, Briaire-de Bruijn IH, Frizzell N, Hoekstra AS, Wijers-Koster PM, Cleton-Jansen AM, Bovee J (2017) IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin Sarcoma Res 7:8.  https://doi.org/10.1186/s13569-017-0074-6 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mondesir J, Willekens C, Touat M, de Botton S (2016) IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med 7:171–180.  https://doi.org/10.2147/JBM.S70716 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Youssoufian H, Pyeritz RE (2002) Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet 3:748–758.  https://doi.org/10.1038/nrg906 CrossRefPubMedGoogle Scholar
  19. 19.
    Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187.  https://doi.org/10.1038/34432 CrossRefPubMedGoogle Scholar
  20. 20.
    Herrmann JL, Byekova Y, Elmets CA, Athar M (2011) Liver kinase B1 (LKB1) in the pathogenesis of epithelial cancers. Cancer Lett 306:1–9.  https://doi.org/10.1016/j.canlet.2011.01.014 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9:563–575.  https://doi.org/10.1038/nrc2676 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Forcet C, Etienne-Manneville S, Gaude H, Fournier L, Debilly S, Salmi M, Baas A, Olschwang S, Clevers H, Billaud M (2005) Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity. Hum Mol Genet 14:1283–1292.  https://doi.org/10.1093/hmg/ddi139 CrossRefPubMedGoogle Scholar
  23. 23.
    Lai LP, Lilley BN, Sanes JR, McMahon AP (2013) Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation. Proc Natl Acad Sci U S A 110:19450–19455.  https://doi.org/10.1073/pnas.1309001110 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Bjorkqvist AM, Knuutila S, Salovaara R, Bodmer W, Shibata D, de la Chapelle A, Aaltonen LA (1997) Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 15:87–90.  https://doi.org/10.1038/ng0197-87 CrossRefPubMedGoogle Scholar
  25. 25.
    Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG (2000) Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene 19:164–168.  https://doi.org/10.1038/sj.onc.1203227 CrossRefPubMedGoogle Scholar
  26. 26.
    Supek F, Minana B, Valcarcel J, Gabaldon T, Lehner B (2014) Synonymous mutations frequently act as driver mutations in human cancers. Cell 156:1324–1335.  https://doi.org/10.1016/j.cell.2014.01.051 CrossRefPubMedGoogle Scholar
  27. 27.
    Capper D, Weissert S, Balss J, Habel A, Meyer J, Jager D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H, Hartmann C, von Deimling A (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254.  https://doi.org/10.1111/j.1750-3639.2009.00352.x CrossRefPubMedGoogle Scholar
  28. 28.
    Jabbar KJ, Luthra R, Patel KP, Singh RR, Goswami R, Aldape KD, Medeiros LJ, Routbort MJ (2015) Comparison of next-generation sequencing mutation profiling with BRAF and IDH1 mutation-specific immunohistochemistry. Am J Surg Pathol 39:454–461.  https://doi.org/10.1097/PAS.0000000000000325 CrossRefPubMedGoogle Scholar
  29. 29.
    Preusser M, Wohrer A, Stary S, Hoftberger R, Streubel B, Hainfellner JA (2011) Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens. J Neuropathol Exp Neurol 70:715–723.  https://doi.org/10.1097/NEN.0b013e31822713f0 CrossRefPubMedGoogle Scholar
  30. 30.
    Agarwal S, Sharma MC, Jha P, Pathak P, Suri V, Sarkar C, Chosdol K, Suri A, Kale SS, Mahapatra AK (2013) Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing. Neuro-Oncology 15:718–726.  https://doi.org/10.1093/neuonc/not015 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Essia Saiji
    • 1
  • Fabienne Gumy Pause
    • 2
  • Pierre Lascombes
    • 3
  • Christelle Cerato Biderbost
    • 1
  • Nathalie Lin Marq
    • 1
  • Margaret Berczy
    • 1
  • Laura Merlini
    • 4
  • Anne-Laure Rougemont
    • 1
    Email author
  1. 1.Division of Clinical Pathology, Molecular Pathology UnitGeneva University HospitalsGenevaSwitzerland
  2. 2.Department of Pediatrics, Onco-hematology UnitGeneva University HospitalsGeneva 14Switzerland
  3. 3.Pediatric Orthopedic DivisionGeneva University HospitalsGeneva 14Switzerland
  4. 4.Pediatric Radiology UnitGeneva University HospitalsGeneva 14Switzerland

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