Advertisement

Acta Neuropathologica

, Volume 136, Issue 2, pp 327–337 | Cite as

Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations

  • Christian Koelsche
  • Martin Mynarek
  • Daniel Schrimpf
  • Luca Bertero
  • Jonathan Serrano
  • Felix Sahm
  • David E. Reuss
  • Yanghao Hou
  • Daniel Baumhoer
  • Christian Vokuhl
  • Uta Flucke
  • Iver Petersen
  • Wolfgang Brück
  • Stefan Rutkowski
  • Sandro Casavilca Zambrano
  • Juan Luis Garcia Leon
  • Rosdali Yesenia Diaz Coronado
  • Manfred Gessler
  • Oscar M. Tirado
  • Jaume Mora
  • Javier Alonso
  • Xavier Garcia del Muro
  • Manel Esteller
  • Dominik Sturm
  • Jonas Ecker
  • Till Milde
  • Stefan M. Pfister
  • Andrey Korshunov
  • Matija Snuderl
  • Gunhild Mechtersheimer
  • Ulrich Schüller
  • David T. W. Jones
  • Andreas von Deimling
Original Paper

Abstract

Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation “spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant” for this intriguing group.

Keywords

DICER1 TP53 MAPK CNS Sarcoma NGS DNA-methylation profiling EPIC array 

Notes

Acknowledgements

We thank the Microarray Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing excellent methylation services. The work was supported by the German Cancer Aid (Grant 70112499). The study was in part supported by Grants from the Friedberg Charitable Foundation and the Sohn Conference Foundation (to M.S.), by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg (to U.S.), and by the Damp Foundation (to M.M.).

Compliance with ethical standards

Conflict of interest

The authors state no conflict of interest.

Supplementary material

401_2018_1871_MOESM1_ESM.tif (23.8 mb)
Supplementary Figure 1 (Online Resource 2): Case with an outstanding heterogeneous morphology. This triple positive case (myogenin, desmin, α-smooth muscle actin) exhibits a striking variation in morphological patterns. This case exhibits areas with increased cellularity of polygonal to spindle-shaped tumor cells (a) and areas with less cellularity and a myxoid tumor matrix, occasionally accompanied with a perivascular accentuation of tumor cells (b). In these areas, some cells are suspicious for rhabdomyoblasts (arrows). The tumor focally exhibits a hyaline collagenous matrix (c). A substantial proportion of the tumor bulk is composed of prominent cartilaginous differentiation (d). Inlets show the myogenin expression in the corresponding area shown in the H&E. Scale bars equal 100 μm (TIFF 24373 kb)
401_2018_1871_MOESM2_ESM.xlsx (11 kb)
Supplementary Table 1 (Online Resource 1): Case numbers of the DNA-methylation reference set (XLSX 10 kb)
401_2018_1871_MOESM3_ESM.xlsx (14 kb)
Supplementary Table 2 (Online Resource 3): Histologic features and immunophenotype (XLSX 13 kb)
401_2018_1871_MOESM4_ESM.xlsx (26 kb)
Supplementary Table 3 (Online Resource 4): Molecular results. Variants called by next generation sequencing are depicted in a two-tier ranking of evidence separated in probably (red colored) and possibly (blue colored) clinically relevant. Copy number alterations of the respective genes were calculated from array-generated methylation data (XLSX 25 kb)

References

  1. 1.
    Capper D, Jones DTW, Sill M et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    de Kock L, Boshari T, Martinelli F, Wojcik E, Niedziela M, Foulkes WD (2016) Adult-onset cervical embryonal rhabdomyosarcoma and DICER1 mutations. J Low Genit Tract Dis 20:e8–e10CrossRefPubMedGoogle Scholar
  3. 3.
    de Kock L, Druker H, Weber E et al (2015) Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome. Hum Pathol 46:917–922CrossRefPubMedGoogle Scholar
  4. 4.
    de Kock L, Foulkes WD (2016) Sarcoma and germ-line DICER1 mutations. Lancet Oncol 17:e470CrossRefPubMedGoogle Scholar
  5. 5.
    de Kock L, Sabbaghian N, Druker H et al (2014) Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128:583–595CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dehner LP, Jarzembowski JA, Hill DA (2012) Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol 25:602–614CrossRefPubMedGoogle Scholar
  7. 7.
    Doros L, Yang J, Dehner L et al (2012) DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr Blood Cancer 59:558–560CrossRefPubMedGoogle Scholar
  8. 8.
    Dropcho EJ, Allen JC (1987) Primary intracranial rhabdomyosarcoma: case report and review of the literature. J Neurooncol 5:139–150CrossRefPubMedGoogle Scholar
  9. 9.
    Drummond CJ, Hanna JA, Garcia MR, Devine DJ, Heyrana AJ, Finkelstein D, Rehg JE, Hatley ME (2018) Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from non-myogenic endothelial progenitors. Cancer Cell 33(108–124):e105Google Scholar
  10. 10.
    Fernandez-Martinez L, Villegas JA, Santamaria I et al (2017) Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree. BMC Cancer 17:146CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Foulkes WD, Bahubeshi A, Hamel N et al (2011) Extending the phenotypes associated with DICER1 mutations. Hum Mutat 32:1381–1384CrossRefPubMedGoogle Scholar
  12. 12.
    Foulkes WD, Priest JR, Duchaine TF (2014) DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer 14:662–672CrossRefPubMedGoogle Scholar
  13. 13.
    Grobner SN, Worst BC, Weischenfeldt J et al (2018) The landscape of genomic alterations across childhood cancers. Nature 555:321–327CrossRefPubMedGoogle Scholar
  14. 14.
    Koelsche C, Hartmann W, Schrimpf D et al (2018) Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod Pathol.  https://doi.org/10.1038/s41379-018-0045-3 CrossRefPubMedGoogle Scholar
  15. 15.
    Koelsche C, Schrimpf D, Tharun L et al (2017) Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases. Clin Sarcoma Res 7:9CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kuhlen M, Borkhardt A (2015) Cancer susceptibility syndromes in children in the area of broad clinical use of massive parallel sequencing. Eur J Pediatr 174:987–997CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lo Muzio L (2008) Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 3:32CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820CrossRefPubMedGoogle Scholar
  19. 19.
    McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MH, Eeles RA, Thomas DM, Mitchell G (2014) Li–Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol 11:260–271CrossRefPubMedGoogle Scholar
  20. 20.
    Nair P, Das KK, Srivastava AK, Sahu RN, Kumar R, Yadava K, Pandey R (2017) Primary intracranial rhabdomyosarcoma of the cerebellopontine angle mimicking a vestibular schwannoma in a child. Asian J Neurosurg 12:109–111CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ognjanovic S, Martel G, Manivel C, Olivier M, Langer E, Hainaut P (2012) Low prevalence of TP53 mutations and MDM2 amplifications in pediatric rhabdomyosarcoma. Sarcoma 2012:492086CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ognjanovic S, Olivier M, Bergemann TL, Hainaut P (2012) Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 118:1387–1396CrossRefPubMedGoogle Scholar
  23. 23.
    Pajtler KW, Witt H, Sill M et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Palta M, Riedel RF, Vredenburgh JJ, Cummings TJ, Green S, Chang Z, Kirkpatrick JP (2011) Primary meningeal rhabdomyosarcoma. Sarcoma 2011:312802CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Paulus W, Slowik F, Jellinger K (1991) Primary intracranial sarcomas: histopathological features of 19 cases. Histopathology 18:395–402CrossRefPubMedGoogle Scholar
  26. 26.
    Ripperger T, Bielack SS, Borkhardt A et al (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 173:1017–1037CrossRefPubMedGoogle Scholar
  27. 27.
    Sahm F, Schrimpf D, Jones DT et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910CrossRefPubMedGoogle Scholar
  28. 28.
    Sahm F, Schrimpf D, Stichel D et al (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694CrossRefPubMedGoogle Scholar
  29. 29.
    Schultz KA, Harris A, Messinger Y, Sencer S, Baldinger S, Dehner LP, Hill DA (2016) Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry. Fam Cancer 15:105–110CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Seki M, Nishimura R, Yoshida K et al (2015) Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. Nat Commun 6:7557CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Shern JF, Chen L, Chmielecki J et al (2014) Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4:216–231CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sturm D, Orr BA, Toprak UH et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sturm D, Witt H, Hovestadt V et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437CrossRefPubMedGoogle Scholar
  34. 34.
    Taratuto AL, Molina HA, Diez B, Zuccaro G, Monges J (1985) Primary rhabdomyosarcoma of brain and cerebellum. Report of four cases in infants: an immunohistochemical study. Acta Neuropathol 66:98–104CrossRefPubMedGoogle Scholar
  35. 35.
    Verrier F, Dubois d’Enghien C, Gauthier-Villars M, Bonadona V, Faure-Conter C, Dijoud F, Stoppa-Lyonnet D, Houdayer C, Golmard L (2018) Mutiple DICER1-related lesions associated with a germline deep intronic mutation. Pediatr Blood Cancer 65:e27005CrossRefPubMedGoogle Scholar
  36. 36.
    Vujanic GM, Kelsey A, Perlman EJ, Sandstedt B, Beckwith JB (2007) Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 31:1459–1468CrossRefPubMedGoogle Scholar
  37. 37.
    Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wu MK, Vujanic GM, Fahiminiya S, Watanabe N, Thorner PS, O’Sullivan MJ, Fabian MR, Foulkes WD (2018) Anaplastic sarcomas of the kidney are characterized by DICER1 mutations. Mod Pathol 31:169–178CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Christian Koelsche
    • 1
    • 2
    • 3
  • Martin Mynarek
    • 4
  • Daniel Schrimpf
    • 1
    • 2
  • Luca Bertero
    • 1
    • 5
  • Jonathan Serrano
    • 6
  • Felix Sahm
    • 1
    • 2
  • David E. Reuss
    • 1
    • 2
  • Yanghao Hou
    • 1
  • Daniel Baumhoer
    • 7
  • Christian Vokuhl
    • 8
  • Uta Flucke
    • 9
  • Iver Petersen
    • 10
  • Wolfgang Brück
    • 11
  • Stefan Rutkowski
    • 4
  • Sandro Casavilca Zambrano
    • 12
  • Juan Luis Garcia Leon
    • 13
    • 14
    • 15
  • Rosdali Yesenia Diaz Coronado
    • 15
  • Manfred Gessler
    • 16
    • 17
  • Oscar M. Tirado
    • 18
  • Jaume Mora
    • 19
  • Javier Alonso
    • 20
  • Xavier Garcia del Muro
    • 21
  • Manel Esteller
    • 22
    • 23
    • 24
  • Dominik Sturm
    • 25
    • 26
    • 27
  • Jonas Ecker
    • 25
    • 27
    • 28
  • Till Milde
    • 25
    • 27
    • 28
  • Stefan M. Pfister
    • 25
    • 26
    • 27
  • Andrey Korshunov
    • 1
    • 2
  • Matija Snuderl
    • 6
  • Gunhild Mechtersheimer
    • 3
  • Ulrich Schüller
    • 4
    • 29
    • 30
  • David T. W. Jones
    • 25
    • 31
  • Andreas von Deimling
    • 1
    • 2
  1. 1.Department of Neuropathology, Institute of PathologyHeidelberg University HospitalHeidelbergGermany
  2. 2.Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)German Consortium for Translational Cancer Research (DKTK)HeidelbergGermany
  3. 3.Department of General Pathology, Institute of PathologyHeidelberg University HospitalHeidelbergGermany
  4. 4.Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  5. 5.Pathology Unit, Department of Medical SciencesUniversity of TurinTurinItaly
  6. 6.Department of PathologyNew York University School of MedicineNew YorkUSA
  7. 7.Bone Tumour Reference Centre, Institute of PathologyBasel University HospitalBaselSwitzerland
  8. 8.Department of Pediatric PathologyUniversity Hospital of Schleswig-HolsteinKielGermany
  9. 9.Department of PathologyRadboud University Medical CenterNijmegenThe Netherlands
  10. 10.Institute of PathologySRH Poliklinik Gera GmbHGeraGermany
  11. 11.Institute of NeuropathologyUniversity Medical CenterGöttingenGermany
  12. 12.Department of PathologyInstituto Nacional de Enfermedades Neoplásicas (INEN)LimaPeru
  13. 13.Pediatric Oncology UnitClínica Anglo AmericanaLimaPeru
  14. 14.Pediatric Oncology UnitClínica DelgadoLimaPeru
  15. 15.Department of Pediatric OncologyInstituto Nacional de Enfermedades Neoplásicas (INEN)LimaPeru
  16. 16.Comprehensive Cancer Center MainfrankenWürzburg UniversityWürzburgGermany
  17. 17.Theodor-Boveri-Institute/Biocenter, Developmental BiochemistryWürzburg UniversityWürzburgGermany
  18. 18.Molecular Oncology Lab, Sarcoma Research GroupBellvitge Biomedical Research Institute (IDIBELL)BarcelonaSpain
  19. 19.Department of Pediatric Onco-Hematology and Developmental Tumor Biology LaboratoryHospital Sant Joan de DéuBarcelonaSpain
  20. 20.Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare DiseasesInstituto de Salud Carlos III (ISCIII)MadridSpain
  21. 21.Oncology DepartmentICO-IDIBELLBarcelonaSpain
  22. 22.Cancer Epigenetics and Biology Program (PEBC)Bellvitge Biomedical Research Institute (IDIBELL)BarcelonaSpain
  23. 23.Department of Physiological Sciences II, School of MedicineUniversity of BarcelonaBarcelonaSpain
  24. 24.Institucio Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain
  25. 25.Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  26. 26.Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ)German Consortium for Translational Cancer Research (DKTK)HeidelbergGermany
  27. 27.Department of Pediatric Oncology, Hematology and ImmunologyHeidelberg University HospitalHeidelbergGermany
  28. 28.Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ)German Consortium for Translational Cancer Research (DKTK)HeidelbergGermany
  29. 29.Institute of NeuropathologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  30. 30.Children’s Cancer Center HamburgResearch InstituteHamburgGermany
  31. 31.Pediatric Glioma Research Group, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK)HeidelbergGermany

Personalised recommendations