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FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas

  • Frank Brand
  • Alisa Förster
  • Anne Christians
  • Martin Bucher
  • Carina M. Thomé
  • Marc S. Raab
  • Manfred Westphal
  • Torsten Pietsch
  • Andreas von Deimling
  • Guido Reifenberger
  • Peter Claus
  • Bettina Hentschel
  • Michael Weller
  • Ruthild G. WeberEmail author
Original Paper

Abstract

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II–IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.

Keywords

FOCAD Astrocytic glioma Prognosis Centrosome Microtubules Cell cycle 

Notes

Acknowledgements

The authors wish to thank Alexander Pfeifer, Institute of Pharmacology and Toxicology, University of Bonn Medical Center and University of Bonn, Bonn, Germany for providing the lentivector construct expressing FOCAD-GFP; Erich Nigg, Biozentrum, University of Basel, Switzerland for helpful scientific discussions; Rudolf Bauerfeind, Research Core Unit for Laser Microscopy, Hannover Medical School, Germany for technical support with regard to live-cell imaging experiments; and the Cell Sorting Core Facility, Hannover Medical School, Germany.

Author contributions

FB, AC, BH, MiW, and RGW designed research; FB, AF, AC, MB, and CMT performed research; MSR, MaW, TP, AvD, GR, and PC contributed materials, patient/tumor data and expertise; FB, AC, BH, and RGW analyzed data and made figures; FB, AC, BH, MiW, and RGW wrote the manuscript; all authors reviewed and revised the manuscript.

Funding

FB received a grant from the Hochschulinterne Leistungsförderung (HiLF) program at Hannover Medical School. The German Glioma Network was supported by the German Cancer Aid (Stiftung Deutsche Krebshilfe) from 2004 to 2012 (Grant No. 70-3163-Wi 3).

Compliance with ethical standards

Conflict of interest

GR received research grants from Roche and Merck as well as honoraria for advisory board activities from AbbVie. All other authors report no conflict of interest.

Statement of human and animal rights

The study was approved by the appropriate institutional research ethics committees. All procedures were in accordance with their ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

401_2019_2067_MOESM1_ESM.pdf (2.4 mb)
Supplementary material 1 (PDF 2453 kb)

References

  1. 1.
    Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T, Motomura K, Ohka F, Shiina S, Yamamoto T, Nagata Y, Yoshizato T, Mizoguchi M, Abe T, Momii Y, Muragaki Y, Watanabe R, Ito I, Sanada M, Yajima H, Morita N, Takeuchi I, Miyano S, Wakabayashi T, Ogawa S, Natsume A (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20:66–77.  https://doi.org/10.1093/neuonc/nox132 CrossRefPubMedGoogle Scholar
  2. 2.
    Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, Colaprico A, Wendl MC, Kim J, Reardon B, Kwok-Shing Ng P, Jeong KJ, Cao S, Wang Z, Gao J, Gao Q, Wang F, Liu EM, Mularoni L, Rubio-Perez C, Nagarajan N, Cortés-Ciriano I, Zhou DC, Liang WW, Hess JM, Yellapantula VD, Tamborero D, Gonzalez-Perez A, Suphavilai C, Ko JY, Khurana E, Park PJ, Van Allen EM, Liang H, MC3 Working Group, Cancer Genome Atlas Research Network, Lawrence MS, Godzik A, Lopez-Bigas N, Stuart J, Wheeler D, Getz G, Chen K, Lazar AJ, Mills GB, Karchin R, Ding L (2018) Comprehensive characterization of cancer driver genes and mutations. Cell 174:1034–1035.  https://doi.org/10.1016/j.cell.2018.07.034 CrossRefPubMedGoogle Scholar
  3. 3.
    Bouchet BP, Noordstra I, van Amersfoort M, Katrukha EA, Ammon YC, Ter Hoeve ND, Hodgson L, Dogterom M, Derksen PW, Akhmanova A (2016) Mesenchymal cell invasion requires cooperative regulation of persistent microtubule growth by SLAIN2 and CLASP1. Dev Cell 39:708–723.  https://doi.org/10.1016/j.devcel.2016.11.009 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Brockschmidt A, Trost D, Peterziel H, Zimmermann K, Ehrler M, Grassmann H, Pfenning PN, Waha A, Wohlleber D, Brockschmidt FF, Jugold M, Hoischen A, Kalla C, Waha A, Seifert G, Knolle PA, Latz E, Hans VH, Wick W, Pfeifer A, Angel P, Weber RG (2012) KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. Brain 135:1027–1041.  https://doi.org/10.1093/brain/aws045 CrossRefPubMedGoogle Scholar
  5. 5.
    Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498.  https://doi.org/10.1056/NEJMoa1402121 CrossRefGoogle Scholar
  6. 6.
    Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG Jr, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH, TCGA Research Network, Noushmehr H, Iavarone A, Verhaak RG (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164:550–563.  https://doi.org/10.1016/j.cell.2015.12.028 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cheng MW, Wang BC, Weng ZQ, Zhu XW (2012) Clinicopathological significance of Polo-like kinase 1 (PLK1) expression in human malignant glioma. Acta Histochem 114:503–509.  https://doi.org/10.1016/j.acthis.2011.09.004 CrossRefPubMedGoogle Scholar
  8. 8.
    Ciciarello M, Mangiacasale R, Casenghi M, Zaira Limongi M, D’Angelo M, Soddu S, Lavia P, Cundari E (2001) p53 displacement from centrosomes and p53-mediated G1 arrest following transient inhibition of the mitotic spindle. J Biol Chem 276:19205–19213.  https://doi.org/10.1074/jbc.M009528200 CrossRefPubMedGoogle Scholar
  9. 9.
    Cirillo L, Gotta M, Meraldi P (2017) The elephant in the room: the role of microtubules in cancer. Adv Exp Med Biol 1002:93–124.  https://doi.org/10.1007/978-3-319-57127-0_5 CrossRefPubMedGoogle Scholar
  10. 10.
    Danovi D, Folarin A, Gogolok S, Ender C, Elbatsh AM, Engström PG, Stricker SH, Gagrica S, Georgian A, Yu D, Harvey KJ, Ferretti P, Paddison PJ, Preston JE, Abbott NJ, Bertone P, Smith A, Pollard SM (2013) A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1. PLoS One 8:e77053.  https://doi.org/10.1371/journal.pone.0077053 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dietzmann K, Kirches E, von Bossanyi Jachau K, Mawrin C (2001) Increased human polo-like kinase-1 expression in gliomas. J Neurooncol 53:1–11.  https://doi.org/10.1023/A:1011808200978 CrossRefPubMedGoogle Scholar
  12. 12.
    Dikovskaya D, Newton IP, Näthke IS (2004) The adenomatous polyposis coli protein is required for the formation of robust spindles formed in CSF Xenopus extracts. Mol Biol Cell 15:2978–2991.  https://doi.org/10.1091/mbc.E03-08-0613 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Dong J, Park SY, Nguyen N, Ezhilarasan R, Martinez-Ledesma E, Wu S, Henry V, Piao Y, Tiao N, Brunell D, Stephan C, Verhaak R, Sulman E, Balasubramaniyan V, de Groot JF (2018) The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells. Oncotarget 9:10497–10509.  https://doi.org/10.18632/oncotarget.24041 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Etienne-Manneville S (2013) Microtubules in cell migration. Annu Rev Cell Dev Biol 29:471–499.  https://doi.org/10.1146/annurev-cellbio-101011-155711 CrossRefPubMedGoogle Scholar
  15. 15.
    Gjertsen BT, Schöffski P (2015) Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia 29:11–19.  https://doi.org/10.1038/leu.2014.222 CrossRefPubMedGoogle Scholar
  16. 16.
    Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, Gak IA, Weisswange I, Mansfeld J, Buchholz F, Hyman AA, Mann M (2015) A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 163:712–723.  https://doi.org/10.1016/j.cell.2015.09.053 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Horpaopan S, Spier I, Zink AM, Altmüller J, Holzapfel S, Laner A, Vogt S, Uhlhaas S, Heilmann S, Stienen D, Pasternack SM, Keppler K, Adam R, Kayser K, Moebus S, Draaken M, Degenhardt F, Engels H, Hofmann A, Nöthen MM, Steinke V, Perez-Bouza A, Herms S, Holinski-Feder E, Fröhlich H, Thiele H, Hoffmann P, Aretz S (2015) Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis. Int J Cancer 136:E578–E589.  https://doi.org/10.1002/ijc.29215 CrossRefPubMedGoogle Scholar
  18. 18.
    Hsu LC, White RL (1998) BRCA1 is associated with the centrosome during mitosis. Proc Natl Acad Sci USA 95:12983–12988.  https://doi.org/10.1073/pnas.95.22.12983 CrossRefPubMedGoogle Scholar
  19. 19.
    Juanes MA, Bouguenina H, Eskin JA, Jaiswal R, Badache A, Goode BL (2017) Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover. J Cell Biol 216:2859–2875.  https://doi.org/10.1083/jcb.201702007 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Körber V, Yang J, Barah P, Wu Y, Stichel D, Gu Z, Fletcher MNC, Jones D, Hentschel B, Lamszus K, Tonn JC, Schackert G, Sabel M, Felsberg J, Zacher A, Kaulich K, Hübschmann D, Herold-Mende C, von Deimling A, Weller M, Radlwimmer B, Schlesner M, Reifenberger G, Höfer T, Lichter P (2019) Evolutionary trajectories of IDHWT glioblastomas reveal a common path of early tumorigenesis instigated years ahead of initial diagnosis. Cancer Cell 35:692–704.  https://doi.org/10.1016/j.ccell.2019.02.007 CrossRefPubMedGoogle Scholar
  21. 21.
    Koncar RF, Chu Z, Romick-Rosendale LE, Wells SI, Chan TA, Qi X, Bahassi EM (2017) PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas. Oncotarget 8:15827–15837.  https://doi.org/10.18632/oncotarget.15015 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Korshunov A, Casalini B, Chavez L, Hielscher T, Sill M, Ryzhova M, Sharma T, Schrimpf D, Stichel D, Capper D, Reuss DE, Sturm D, Absalyamova O, Golanov A, Lambo S, Bewerunge-Hudler M, Lichter P, Herold-Mende C, Wick W, Pfister SM, Kool M, Jones DTW, von Deimling A, Sahm F (2019) Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol Appl Neurobiol 45:108–118.  https://doi.org/10.1111/nan.12523 CrossRefPubMedGoogle Scholar
  23. 23.
    Krämer A, Mailand N, Lukas C, Syljuåsen RG, Wilkinson CJ, Nigg EA, Bartek J, Lukas J (2004) Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat Cell Biol 6:884–891.  https://doi.org/10.1038/ncb1165 CrossRefPubMedGoogle Scholar
  24. 24.
    Krepischi AC, Achatz MI, Santos EM, Costa SS, Lisboa BC, Brentani H, Santos TM, Gonçalves A, Nóbrega AF, Pearson PL, Vianna-Morgante AM, Carraro DM, Brentani RR, Rosenberg C (2012) Germline DNA copy number variation in familial and early-onset breast cancer. Breast Cancer Res 14:R24.  https://doi.org/10.1186/bcr3109 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    LaPak KM, Burd CE (2014) The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res 12:167–183.  https://doi.org/10.1158/1541-7786.MCR-13-0350 CrossRefPubMedGoogle Scholar
  26. 26.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) World Health Organization histological classification of tumours of the central nervous system. International Agency for Research on Cancer, LyonGoogle Scholar
  27. 27.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) World Health Organization histological classification of tumours of the central nervous system. International Agency for Research on Cancer, LyonGoogle Scholar
  28. 28.
    Macůrek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH (2008) Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 455:119–123.  https://doi.org/10.1038/nature07185 CrossRefPubMedGoogle Scholar
  29. 29.
    Natrajan R, Mackay A, Lambros MB, Weigelt B, Wilkerson PM, Manie E, Grigoriadis A, Ahern R, van der Groep P, Kozarewa I, Popova T, Mariani O, Turajlic S, Furney SJ, Marais R, Rodruigues DN, Flora AC, Wai P, Pawar V, McDade S, Carroll J, Stoppa-Lyonnet D, Green AR, Ellis IO, Swanton C, van Diest P, Delattre O, Lord CJ, Foulkes WD, Vincent-Salomon A, Ashworth A, Henri Stern M, Reis-Filho JS (2012) A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol 227:29–41.  https://doi.org/10.1002/path.4003 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nigg EA, Schnerch D, Ganier O (2017) Impact of centrosome aberrations on chromosome segregation and tissue architecture in cancer. Cold Spring Harb Symp Quant Biol 82:137–144.  https://doi.org/10.1101/sqb.2017.82.034421 CrossRefPubMedGoogle Scholar
  31. 31.
    Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, Weil S, Horstmann H, Wiestler B, Syed M, Huang L, Ratliff M, Karimian Jazi K, Kurz FT, Schmenger T, Lemke D, Gömmel M, Pauli M, Liao Y, Häring P, Pusch S, Herl V, Steinhäuser C, Krunic D, Jarahian M, Miletic H, Berghoff AS, Griesbeck O, Kalamakis G, Garaschuk O, Preusser M, Weiss S, Liu H, Heiland S, Platten M, Huber PE, Kuner T, von Deimling A, Wick W, Winkler F (2015) Brain tumour cells interconnect to a functional and resistant network. Nature 528:93–98.  https://doi.org/10.1038/nature16071 CrossRefPubMedGoogle Scholar
  32. 32.
    Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P, Doxsey SJ (1998) Centrosome defects and genetic instability in malignant tumors. Cancer Res 58:3974–3985PubMedGoogle Scholar
  33. 33.
    Reifenberger G, Weber RG, Riehmer V, Kaulich K, Willscher E, Wirth H, Gietzelt J, Hentschel B, Westphal M, Simon M, Schackert G, Schramm J, Matschke J, Sabel MC, Gramatzki D, Felsberg J, Hartmann C, Steinbach JP, Schlegel U, Wick W, Radlwimmer B, Pietsch T, Tonn JC, von Deimling A, Binder H, Weller M, Loeffler M, Network German Glioma (2014) Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling. Int J Cancer 135:1822–1831.  https://doi.org/10.1002/ijc.28836 CrossRefPubMedGoogle Scholar
  34. 34.
    Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M (2017) Advances in the molecular genetics of gliomas—implications for classification and therapy. Nat Rev Clin Oncol 14:434–452.  https://doi.org/10.1038/nrclinonc.2016.204 CrossRefPubMedGoogle Scholar
  35. 35.
    Riehmer V, Gietzelt J, Beyer U, Hentschel B, Westphal M, Schackert G, Sabel MC, Radlwimmer B, Pietsch T, Reifenberger G, Weller M, Weber RG, Loeffler M, Network German Glioma (2014) Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild-type glioblastoma. Genes Chromosomes Cancer 53:589–605.  https://doi.org/10.1002/gcc.22169 CrossRefPubMedGoogle Scholar
  36. 36.
    Roy DM, Walsh LA, Desrichard A, Huse JT, Wu W, Gao J, Bose P, Lee W, Chan TA (2016) Integrated genomics for pinpointing survival loci within arm-level somatic copy number alterations. Cancer Cell 29:737–750.  https://doi.org/10.1016/j.ccell.2016.03.025 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sbalzarini IF, Koumoutsakos P (2005) Feature point tracking and trajectory analysis for video imaging in cell biology. J Struct Biol 151:182–195.  https://doi.org/10.1016/j.jsb.2005.06.002 CrossRefPubMedGoogle Scholar
  38. 38.
    Seki A, Coppinger JA, Jang CY, Yates JR, Fang G (2008) Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 320:1655–1658.  https://doi.org/10.1126/science.1157425 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, Koelsche C, Wefers A, Reinhardt A, Huang K, Sievers P, Shimizu H, Nanjo H, Kobayashi Y, Miyake Y, Suzuki T, Adachi JI, Mishima K, Sasaki A, Nishikawa R, Bewerunge-Hudler M, Ryzhova M, Absalyamova O, Golanov A, Sinn P, Platten M, Jungk C, Winkler F, Wick A, Hänggi D, Unterberg A, Pfister SM, Jones DTW, van den Bent M, Hegi M, French P, Baumert BG, Stupp R, Gorlia T, Weller M, Capper D, Korshunov A, Herold-Mende C, Wick W, Louis DN, von Deimling A (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:153–166.  https://doi.org/10.1007/s00401-018-1849-4 CrossRefPubMedGoogle Scholar
  40. 40.
    Stehbens S, Wittmann T (2012) Targeting and transport: how microtubules control focal adhesion dynamics. J Cell Biol 198:481–489.  https://doi.org/10.1083/jcb.201206050 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    van der Vaart B, Manatschal C, Grigoriev I, Olieric V, Gouveia SM, Bjelic S, Demmers J, Vorobjev I, Hoogenraad CC, Steinmetz MO, Akhmanova A (2011) SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase. J Cell Biol 193:1083–1099.  https://doi.org/10.1083/jcb.201012179 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Vaubel RA, Caron AA, Yamada S, Decker PA, Eckel Passow JE, Rodriguez FJ, Nageswara Rao AA, Lachance D, Parney I, Jenkins R, Giannini C (2018) Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. Brain Pathol 28:172–182.  https://doi.org/10.1111/bpa.12495 CrossRefPubMedGoogle Scholar
  43. 43.
    Venkatachalam R, Verwiel ET, Kamping EJ, Hoenselaar E, Görgens H, Schackert HK, van Krieken JH, Ligtenberg MJ, Hoogerbrugge N, van Kessel AG, Kuiper RP (2011) Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients. Int J Cancer 129:1635–1642.  https://doi.org/10.1002/ijc.25821 CrossRefPubMedGoogle Scholar
  44. 44.
    Vertii A, Hehnly H, Doxsey S (2016) The centrosome, a multitalented renaissance organelle. Cold Spring Harb Perspect Biol 8:a025049.  https://doi.org/10.1101/cshperspect.a025049 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Weber RG, Bridger JM, Benner A, Weisenberger D, Ehemann V, Reifenberger G, Lichter P (1998) Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations. Cytogenet Cell Genet 83:266–269.  https://doi.org/10.1159/000015168 CrossRefPubMedGoogle Scholar
  46. 46.
    Weller M, Weber RG, Willscher E, Riehmer V, Hentschel B, Kreuz M, Felsberg J, Beyer U, Löffler-Wirth H, Kaulich K, Steinbach JP, Hartmann C, Gramatzki D, Schramm J, Westphal M, Schackert G, Simon M, Martens T, Boström J, Hagel C, Sabel M, Krex D, Tonn JC, Wick W, Noell S, Schlegel U, Radlwimmer B, Pietsch T, Loeffler M, von Deimling A, Binder H, Reifenberger G (2015) Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 129:679–693.  https://doi.org/10.1007/s00401-015-1409-0 CrossRefPubMedGoogle Scholar
  47. 47.
    Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Le Rhun E, Balana C, Chinot O, Bendszus M, Reijneveld JC, Dhermain F, French P, Marosi C, Watts C, Oberg I, Pilkington G, Baumert BG, Taphoorn MJB, Hegi M, Westphal M, Reifenberger G, Soffietti R, Wick W, European Association for Neuro-Oncology (EANO) Task Force on Gliomas (2017) European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol 18:e315–e329.  https://doi.org/10.1016/S1470-2045(17)30194-8 CrossRefGoogle Scholar
  48. 48.
    Weren RD, Venkatachalam R, Cazier JB, Farin HF, Kets CM, de Voer RM, Vreede L, Verwiel ET, van Asseldonk M, Kamping EJ, Kiemeney LA, Neveling K, Aben KK, Carvajal-Carmona L, Nagtegaal ID, Schackert HK, Clevers H, van de Wetering M, Tomlinson IP, Ligtenberg MJ, Hoogerbrugge N, Geurts van Kessel A, Kuiper RP (2015) Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development. J Pathol 236:155–164.  https://doi.org/10.1002/path.4520 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Frank Brand
    • 1
  • Alisa Förster
    • 1
  • Anne Christians
    • 1
  • Martin Bucher
    • 1
  • Carina M. Thomé
    • 2
  • Marc S. Raab
    • 3
    • 4
  • Manfred Westphal
    • 5
  • Torsten Pietsch
    • 6
  • Andreas von Deimling
    • 7
    • 8
  • Guido Reifenberger
    • 9
    • 10
  • Peter Claus
    • 11
    • 12
  • Bettina Hentschel
    • 13
  • Michael Weller
    • 14
  • Ruthild G. Weber
    • 1
    Email author
  1. 1.Department of Human Genetics OE 6300Hannover Medical SchoolHannoverGermany
  2. 2.Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of Internal Medicine V, Hematology, Oncology and RheumatologyUniversity of HeidelbergHeidelbergGermany
  4. 4.Clinical Cooperation Unit Molecular Hematology/OncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Department of NeurosurgeryUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Department of NeuropathologyUniversity of Bonn Medical SchoolBonnGermany
  7. 7.Department of Neuropathology, Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  8. 8.Clinical Cooperation Unit NeuropathologyGerman Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.Department of NeuropathologyHeinrich-Heine-UniversityDüsseldorfGermany
  10. 10.German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ)HeidelbergGermany
  11. 11.Department of Neuroanatomy and Cell BiologyHannover Medical SchoolHannoverGermany
  12. 12.Center for Systems Neuroscience (ZSN)HannoverGermany
  13. 13.Institute for Medical Informatics, Statistics and EpidemiologyUniversity of LeipzigLeipzigGermany
  14. 14.Department of NeurologyUniversity Hospital and University of ZurichZurichSwitzerland

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