Top

Published in:

Open Access 01-12-2016 | Research

Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles

Authors: Annett Hölsken, Martin Sill, Jessica Merkle, Leonille Schweizer, Michael Buchfelder, Jörg Flitsch, Rudolf Fahlbusch, Markus Metzler, Marcel Kool, Stefan M. Pfister, Andreas von Deimling, David Capper, David T. W. Jones, Rolf Buslei

Published in: Acta Neuropathologica Communications | Issue 1/2016

Abstract

Introduction

Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP.

Results

BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP.

Conclusions

AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.

Available only for authorised users

Andoniadou CL, Gaston-Massuet C, Reddy R, Schneider RP, Blasco MA, Le Tissier P, Jacques TS, Pevny LH, Dattani MT, Martinez-Barbera JP. Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma. Acta Neuropathol. 2012;124:259–71.

Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, Gaston-Massuet C, Mollard P, Jacques TS, Le Tissier P, Dattani MT, Pevny LH, Martinez-Barbera JP. Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell. 2013;13:433–45.

Aylwin SJ, Bodi I, Beaney R. Pronounced response of papillary craniopharyngioma to treatment with vemurafenib, a BRAF inhibitor. 2015. Pituitary.

Brastianos PK, Shankar GM, Gill CM, Taylor-Weiner A, Nayyar N, Panka DJ, Sullivan RJ, Frederick DT, Abedalthagafi M, Jones PS, Dunn IF, Nahed BV, Romero JM, Louis DN, Getz G, Cahill DP, Santagata S, Curry WT, Jr., Barker FG. 2nd Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy. J Natl Cancer Inst. 2015;108(2). pii: djv310. doi:10.1093/jnci/djv310.

Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L, Sunkavalli A, Shillingford N, Calicchio ML, Lidov HG, Taha H, Martinez-Lage M, Santi M, Storm PB, Lee JY, Palmer JN, Adappa ND, Scott RM, Dunn IF, Laws ER, Jr., Stewart C, Ligon KL, Hoang MP, Van Hummelen P, Hahn WC, Louis DN, Resnick AC, Kieran MW, Getz G, Santagata S. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet. 2014;46:161–5.

Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, Allen RC. Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE. Am J Hum Genet. 1991;48:137–44.PubMedCentralPubMed

Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM. The descriptive epidemiology of craniopharyngioma. J Neurosurg. 1998;89:547–51.CrossRefPubMed

Burghaus S, Holsken A, Buchfelder M, Fahlbusch R, Riederer BM, Hans V, Blumcke I, Buslei R. A tumor-specific cellular environment at the brain invasion border of adamantinomatous craniopharyngiomas. Virchows Arch. 2010;456:287–300.

Buslei R, Holsken A, Hofmann B, Kreutzer J, Siebzehnrubl F, Hans V, Oppel F, Buchfelder M, Fahlbusch R, Blumcke I. Nuclear beta-catenin accumulation associates with epithelial morphogenesis in craniopharyngiomas. Acta Neuropathol. 2007;113:585–90.

10.

Buslei R, Nolde M, Hofmann B, Meissner S, Eyupoglu IY, Siebzehnrubl F, Hahnen E, Kreutzer J, Fahlbusch R. Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathol. 2005;109:589–97.

11.

Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 2011;122:11–9.

12.

Crotty TB, Scheithauer BW, Young Jr WF, Davis DH, Shaw EG, Miller GM, Burger PC. Papillary craniopharyngioma: a clinicopathological study of 48 cases. J Neurosurg. 1995;83:206–14.

13.

Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, Borger DR, Batchelor TT, Ligon KL, Iafrate AJ, Ligon AH, Louis DN, Santagata S. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011;6, e17948.

14.

Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012;366:2038–40.CrossRefPubMed

15.

Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 2012;14 Suppl 5:v1–49.PubMedCentralCrossRefPubMed

16.

Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

17.

Garcia-Lavandeira M, Saez C, Diaz-Rodriguez E, Perez-Romero S, Senra A, Dieguez C, Japon MA, Alvarez CV. Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors. J Clin Endocrinol Metab. 2012;97:E80–7.

18.

Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, Dattani MT, Martinez-Barbera JP. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci U S A. 2011;108:11428–7.

19.

Gjerris F, Agerlin N, Borgesen SE, Buhl L, Haase J, Klinken L, Mortensen AC, Olsen JH, Ovesen N, Reske-Nielsen E, Schmidt K. Epidemiology and prognosis in children treated for intracranial tumours in Denmark 1960–1984. Childs Nerv Syst. 1998;14:302–11.

20.

Gump JM, Donson AM, Birks DK, Amani VM, Rao KK, Griesinger AM, Kleinschmidt-DeMasters BK, Johnston JM, Anderson RC, Rosenfeld A, Handler M, Gore L, Foreman N, Hankinson TC. Identification of targets for rational pharmacological therapy in childhood craniopharyngioma. Acta Neuropathol Commun. 2015;3:30.

21.

Hofmann BM, Kreutzer J, Saeger W, Buchfelder M, Blumcke I, Fahlbusch R, Buslei R. Nuclear beta-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and rathke cleft cysts: a clinico-pathologic approach. Am J Surg Pathol. 2006;30:1595–603.

22.

Holsken A, Buchfelder M, Fahlbusch R, Blumcke I, Buslei R. Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling. Acta Neuropathol. 2010;119:631–9.CrossRefPubMed

23.

Holsken A, Gebhardt M, Buchfelder M, Fahlbusch R, Blumcke I, Buslei R. EGFR signaling regulates tumor cell migration in craniopharyngiomas. Clin Cancer Res. 2011;17:4367–77.CrossRefPubMed

24.

Holsken A, Kreutzer J, Hofmann BM, Hans V, Oppel F, Buchfelder M, Fahlbusch R, Blumcke I, Buslei R. Target gene activation of the Wnt signaling pathway in nuclear beta-catenin accumulating cells of adamantinomatous craniopharyngiomas. Brain Pathol. 2009;19:357–64.

25.

Holsken A, Stache C, Schlaffer SM, Flitsch J, Fahlbusch R, Buchfelder M, Buslei R. Adamantinomatous craniopharyngiomas express tumor stem cell markers in cells with activated Wnt signaling: further evidence for the existence of a tumor stem cell niche? Pituitary. 2014;17:546–56.

26.

Karavitaki N, Cudlip S, Adams CB, Wass JA. Craniopharyngiomas. Endocr Rev. 2006;27:371–97.CrossRefPubMed

27.

Karavitaki N, Wass JA. Craniopharyngiomas. Endocrinol Metab Clin North Am. 2008;37:173–93.CrossRefPubMed

28.

Kato K, Nakatani Y, Kanno H, Inayama Y, Ijiri R, Nagahara N, Miyake T, Tanaka M, Ito Y, Aida N, Tachibana K, Sekido K, Tanaka Y. Possible linkage between specific histological structures and aberrant reactivation of the Wnt pathway in adamantinomatous craniopharyngioma. J Pathol. 2004;203:814–21.

29.

Kim JH, Paulus W, Heim S. BRAF V600E mutation is a useful marker for differentiating Rathke’s cleft cyst with squamous metaplasia from papillary craniopharyngioma. J Neurooncol. 2015;123:189–91.CrossRefPubMed

30.

Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O. BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniopharyngioma. Acta Neuropathol. 2014;127:927–9.PubMedCentralCrossRefPubMed

31.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. 2007. IARC Lyon.

32.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

33.

MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, Corso G, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, Meyerson ML, Garraway LA. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009;4, e7887.

34.

Martinez-Barbera JP, Buslei R. Adamantinomatous craniopharyngioma: pathology, molecular genetics and mouse models. J Pediatr Endocrinol Metab. 2015;28:7–17.CrossRefPubMed

35.

Monti S, Tamayo P, Mesirov J, Golub T. Consensus Clustering: A Resampling-Based Method for Class Discovery and Visualization of Gene Expression Microarray Data. Machine Learning. 2003;52:91–118.CrossRef

36.

Muller HL. Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother. 2010;10:515–24.CrossRefPubMed

37.

Muller HL. Craniopharyngioma. Handb Clin Neurol. 2014;124:235–53.CrossRefPubMed

38.

Muller HL, Gebhardt U, Teske C, Faldum A, Zwiener I, Warmuth-Metz M, Pietsch T, Pohl F, Sorensen N, Calaminus G. Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol. 2011;165:17–24.

39.

Nielsen EH, Feldt-Rasmussen U, Poulsgaard L, Kristensen LO, Astrup J, Jorgensen JO, Bjerre P, Andersen M, Andersen C, Jorgensen J, Lindholm J, Laurberg P. Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults. J Neurooncol. 2011;104:755–63.

40.

Okada T, Fujitsu K, Ichikawa T, Mukaihara S, Miyahara K, Kaku S, Uryuu Y, Niino H, Yagishita S, Shiina T. Coexistence of adamantinomatous and squamous‐papillary type craniopharyngioma: Case report and discussion of etiology and pathology. Neuropathology. 2012;32:171–3.

41.

Prieto R, Pascual JM, Subhi-Issa I, Jorquera M, Yus M, Martinez R. Predictive factors for craniopharyngioma recurrence: a systematic review and illustrative case report of a rapid recurrence. World Neurosurg. 2013;79:733–49.CrossRefPubMed

42.

Rosemberg S, Fujiwara D. Epidemiology of pediatric tumors of the nervous system according to the WHO 2000 classification: a report of 1,195 cases from a single institution. Childs Nerv Syst. 2005;21:940–4.CrossRefPubMed

43.

Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405.

44.

Schweizer L, Capper D, Holsken A, Fahlbusch R, Flitsch J, Buchfelder M, Herold-Mende C, von Deimling A, Buslei R. BRAF V600E analysis for the differentiation of papillary Craniopharyngiomas and Rathke's Cleft Cysts. 2014. Neuropathol Appl Neurobiol.

45.

Sekine S, Shibata T, Kokubu A, Morishita Y, Noguchi M, Nakanishi Y, Sakamoto M, Hirohashi S. Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol. 2002;161:1997–2001.

46.

Sekine S, Takata T, Shibata T, Mori M, Morishita Y, Noguchi M, Uchida T, Kanai Y, Hirohashi S. Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation. Histopathology. 2004;45:573–9.

47.

Stache C, Holsken A, Fahlbusch R, Flitsch J, Schlaffer SM, Buchfelder M, Buslei R. Tight junction protein claudin-1 is differentially expressed in craniopharyngioma subtypes and indicates invasive tumor growth. Neuro Oncol. 2014;16:256–64.

48.

Stache C, Holsken A, Schlaffer SM, Hess A, Metzler M, Frey B, Fahlbusch R, Flitsch J, Buchfelder M, Buslei R. Insights into the infiltrative behavior of adamantinomatous craniopharyngioma in a new xenotransplant mouse model. Brain Pathol. 2015;25:1–10.

49.

Weiner HL, Wisoff JH, Rosenberg ME, Kupersmith MJ, Cohen H, Zagzag D, Shiminski-Maher T, Flamm ES, Epstein FJ, Miller DC. Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery. 1994;35:1001–10. discussion 1010–1001.

Title: Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles
Authors: Annett Hölsken
Martin Sill
Jessica Merkle
Leonille Schweizer
Michael Buchfelder
Jörg Flitsch
Rudolf Fahlbusch
Markus Metzler
Marcel Kool
Stefan M. Pfister
Andreas von Deimling
David Capper
David T. W. Jones
Rolf Buslei
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2016
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-016-0287-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles

Abstract

Introduction

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner

Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics

Increased Caspase-6 activity in the human anterior olfactory nuclei of the olfactory bulb is associated with cognitive impairment

Activation of the Keap1/Nrf2 stress response pathway in autophagic vacuolar myopathies

Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia

ALS-linked misfolded SOD1 species have divergent impacts on mitochondria