DNA methylation-based reclassification of olfactory neuroblastoma

被引：57

作者：

Capper, David ^{[1
,2
,17
,18
,19
]}

Engel, Nils W. ^{[3
,4
,5
]}

Stichel, Damian ^{[1
]}

Lechner, Matt ^{[6
,7
,8
]}

Gloess, Stefanie ^{[17
,18
,19
]}

Schmid, Simone ^{[17
,18
,19
]}

Koelsche, Christian ^{[1
,2
]}

Schrimpf, Daniel ^{[1
,2
]}

Niesen, Judith ^{[30
,31
]}

Wefers, Annika K. ^{[1
,2
]}

Jones, David T. W. ^{[9
,10
]}

Sill, Martin ^{[9
,10
]}

Weigert, Oliver ^{[11
]}

Ligon, Keith L. ^{[12
,13
]}

Olar, Adriana ^{[14
,15
,16
]}

Koch, Arend ^{[17
]}

Forster, Martin ^{[7
,8
]}

Moran, Sebastian ^{[33
]}

Tirado, Oscar M. ^{[34
]}

Sainz-Jaspeado, Miguel ^{[34
]}

Mora, Jaume ^{[35
,36
]}

Esteller, Manel ^{[30
,37
,38
]}

Alonso, Javier ^{[39
]}

Garcia del Muro, Xavier ^{[40
]}

Paulus, Werner ^{[20
]}

Felsberg, Joerg ^{[21
,22
]}

Reifenberger, Guido ^{[21
,22
]}

Glatzel, Markus ^{[23
]}

Frank, Stephan ^{[24
]}

Monoranu, Camelia M. ^{[25
]}

Lund, Valerie J. ^{[6
,8
]}

von Deimling, Andreas ^{[1
,2
]}

Pfister, Stefan ^{[9
,10
,32
]}

Buslei, Rolf ^{[26
,41
]}

Ribbat-Idel, Julika ^{[27
,42
,43
]}

Perner, Sven ^{[27
,42
,43
]}

Gudziol, Volker ^{[28
]}

Meinhardt, Matthias ^{[29
]}

Schueller, Ulrich ^{[3
,23
,30
,31
]}

机构：

[1] German Canc Res Ctr, German Canc Consortium DKTK, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[2] Univ Hosp Heidelberg, Dept Neuropathol, Heidelberg, Germany

[3] Ludwig Maximilians Univ Munchen, Ctr Neuropathol, Munich, Germany

[4] Univ Med Ctr Hamburg, Univ Canc Ctr Hamburg, Hubertus Wald Tumorzentrum, Dept Oncol & Hematol,Sect Bone Marrow Transplant, Hamburg, Germany

[5] Univ Med Ctr Hamburg, Univ Canc Ctr Hamburg, Hubertus Wald Tumorzentrum, Dept Oncol & Hematol,Sect Pneumol, Hamburg, Germany

[6] Univ Coll London Hosp NHS Trust, Nose & Ear Hosp, Royal Natl Throat, London, England

[7] UCL, Inst Canc, London, England

[8] Univ Coll London Hosp NHS Trust, Head & Neck Ctr, London, England

[9] NCT Heidelberg KiTZ, Hopp Childrens Canc Ctr, Heidelberg, Germany

[10] German Canc Res Ctr, German Canc Consortium DKTK, Div Pediat Neurooncol, Heidelberg, Germany

[11] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Internal Med 3, Munich, Germany

[12] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA

[13] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Ctr Mol Oncol Pathol, Boston, MA USA

[14] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA

[15] Med Univ South Carolina, Dept Neurosurg, Charleston, SC 29425 USA

[16] Hollings Canc Ctr, Charleston, SC USA

[17] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Berlin, Germany

[18] Berlin Inst Hlth, Inst Neuropathol, Berlin, Germany

[19] German Canc Consortium DKTK, Partner Site Berlin, Berlin, Germany

[20] Univ Hosp Munster, Inst Neuropathol, Munster, Germany

[21] Heinrich Heine Univ, Inst Neuropathol, Med Fac, Dusseldorf, Germany

[22] German Canc Consortium DKTK, Partner Site Essen Dusseldorf, Dusseldorf, Germany

[23] Univ Med Ctr Hamburg, Inst Neuropathol, Hamburg, Germany

[24] Univ Spital Basel, Dept Pathol, Basel, Switzerland

[25] Julius Maximilians Univ, Inst Pathol, Wurzburg, Germany

[26] Univ Erlangen Nurnberg, Dept Neuropathol, Erlangen, Germany

[27] Univ Hosp Bonn, Inst Pathol, Bonn, Germany

[28] Univ Klinikum Carl Gustav Carus Dresden, ENT Dept, Dresden, Germany

[29] Univ Klinikum Carl Gustav Carus Dresden, Inst Pathol, Dresden, Germany

[30] Univ Med Ctr, Dept Pediat Hematol & Oncol, Hamburg, Germany

[31] Childrens Canc Ctr Hamburg, Res Inst, Hamburg, Germany

[32] Heidelberg Univ Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[33] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Catalonia, Spain

[34] Bellvitge Biomed Res Inst IDIBELL, Mol Oncol Lab, Sarcoma Res Grp, Barcelona, Catalonia, Spain

[35] Hosp St Joan Deu, Dept Pediat Oncohematol, Barcelona, Catalonia, Spain

[36] Hosp St Joan Deu, Dev Tumor Biol Lab, Barcelona, Catalonia, Spain

[37] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain

[38] ICREA, Barcelona, Catalonia, Spain

[39] Inst Salud Carlos III, Res Inst Rare Dis, Human Genet Dept, Pediat Solid Tumor Lab, Madrid, Spain

[40] ICO IDIBELL, Oncol Dept, Barcelona, Spain

[41] Sozialstiftung Bamberg, Klinikum Bruderwald, Inst Pathol Neuropathol, Bamberg, Germany

[42] Univ Hosp Schleswig Holstein, Pathol, Campus Lubeck, D-23538 Lubeck, Germany

[43] Leibniz Ctr Med & Biosci, Res Ctr Borstel, D-23845 Borstel, Germany

来源：

ACTA NEUROPATHOLOGICA | 2018年 / 136卷 / 02期

关键词：

CENTRAL-NERVOUS-SYSTEM; MOLECULAR CLASSIFICATION; NEUROENDOCRINE CARCINOMA; DIFFERENTIAL-DIAGNOSIS; TUMORS; MUTATIONS; NEOPLASMS; ESTHESIONEUROBLASTOMA; SUBGROUPS; PHENOTYPE;

D O I：

10.1007/s00401-018-1854-7

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

引用

页码：255 / 271

页数：17

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