Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

Matija Snuderl; Kasthuri Kannan; Elke Pfaff; Shiyang Wang; James M. Stafford; Jonathan Serrano; Adriana Heguy; Karina Ray; Arline Faustin; Olga Aminova; Igor Dolgalev; Stacie L. Stapleton; David Zagzag; Luis Chiriboga; Sharon L. Gardner; Jeffrey H. Wisoff; John G. Golfinos; David Capper; Volker Hovestadt; Marc K. Rosenblum; Dimitris G. Placantonakis; Sarah E. LeBoeuf; Thales Y. Papagiannakopoulos; Lukas Chavez; Sama Ahsan; Charles G. Eberhart; Stefan M. Pfister; David T.W. Jones; Matthias A. Karajannis

doi:10.1038/s41467-018-05029-3

Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

Matija Snuderl, Kasthuri Kannan, Elke Pfaff, Shiyang Wang, James M. Stafford, Jonathan Serrano, Adriana Heguy, Karina Ray, Arline Faustin, Olga Aminova, Igor Dolgalev, Stacie L. Stapleton, David Zagzag, Luis Chiriboga, Sharon L. Gardner, Jeffrey H. Wisoff, John G. Golfinos, David Capper, Volker Hovestadt, Marc K. RosenblumDimitris G. Placantonakis, Sarah E. LeBoeuf, Thales Y. Papagiannakopoulos, Lukas Chavez, Sama Ahsan, Charles G. Eberhart, Stefan M. Pfister, David T.W. Jones, Matthias A. Karajannis

School of Medicine

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Abstract

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

Original language	English (US)
Article number	2868
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05029-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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Snuderl, M., Kannan, K., Pfaff, E., Wang, S., Stafford, J. M., Serrano, J., Heguy, A., Ray, K., Faustin, A., Aminova, O., Dolgalev, I., Stapleton, S. L., Zagzag, D., Chiriboga, L., Gardner, S. L., Wisoff, J. H., Golfinos, J. G., Capper, D., Hovestadt, V., ... Karajannis, M. A. (2018). Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nature communications, 9(1), Article 2868. https://doi.org/10.1038/s41467-018-05029-3

Snuderl, M, Kannan, K, Pfaff, E, Wang, S, Stafford, JM, Serrano, J, Heguy, A, Ray, K, Faustin, A, Aminova, O, Dolgalev, I, Stapleton, SL, Zagzag, D, Chiriboga, L, Gardner, SL, Wisoff, JH, Golfinos, JG, Capper, D, Hovestadt, V, Rosenblum, MK, Placantonakis, DG, LeBoeuf, SE, Papagiannakopoulos, TY, Chavez, L, Ahsan, S, Eberhart, CG, Pfister, SM, Jones, DTW & Karajannis, MA 2018, 'Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma', Nature communications, vol. 9, no. 1, 2868. https://doi.org/10.1038/s41467-018-05029-3

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title = "Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma",

abstract = "Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.",

author = "Matija Snuderl and Kasthuri Kannan and Elke Pfaff and Shiyang Wang and Stafford, {James M.} and Jonathan Serrano and Adriana Heguy and Karina Ray and Arline Faustin and Olga Aminova and Igor Dolgalev and Stapleton, {Stacie L.} and David Zagzag and Luis Chiriboga and Gardner, {Sharon L.} and Wisoff, {Jeffrey H.} and Golfinos, {John G.} and David Capper and Volker Hovestadt and Rosenblum, {Marc K.} and Placantonakis, {Dimitris G.} and LeBoeuf, {Sarah E.} and Papagiannakopoulos, {Thales Y.} and Lukas Chavez and Sama Ahsan and Eberhart, {Charles G.} and Pfister, {Stefan M.} and Jones, {David T.W.} and Karajannis, {Matthias A.}",

note = "Funding Information: This study was in part supported by grants from the Friedberg Charitable Foundation, the Sohn Conference Foundation and the Making Headway Foundation to M.S. and M. A.K. and the Alice and Thomas J. Tisch Brain Tumor Research Fund to J.G.G. The NYU Experimental Pathology Immunohistochemistry Core Laboratory and the Genome Technology Center are supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant; NIH/NCI P30CA016087 and the National Institutes of Health S10 Instrumentation Grants; NIH/ORIP S10OD01058 and S10OD018338. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. The authors would like to thank William L. Carroll, MD for his critical review of the manuscript and Stephen Conley for help with figures. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05029-3",

language = "English (US)",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

AU - Snuderl, Matija

AU - Kannan, Kasthuri

AU - Pfaff, Elke

AU - Wang, Shiyang

AU - Stafford, James M.

AU - Serrano, Jonathan

AU - Heguy, Adriana

AU - Ray, Karina

AU - Faustin, Arline

AU - Aminova, Olga

AU - Dolgalev, Igor

AU - Stapleton, Stacie L.

AU - Zagzag, David

AU - Chiriboga, Luis

AU - Gardner, Sharon L.

AU - Wisoff, Jeffrey H.

AU - Golfinos, John G.

AU - Capper, David

AU - Hovestadt, Volker

AU - Rosenblum, Marc K.

AU - Placantonakis, Dimitris G.

AU - LeBoeuf, Sarah E.

AU - Papagiannakopoulos, Thales Y.

AU - Chavez, Lukas

AU - Ahsan, Sama

AU - Eberhart, Charles G.

AU - Pfister, Stefan M.

AU - Jones, David T.W.

AU - Karajannis, Matthias A.

N1 - Funding Information: This study was in part supported by grants from the Friedberg Charitable Foundation, the Sohn Conference Foundation and the Making Headway Foundation to M.S. and M. A.K. and the Alice and Thomas J. Tisch Brain Tumor Research Fund to J.G.G. The NYU Experimental Pathology Immunohistochemistry Core Laboratory and the Genome Technology Center are supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant; NIH/NCI P30CA016087 and the National Institutes of Health S10 Instrumentation Grants; NIH/ORIP S10OD01058 and S10OD018338. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. The authors would like to thank William L. Carroll, MD for his critical review of the manuscript and Stephen Conley for help with figures. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

AB - Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

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JO - Nature communications

JF - Nature communications

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Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

Abstract

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