Spatial heterogeneity in medulloblastoma

A. Sorana Morrissy; Florence M.G. Cavalli; Marc Remke; Vijay Ramaswamy; David J.H. Shih; Borja L. Holgado; Hamza Farooq; Laura K. Donovan; Livia Garzia; Sameer Agnihotri; Erin N. Kiehna; Eloi Mercier; Chelsea Mayoh; Simon Papillon-Cavanagh; Hamid Nikbakht; Tenzin Gayden; Jonathon Torchia; Daniel Picard; Diana M. Merino; Maria Vladoiu; Betty Luu; Xiaochong Wu; Craig Daniels; Stuart Horswell; Yuan Yao Thompson; Volker Hovestadt; Paul A. Northcott; David T.W. Jones; John Peacock; Xin Wang; Stephen C. Mack; Jüri Reimand; Steffen Albrecht; Adam M. Fontebasso; Nina Thiessen; Yisu Li; Jacqueline E. Schein; Darlene Lee; Rebecca Carlsen; Michael Mayo; Kane Tse; Angela Tam; Noreen Dhalla; Adrian Ally; Eric Chuah; Young Cheng; Patrick Plettner; Haiyan I. Li; Richard D. Corbett; Tina Wong; William Long; James Loukides; Pawel Buczkowicz; Cynthia E. Hawkins; Uri Tabori; Brian R. Rood; John S. Myseros; Roger J. Packer; Andrey Korshunov; Peter Lichter; Marcel Kool; Stefan M. Pfister; Ulrich Schüller; Peter Dirks; Annie Huang; Eric Bouffet; James T. Rutka; Gary D. Bader; Charles Swanton; Yusanne Ma; Richard A. Moore; Andrew J. Mungall; Jacek Majewski; Steven J.M. Jones; Sunit Das; David Malkin; Nada Jabado; Marco A. Marra; Michael D. Taylor

doi:10.1038/ng.3838

Spatial heterogeneity in medulloblastoma

A. Sorana Morrissy
, Florence M.G. Cavalli
, Marc Remke
, Vijay Ramaswamy
, David J.H. Shih
, Borja L. Holgado
, Hamza Farooq
, Laura K. Donovan
, Livia Garzia
, Sameer Agnihotri
, Erin N. Kiehna
, Eloi Mercier
, Chelsea Mayoh
, Simon Papillon-Cavanagh
, Hamid Nikbakht
, Tenzin Gayden
, Jonathon Torchia
, Daniel Picard
, Diana M. Merino
, Maria Vladoiu

Betty Luu, Xiaochong Wu, Craig Daniels, Stuart Horswell, Yuan Yao Thompson, Volker Hovestadt, Paul A. Northcott, David T.W. Jones, John Peacock, Xin Wang, Stephen C. Mack, Jüri Reimand, Steffen Albrecht, Adam M. Fontebasso, Nina Thiessen, Yisu Li, Jacqueline E. Schein, Darlene Lee, Rebecca Carlsen, Michael Mayo, Kane Tse, Angela Tam, Noreen Dhalla, Adrian Ally, Eric Chuah, Young Cheng, Patrick Plettner, Haiyan I. Li, Richard D. Corbett, Tina Wong, William Long, James Loukides, Pawel Buczkowicz, Cynthia E. Hawkins, Uri Tabori, Brian R. Rood, John S. Myseros, Roger J. Packer, Andrey Korshunov, Peter Lichter, Marcel Kool, Stefan M. Pfister, Ulrich Schüller, Peter Dirks, Annie Huang, Eric Bouffet, James T. Rutka, Gary D. Bader, Charles Swanton, Yusanne Ma, Richard A. Moore, Andrew J. Mungall, Jacek Majewski, Steven J.M. Jones, Sunit Das, David Malkin, Nada Jabado, Marco A. Marra, Michael D. Taylor

Research output: Contribution to journal › Article › peer-review

110 Citations (Scopus)

Abstract

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Original language	English
Pages (from-to)	780-788
Number of pages	9
Journal	Nature Genetics
Volume	49
Issue number	5
DOIs	https://doi.org/10.1038/ng.3838
Publication status	Published - 1 May 2017
Externally published	Yes

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10.1038/ng.3838

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Morrissy, A. S., Cavalli, F. M. G., Remke, M., Ramaswamy, V., Shih, D. J. H., Holgado, B. L., Farooq, H., Donovan, L. K., Garzia, L., Agnihotri, S., Kiehna, E. N., Mercier, E., Mayoh, C., Papillon-Cavanagh, S., Nikbakht, H., Gayden, T., Torchia, J., Picard, D., Merino, D. M., ... Taylor, M. D. (2017). Spatial heterogeneity in medulloblastoma. Nature Genetics, 49(5), 780-788. https://doi.org/10.1038/ng.3838

@article{e4f1ac0164cc47adabb6847c44374a6c,

title = "Spatial heterogeneity in medulloblastoma",

abstract = "Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.",

author = "Morrissy, \{A. Sorana\} and Cavalli, \{Florence M.G.\} and Marc Remke and Vijay Ramaswamy and Shih, \{David J.H.\} and Holgado, \{Borja L.\} and Hamza Farooq and Donovan, \{Laura K.\} and Livia Garzia and Sameer Agnihotri and Kiehna, \{Erin N.\} and Eloi Mercier and Chelsea Mayoh and Simon Papillon-Cavanagh and Hamid Nikbakht and Tenzin Gayden and Jonathon Torchia and Daniel Picard and Merino, \{Diana M.\} and Maria Vladoiu and Betty Luu and Xiaochong Wu and Craig Daniels and Stuart Horswell and Thompson, \{Yuan Yao\} and Volker Hovestadt and Northcott, \{Paul A.\} and Jones, \{David T.W.\} and John Peacock and Xin Wang and Mack, \{Stephen C.\} and J{\"u}ri Reimand and Steffen Albrecht and Fontebasso, \{Adam M.\} and Nina Thiessen and Yisu Li and Schein, \{Jacqueline E.\} and Darlene Lee and Rebecca Carlsen and Michael Mayo and Kane Tse and Angela Tam and Noreen Dhalla and Adrian Ally and Eric Chuah and Young Cheng and Patrick Plettner and Li, \{Haiyan I.\} and Corbett, \{Richard D.\} and Tina Wong and William Long and James Loukides and Pawel Buczkowicz and Hawkins, \{Cynthia E.\} and Uri Tabori and Rood, \{Brian R.\} and Myseros, \{John S.\} and Packer, \{Roger J.\} and Andrey Korshunov and Peter Lichter and Marcel Kool and Pfister, \{Stefan M.\} and Ulrich Sch{\"u}ller and Peter Dirks and Annie Huang and Eric Bouffet and Rutka, \{James T.\} and Bader, \{Gary D.\} and Charles Swanton and Yusanne Ma and Moore, \{Richard A.\} and Mungall, \{Andrew J.\} and Jacek Majewski and Jones, \{Steven J.M.\} and Sunit Das and David Malkin and Nada Jabado and Marra, \{Marco A.\} and Taylor, \{Michael D.\}",

year = "2017",

month = may,

day = "1",

doi = "10.1038/ng.3838",

language = "English",

volume = "49",

pages = "780--788",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

Morrissy, AS, Cavalli, FMG, Remke, M, Ramaswamy, V, Shih, DJH, Holgado, BL, Farooq, H, Donovan, LK, Garzia, L, Agnihotri, S, Kiehna, EN, Mercier, E, Mayoh, C, Papillon-Cavanagh, S, Nikbakht, H, Gayden, T, Torchia, J, Picard, D, Merino, DM, Vladoiu, M, Luu, B, Wu, X, Daniels, C, Horswell, S, Thompson, YY, Hovestadt, V, Northcott, PA, Jones, DTW, Peacock, J, Wang, X, Mack, SC, Reimand, J, Albrecht, S, Fontebasso, AM, Thiessen, N, Li, Y, Schein, JE, Lee, D, Carlsen, R, Mayo, M, Tse, K, Tam, A, Dhalla, N, Ally, A, Chuah, E, Cheng, Y, Plettner, P, Li, HI, Corbett, RD, Wong, T, Long, W, Loukides, J, Buczkowicz, P, Hawkins, CE, Tabori, U, Rood, BR, Myseros, JS, Packer, RJ, Korshunov, A, Lichter, P, Kool, M, Pfister, SM, Schüller, U, Dirks, P, Huang, A, Bouffet, E, Rutka, JT, Bader, GD, Swanton, C, Ma, Y, Moore, RA, Mungall, AJ, Majewski, J, Jones, SJM, Das, S, Malkin, D, Jabado, N, Marra, MA & Taylor, MD 2017, 'Spatial heterogeneity in medulloblastoma', Nature Genetics, vol. 49, no. 5, pp. 780-788. https://doi.org/10.1038/ng.3838

TY - JOUR

T1 - Spatial heterogeneity in medulloblastoma

AU - Morrissy, A. Sorana

AU - Cavalli, Florence M.G.

AU - Remke, Marc

AU - Ramaswamy, Vijay

AU - Shih, David J.H.

AU - Holgado, Borja L.

AU - Farooq, Hamza

AU - Donovan, Laura K.

AU - Garzia, Livia

AU - Agnihotri, Sameer

AU - Kiehna, Erin N.

AU - Mercier, Eloi

AU - Mayoh, Chelsea

AU - Papillon-Cavanagh, Simon

AU - Nikbakht, Hamid

AU - Gayden, Tenzin

AU - Torchia, Jonathon

AU - Picard, Daniel

AU - Merino, Diana M.

AU - Vladoiu, Maria

AU - Luu, Betty

AU - Wu, Xiaochong

AU - Daniels, Craig

AU - Horswell, Stuart

AU - Thompson, Yuan Yao

AU - Hovestadt, Volker

AU - Northcott, Paul A.

AU - Jones, David T.W.

AU - Peacock, John

AU - Wang, Xin

AU - Mack, Stephen C.

AU - Reimand, Jüri

AU - Albrecht, Steffen

AU - Fontebasso, Adam M.

AU - Thiessen, Nina

AU - Li, Yisu

AU - Schein, Jacqueline E.

AU - Lee, Darlene

AU - Carlsen, Rebecca

AU - Mayo, Michael

AU - Tse, Kane

AU - Tam, Angela

AU - Dhalla, Noreen

AU - Ally, Adrian

AU - Chuah, Eric

AU - Cheng, Young

AU - Plettner, Patrick

AU - Li, Haiyan I.

AU - Corbett, Richard D.

AU - Wong, Tina

AU - Long, William

AU - Loukides, James

AU - Buczkowicz, Pawel

AU - Hawkins, Cynthia E.

AU - Tabori, Uri

AU - Rood, Brian R.

AU - Myseros, John S.

AU - Packer, Roger J.

AU - Korshunov, Andrey

AU - Lichter, Peter

AU - Kool, Marcel

AU - Pfister, Stefan M.

AU - Schüller, Ulrich

AU - Dirks, Peter

AU - Huang, Annie

AU - Bouffet, Eric

AU - Rutka, James T.

AU - Bader, Gary D.

AU - Swanton, Charles

AU - Ma, Yusanne

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Majewski, Jacek

AU - Jones, Steven J.M.

AU - Das, Sunit

AU - Malkin, David

AU - Jabado, Nada

AU - Marra, Marco A.

AU - Taylor, Michael D.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

AB - Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

UR - https://www.scopus.com/pages/publications/85017216540

U2 - 10.1038/ng.3838

DO - 10.1038/ng.3838

M3 - Article

C2 - 28394352

AN - SCOPUS:85017216540

SN - 1061-4036

VL - 49

SP - 780

EP - 788

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Spatial heterogeneity in medulloblastoma

Abstract

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