Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution
Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ~7 mo after diagnosis. Understanding the molecular architecture of this residual...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2015
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| Online Access: | http://hdl.handle.net/1721.1/98018 |
| _version_ | 1826217910508453888 |
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| author | Kim, Hoon Zheng, Siyuan Amini, Seyed S. Virk, Selene M. Mikkelsen, Tom Brat, Daniel J. Grimsby, Jonna Sougnez, Carrie Muller, Florian Hu, Jian Sloan, Andrew E. Cohen, Mark L. Van Meir, Erwin G. Scarpace, Lisa Laird, Peter W. Weinstein, John N. Gabriel, Stacey B. Getz, Gad Meyerson, Matthew L. Chin, Lynda Barnholtz-Sloan, Jill S. Verhaak, Roel G.W. Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kim, Hoon Zheng, Siyuan Amini, Seyed S. Virk, Selene M. Mikkelsen, Tom Brat, Daniel J. Grimsby, Jonna Sougnez, Carrie Muller, Florian Hu, Jian Sloan, Andrew E. Cohen, Mark L. Van Meir, Erwin G. Scarpace, Lisa Laird, Peter W. Weinstein, John N. Gabriel, Stacey B. Getz, Gad Meyerson, Matthew L. Chin, Lynda Barnholtz-Sloan, Jill S. Verhaak, Roel G.W. Lander, Eric Steven |
| author_sort | Kim, Hoon |
| collection | MIT |
| description | Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ~7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity. |
| first_indexed | 2024-09-23T17:11:00Z |
| format | Article |
| id | mit-1721.1/98018 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:11:00Z |
| publishDate | 2015 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/980182022-09-30T00:15:17Z Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution Kim, Hoon Zheng, Siyuan Amini, Seyed S. Virk, Selene M. Mikkelsen, Tom Brat, Daniel J. Grimsby, Jonna Sougnez, Carrie Muller, Florian Hu, Jian Sloan, Andrew E. Cohen, Mark L. Van Meir, Erwin G. Scarpace, Lisa Laird, Peter W. Weinstein, John N. Gabriel, Stacey B. Getz, Gad Meyerson, Matthew L. Chin, Lynda Barnholtz-Sloan, Jill S. Verhaak, Roel G.W. Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Lander, Eric S. Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ~7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity. 2015-08-04T19:20:24Z 2015-08-04T19:20:24Z 2015-03 2014-06 Article http://purl.org/eprint/type/JournalArticle 1088-9051 1549-5469 http://hdl.handle.net/1721.1/98018 Kim, Hoon, Siyuan Zheng, Seyed S. Amini, Selene M. Virk, Tom Mikkelsen, Daniel J. Brat, Jonna Grimsby, et al. “Whole-Genome and Multisector Exome Sequencing of Primary and Post-Treatment Glioblastoma Reveals Patterns of Tumor Evolution.” Genome Res. 25, no. 3 (February 3, 2015): 316–327. en_US http://dx.doi.org/10.1101/gr.180612.114 Genome Research Creative Commons Attribution http://creativecommons.org/licenses/by-nc/4.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Kim, Hoon Zheng, Siyuan Amini, Seyed S. Virk, Selene M. Mikkelsen, Tom Brat, Daniel J. Grimsby, Jonna Sougnez, Carrie Muller, Florian Hu, Jian Sloan, Andrew E. Cohen, Mark L. Van Meir, Erwin G. Scarpace, Lisa Laird, Peter W. Weinstein, John N. Gabriel, Stacey B. Getz, Gad Meyerson, Matthew L. Chin, Lynda Barnholtz-Sloan, Jill S. Verhaak, Roel G.W. Lander, Eric Steven Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title | Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title_full | Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title_fullStr | Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title_full_unstemmed | Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title_short | Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution |
| title_sort | whole genome and multisector exome sequencing of primary and post treatment glioblastoma reveals patterns of tumor evolution |
| url | http://hdl.handle.net/1721.1/98018 |
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