The intratumoral heterogeneity of glioblastoma suggests a pivotal role for clonal evolution.

To investigate therapy induced evolutionary patterns in glioblastoma (GBM), we completed whole exome sequencing of all samples, as well as transcriptome sequencing, DNA copy number, DNA methylation, and mRNA from at least one primary sample, and one (post-therapy) recurrent sample. Sample collection was enabled through The Cancer Genome Atlas Research Network (TCGA). Multiple spatially distinct samples were available for five primary and six recurrent cases, allowing the integration of intratumoral heterogeneity with the evolutionary processes that shape the tumor recurrence after therapeutic intervention. Sample unique mutations were common, but most of the somatic variants in driver genes (like TP53 and EGFR) were preserved across the tumor and after therapy. We found that the therapeutic bottleneck resulted in proportionally higher numbers of (mostly clonal) mutations, reduced clonal complexity and changes in the mutation spectrum. GBM recurrence could be grouped into two categories, characterized by drastically different clonal evolution patterns. Our findings suggest that multi-sector sequencing sharpens the analysis but is not essential for precise delineation of the tumor progression process. Projecting our results on genomic data from 253 primary GBMs, we observed that the number of clonal, but not subclonal, mutations increased with age at diagnosis, and the two categories differed in their mutation spectrum. This study represents an important advance toward comprehensive characterization of the genomic alterations of GBM before and after cytotoxic treatment and surgery. Our analysis of spatially and temporally distinct samples provides new insights into the relevance of intratumoral heterogeneity on disease progression in GBM. Acknowledgements: This work is supported by Award Numbers 5 P50 CA127001 and 5 P50 CA083639-12 from the National Cancer Institute (NCI) to RGWV. H.K. is supported in part by the Odyssey Program and Theodore N. Law Endowment for Scientific Achievement at The University of Texas MD Anderson Cancer Center. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas project established by the NCI and NHGRI. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B130. Citation Format: Hoon Kim, Siyuan Zheng, Seyed S. Amini, Selene Virk, Tom Mikkelsen, Daniel J. Brat, Jonna Grimsby, Carrie Sougnez, Andrew E. Sloan, Mark L. Cohen, Erwin G. Van Meir, Lisa Scarpace, Peter W. Laird, John N. Weinstein, Eric S. Lander, Stacey Gabriel, Gaddy Getz, Matthew Meyerson, Lynda Chin, Jill S. Barnholtz-Sloan, Roeland GW Verhaak. The intratumoral heterogeneity of glioblastoma suggests a pivotal role for clonal evolution. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B130.