RT Journal
A1 Kim, Hoon
A1 Zheng, Siyuan
A1 Amini, Seyed S.
A1 Virk, Selene M.
A1 Mikkelsen, Tom
A1 Brat, Daniel J.
A1 Grimsby, Jonna
A1 Sougnez, Carrie
A1 Muller, Florian
A1 Hu, Jian
A1 Sloan, Andrew E.
A1 Cohen, Mark L.
A1 Van Meir, Erwin G.
A1 Scarpace, Lisa
A1 Laird, Peter W.
A1 Weinstein, John N.
A1 Lander, Eric S.
A1 Gabriel, Stacey
A1 Getz, Gad
A1 Meyerson, Matthew
A1 Chin, Lynda
A1 Barnholtz-Sloan, Jill S.
A1 Verhaak, Roel G.W.
T1 Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution
JF Genome Research 
JO Genome Research 
YR 2015 
FD March 01 
VO 25 
IS 3 
SP 316 
OP 327 
DO 10.1101/gr.180612.114 
UL http://genome.cshlp.org/content/25/3/316.abstract 
AB 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.