Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

Akash Kumar, Evan A Boyle, Mari Tokita, Andrei M Mikheev, Michelle C Sanger, Emily Girard, John R Silber, Luis F Gonzalez-Cuyar, Joseph B Hiatt, Andrew Adey, Choli Lee, Jacob O Kitzman, Donald E Born, Daniel L Silbergeld, James M Olson, Robert C Rostomily, Jay Shendure

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


BACKGROUND: The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.

RESULTS: We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.

CONCLUSIONS: Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.

Original languageEnglish (US)
Pages (from-to)530
JournalGenome Biology
Issue number12
StatePublished - Dec 3 2014


  • Brain Neoplasms
  • Gene Amplification
  • Genetic Heterogeneity
  • Glioblastoma
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Molecular Sequence Data
  • Oligodendroglioma
  • Point Mutation
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha
  • Salivary Proline-Rich Proteins
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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