title: Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes.
abstract: 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.
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.forename: Evan A
authors.initials: EA
authors.lastname: Boyle
authors.forename: Mari
authors.initials: M
authors.lastname: Tokita
authors.forename: Andrei M
authors.initials: AM
authors.lastname: Mikheev
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Sanger
authors.forename: Emily
authors.initials: E
authors.lastname: Girard
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
authors.forename: Luis F
authors.initials: LF
authors.lastname: Gonzalez-Cuyar
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Hiatt
authors.forename: Andrew
authors.initials: A
authors.lastname: Adey
authors.forename: Choli
authors.initials: C
authors.lastname: Lee
authors.forename: Jacob O
authors.initials: JO
authors.lastname: Kitzman
authors.forename: Donald E
authors.initials: DE
authors.lastname: Born
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Silbergeld
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rostomily
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D005784:Gene Amplification; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D055273:Salivary Proline-Rich Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C524744:PRB1 protein, human; D055273:Salivary Proline-Rich Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha