title: Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence.
abstract: Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next-generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Gabrielle C
authors.initials: GC
authors.lastname: Nickel
authors.forename: Jill
authors.initials: J
authors.lastname: Barnholtz-Sloan
authors.forename: Meetha P
authors.initials: MP
authors.lastname: Gould
authors.forename: Sarah
authors.initials: S
authors.lastname: McMahon
authors.forename: Andrea
authors.initials: A
authors.lastname: Cohen
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.forename: Kishore
authors.initials: K
authors.lastname: Guda
authors.forename: Mark
authors.initials: M
authors.lastname: Cohen
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D058534:Class I Phosphatidylinositol 3-Kinases; D003131:Combined Modality Therapy; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human