Spatial heterogeneity in medulloblastoma.
A Sorana MorrissyFlorence M G CavalliMarc RemkeVijay RamsawamiDavid J H ShihBorja L HolgadoHamza FarooqLaura K DonovanLivia GarziaSameer AgnihotriErin N KiehnaEloi MercierChelsea MayohSimon Papillon-CavanaghHamid NikbakhtTenzin GaydenJonathon TorchiaDaniel PicardDiana Merino VegaMaria VladoiuBetty LuuXiaochong WuCraig DanielsStuart HorswellYuan Yao ThompsonVolker HovestadtPaul A NorthcottDavid T W JonesJohn PeacockXin WangStephen C MackJüri ReimandSteffen AlbrechtAdam M FontebassoNina ThiessenYisu LiJacqueline E ScheinDarlene LeeRebecca CarlsenMichael MayoKane TseAngela TamNoreen DhallaAdrian AllyEric ChuahYoung ChengPatrick PlettnerHaiyan I LiRichard D CorbettTina WongWilliam LongJames LoukidesPawel BuczkowiczCynthia E HawkinsUri TaboriBrian R RoodJohn S MyserosRoger J PackerAndrey KorshunovPeter LichterMarcel KoolStefan M PfisterUlrich SchüllerPeter DirksAnnie HuangEric BouffetJames T RutkaGary D BaiderCharles SwantonYusanne MaRichard A MooreAndrew J MungallJacek MajewskiSteven J M JonesSunit DasDavid MalkinNada JabadoMarco A MarraMichael D TaylorPublished in: Nature genetics (2017)
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
Keyphrases
- single cell
- high grade
- renal cell carcinoma
- ultrasound guided
- clinical trial
- rna seq
- end stage renal disease
- copy number
- genome wide
- ejection fraction
- low grade
- newly diagnosed
- chronic kidney disease
- gene expression
- peritoneal dialysis
- fine needle aspiration
- bioinformatics analysis
- high resolution
- oxidative stress
- mass spectrometry
- patient reported
- heat stress
- genome wide analysis