Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.
Matthew ClarkeAlan MackayBritta IsmerJessica C PicklesRuth G TatevossianScott NewmanTejus A BaleIris StolerElisa IzquierdoSara TemelsoDiana M CarvalhoValeria MolinariAnna BurfordLouise HowellAlex VirasamiAmy R FairchildAimee AveryJane ChalkerMark KristiansenKelly HaupfearJames D DaltonWilda OrismeJi WenMichael HubankKathreena M KurianCatherine RoweMellissa MayburyStephen CrosierJeffrey KnipsteinUlrich SchüllerUwe KordesDavid E KramMatija SnuderlLeslie BridgesAndrew J MartinLawrence J DoeySafa Al-SarrajChristopher ChandlerBassel ZebianClaire CairnsRachael NatrajanJessica K R BoultSimon P RobinsonMartin SillIra J DunkelStephen W GilheeneyMarc K RosenblumDebbie HughesPaula Z ProszekTobey J MacdonaldMatthias PreusserChristine HaberlerIrene SlavcRoger PackerHo-Keung NgShani CaspiMara PopovićBarbara Faganel KotnikMatthew D WoodLissa BairdMonika Ashok DavareDavid A SolomonThale Kristin OlsenPetter BrandalMichael FarrellJane B CryanMichael CapraMichael KarremannCornelia BrendleMartin Ulrich SchuhmannMartin EbingerWinand N M DinjensKornelius KerlSimone HettmerTorsten PietschFelipe AndreiuoloPablo Hernáiz DrieverAndrey KorshunovLotte HiddinghBarbara C WorstDominik SturmMarc ZuckermannOlaf WittTabitha BloomClare MitchellEvelina MieleGiovanna Stefania ColafatiFrancesca Diomedi-CamasseiSimon BaileyAndrew S MooreTimothy E G HassallStephen P LowisMaria TsoliMark J CowleyDavid S ZieglerMatthias A KarajannisKristian AquilinaDarren R HargraveFernando CarcellerLynley V MarshallAndreas von DeimlingChristof Maria KrammStefan M PfisterFelix SahmSuzanne J BakerAngela MastronuzziAndrea CaraiMaria VinciDavid CapperSergey PopovDavid W EllisonThomas S JacquesDavid T W JonesChris JonesPublished in: Cancer discovery (2020)
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.
Keyphrases
- high grade
- low grade
- genome wide
- copy number
- stem cells
- primary care
- tyrosine kinase
- dna methylation
- cell death
- healthcare
- single cell
- dna damage
- young adults
- genome wide identification
- risk factors
- signaling pathway
- cancer therapy
- deep learning
- machine learning
- gene expression
- insulin resistance
- adipose tissue
- reactive oxygen species
- mesenchymal stem cells
- metabolic syndrome
- quality improvement
- cell proliferation
- bone marrow
- transcription factor
- skeletal muscle
- pi k akt
- drug delivery
- drug induced
- brain injury