Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

Abstract

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.Nature. 2015 Sep 3;525(7567):114-8. (PMID: 26266975); Acta Neuropathol. 2014 Oct;128(4):573-81. (PMID: 25047029); Nat Methods. 2013 Oct;10(10):1003-5. (PMID: 23995387); Nature. 2012 Feb 9;482(7384):226-31. (PMID: 22286061); Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6. (PMID: 22323597); Nat Genet. 2014 May;46(5):462-6. (PMID: 24705250); Acta Neuropathol. 2015 Dec;130(6):815-27. (PMID: 26399631); Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886); Bioinformatics. 2009 Jan 15;25(2):288-9. (PMID: 19033274); Bioinformatics. 2015 Feb 1;31(3):429-31. (PMID: 25297069); Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14. (PMID: 23412337); Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199); Nat Genet. 2014 May;46(5):451-6. (PMID: 24705254); Acta Neuropathol. 2014 Nov;128(5):733-41. (PMID: 25200321); N Engl J Med. 2012 Mar 8;366(10):883-92. (PMID: 22397650); Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943); Nat Genet. 2012 Mar;44(3):251-3. (PMID: 22286216); Science. 2013 May 17;340(6134):857-61. (PMID: 23539183); Genome Biol. 2015;16:35. (PMID: 25786235); Nature. 2012 Feb 23;482(7386):529-33. (PMID: 22343890); Acta Neuropathol. 2012 Sep;124(3):439-47. (PMID: 22661320); Oncotarget. 2015 May 20;6(14):12740-7. (PMID: 25749048); Neuro Oncol. 2013 Apr;15(4):462-8. (PMID: 23502427); Nat Genet. 2014 Jul;46(7):726-30. (PMID: 24880341); Genome Biol. 2015;16:91. (PMID: 25944252); Cell. 2012 May 25;149(5):979-93. (PMID: 22608084); Bioinformatics. 2013 Jun 1;29(11):1461-2. (PMID: 23539306); Science. 2014 Dec 19;346(6216):1529-33. (PMID: 25525250); Science. 2014 Jan 10;343(6167):189-93. (PMID: 24336570); Nat Genet. 2014 May;46(5):444-50. (PMID: 24705251); Acta Neuropathol. 2014 Oct;128(4):605-7. (PMID: 24929912); Bioinformatics. 2009 Jul 15;25(14):1754-60. (PMID: 19451168); Nat Protoc. 2009;4(1):44-57. (PMID: 19131956); Genome Biol. 2014;15(12):530. (PMID: 25608559); Nucleic Acids Res. 2010 Sep;38(16):e164. (PMID: 20601685); Nat Genet. 2015 Aug;47(8):864-71. (PMID: 26121087); Front Mol Neurosci. 2011 Dec 02;4:51. (PMID: 22144946); Genome Biol. 2014;15(12):550. (PMID: 25516281). Linking ISSN: 20411723. Subset: MEDLINE; Grant Information: KL2 TR000076 United States TR NCATS NIH HHS; KL2TR000076 United States TR NCATS NIH HHS; UL1 TR000075 United States TR NCATS NIH HHS; P01 CA196539 United States CA NCI NIH HHS; Canada Canadian Institutes of Health Research; UL1TR000075 United States TR NCATS NIH HHS Date of Electronic Publication: 2016 Apr 06. ; Original Imprints: Publication: [London] : Nature Pub. Group <br />