长期癫痫相关肿瘤的分子遗传学研究进展
摘要
长期癫痫相关肿瘤(long-term epilepsy associated tumor, LEAT)生长缓慢,组织学级别较低,伴有不同程度的胶质及神经元分化。随着分子遗传学的发展,LEAT相关的、具有诊断和(或)预后意义的基因变异被发现。BRAF基因变异为节细胞胶质瘤最常见的基因改变,BRAF V600E突变为最常见的变异形式。胚胎发育不良性神经上皮肿瘤最常见的基因改变为FGFR1突变。毛细胞星形细胞瘤最常见的基因改变是KIAA1549和BRAF基因的融合。几乎所有的血管中心性胶质瘤都含有MYB-QKI融合。儿童多形性低级别神经上皮肿瘤常伴有BRAF V600E突变或FGFR2/FGFR3融合改变,并且两种改变常常以相互排斥的方式发生。全基因组DNA甲基化分析成为原发性脑肿瘤分类的有力手段,促进了组织学类型不明确的肿瘤分类。
引文
[1]Piao YS,Lu DH,Chen L,et al.Neuropathological findings in intractable epilepsy:435 Chinese cases[J].Brain Pathol,2010,20:902-908.
[2]Blümcke I,Spreafico R,Haaker G,et al.Histopathological findings in brain tissue obtained during epilepsy surgery[J].N Engl J Med,2017,377:1648-1656.
[3]Luyken C,Blümcke I,Fimmers R,et al.The spectrum of long-term epilepsy-associated tumors:long-term seizure and tumor outcome and neurosurgical aspects[J].Epilepsia,2003,44:822-830.
[4]Thom M,Blümcke I,Aronica E.Long-term epilepsy-associated tumors[J].Brain Pathol,2012,22:350-379.
[5]Blümcke I,Aronica E,Becker A,et al.Low-grade epilepsy-associated neuroepithelial tumours-the 2016 WHO classification[J].Nat Rev Neurol,2016,12:732-740.
[6]Hovestadt V,Jones DT,Picelli S,et al.Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing[J].Nature,2014,510:537-541.
[7]Qaddoumi I,Orisme W,Wen J,et al.Genetic alterations in uncommon low-grade neuroepithelial tumors:BRAF,FGFR1,and MYB mutations occur at high frequency and align with morphology[J].Acta Neuropathol,2016,131:833-845.
[8]Dahiya S,Haydon DH,Alvarado D,et al.BRAF(V600E)mutation is a negative prognosticator in pediatric ganglioglioma[J].Acta Neuropathol,2013,125:901-910.
[9]Becker AJ,L?bach M,Klein H,et al.Mutational analysis of TSC1and TSC2 genes in gangliogliomas[J].Neuropathol Appl Neurobiol,2001,27:105-114.
[10]Kleinschmidt-DeMasters BK,Donson A,Foreman NK,et al.H3K27M mutation in gangliogliomas can be associated with poor prognosis[J].Brain Pathol,2017,27:846-850.
[11]Kam R,Chen J,Blümcke I,et al.The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis[J].Neuropathol Appl Neurobiol,2004,30:225-232.
[12]Chapman PB,Hauschild A,Robert C,et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation[J].N Engl JMed,2011,364:2507-2516.
[13]Thom M,Toma A,An S,et al.One hundred and one dysembryoplastic neuroepithelial tumors:an adult epilepsy series with immunohistochemical,molecular genetic,and clinical correlations and a review of the literature[J].J Neuropathol Exp Neurol,2011,70:859-878.
[14]Rivera B,Gayden T,Carrot-Zhang J,et al.Germline and somatic FG-FR1 abnormalities in dysembryoplastic neuroepithelial tumors[J].Acta Neuropathol,2016,131:847-863.
[15]Zhang JH,Wu G,Miller CP,et al.Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas[J].Nat Genet,2013,45:602-612.
[16]Stone TJ,Keeley A,Virasami A,et al.Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours[J].Acta Neuropathol,2018,135:115-129.
[17]Forsyth PA,Shaw EG,Scheithauer BW,et al.Supratentorial pilocytic astrocytomas.A clinicopathologic,prognostic,and flow cytometric study of 51 patients[J].Cancer,1993,72:1335-1342.
[18]Blümcke I,Wiestler OD.Gangliogliomas:an intriguing tumor entity associated with focal epilepsies[J].J Neuropathol Exp Neurol,2002,61:575-584.
[19]Forshew T,Tatevossian RG,Lawson AR,et al.Activation of the ERK/MAPK pathway:a signature genetic defect in posterior fossa pilocytic astrocytomas[J].J Pathol,2009,218:172-181.
[20]Dubuc AM,Northcott PA,Mack S,et al.The genetics of pediatric brain tumors[J].Curr Neurol Neurosci Rep,2010,10:215-223.
[21]Rodriguez EF,Scheithauer BW,Giannini C,et al.PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma[J].Acta Neuropathol,2011,121:407-420.
[22]Lellouch-Tubiana A,Boddaert N,Bourgeois M,et al.Angiocentric neuroepithelial tumor(ANET):a new epilepsy-related clinicopathological entity with distinctive MRI[J].Brain Pathol,2010,15:281-286.
[23]Wang M,Tihan T,Rojiani AM,et al.Monomorphous angiocentric gli-395oma:a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma[J].J Neuropathol Exp Neurol,2005,64:875-881.
[24]Ni HC,Chen SY,Chen L,et al.Angiocentric glioma:a report of nine new cases,including four with atypical histological features[J].Neuropathol Appl Neurobiol,2015,41:333-346.
[25]Preusser M,Hoischen A,Novak K,et al.Angiocentric glioma:report of clinico-pathologic and genetic findings in 8 cases[J].Am J Surg Pathol,2007,31:1709-1718.
[26]Tatevossian RG,Tang B,Dalton J,et al.MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas[J].Acta Neuropathol,2010,120:731-743.
[27]Ramkissoon LA,Horowitz PM,Craig JM,et al.Genomic analysis of396diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1[J].Proc Natl Acad Sci U S A,2013,110:8188-8193.
[28]Bandopadhayay P,Ramkissoon LA,Jain P,et al.MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism[J].Nat Genet,2016,48:273-282.
[29]Huse JT,Snuderl M,Jones DTW,et al.Polymorphous low-grade neuroepithelial tumor of the young(PLNTY):an epileptogenic neoplasm with oligodendroglioma-like components,aberrant CD34 expression,and genetic alterations involving the MAP kinase pathway[J].Acta Neuropathol,2017,133:417-429.
[2]Blümcke I,Spreafico R,Haaker G,et al.Histopathological findings in brain tissue obtained during epilepsy surgery[J].N Engl J Med,2017,377:1648-1656.
[3]Luyken C,Blümcke I,Fimmers R,et al.The spectrum of long-term epilepsy-associated tumors:long-term seizure and tumor outcome and neurosurgical aspects[J].Epilepsia,2003,44:822-830.
[4]Thom M,Blümcke I,Aronica E.Long-term epilepsy-associated tumors[J].Brain Pathol,2012,22:350-379.
[5]Blümcke I,Aronica E,Becker A,et al.Low-grade epilepsy-associated neuroepithelial tumours-the 2016 WHO classification[J].Nat Rev Neurol,2016,12:732-740.
[6]Hovestadt V,Jones DT,Picelli S,et al.Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing[J].Nature,2014,510:537-541.
[7]Qaddoumi I,Orisme W,Wen J,et al.Genetic alterations in uncommon low-grade neuroepithelial tumors:BRAF,FGFR1,and MYB mutations occur at high frequency and align with morphology[J].Acta Neuropathol,2016,131:833-845.
[8]Dahiya S,Haydon DH,Alvarado D,et al.BRAF(V600E)mutation is a negative prognosticator in pediatric ganglioglioma[J].Acta Neuropathol,2013,125:901-910.
[9]Becker AJ,L?bach M,Klein H,et al.Mutational analysis of TSC1and TSC2 genes in gangliogliomas[J].Neuropathol Appl Neurobiol,2001,27:105-114.
[10]Kleinschmidt-DeMasters BK,Donson A,Foreman NK,et al.H3K27M mutation in gangliogliomas can be associated with poor prognosis[J].Brain Pathol,2017,27:846-850.
[11]Kam R,Chen J,Blümcke I,et al.The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis[J].Neuropathol Appl Neurobiol,2004,30:225-232.
[12]Chapman PB,Hauschild A,Robert C,et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation[J].N Engl JMed,2011,364:2507-2516.
[13]Thom M,Toma A,An S,et al.One hundred and one dysembryoplastic neuroepithelial tumors:an adult epilepsy series with immunohistochemical,molecular genetic,and clinical correlations and a review of the literature[J].J Neuropathol Exp Neurol,2011,70:859-878.
[14]Rivera B,Gayden T,Carrot-Zhang J,et al.Germline and somatic FG-FR1 abnormalities in dysembryoplastic neuroepithelial tumors[J].Acta Neuropathol,2016,131:847-863.
[15]Zhang JH,Wu G,Miller CP,et al.Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas[J].Nat Genet,2013,45:602-612.
[16]Stone TJ,Keeley A,Virasami A,et al.Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours[J].Acta Neuropathol,2018,135:115-129.
[17]Forsyth PA,Shaw EG,Scheithauer BW,et al.Supratentorial pilocytic astrocytomas.A clinicopathologic,prognostic,and flow cytometric study of 51 patients[J].Cancer,1993,72:1335-1342.
[18]Blümcke I,Wiestler OD.Gangliogliomas:an intriguing tumor entity associated with focal epilepsies[J].J Neuropathol Exp Neurol,2002,61:575-584.
[19]Forshew T,Tatevossian RG,Lawson AR,et al.Activation of the ERK/MAPK pathway:a signature genetic defect in posterior fossa pilocytic astrocytomas[J].J Pathol,2009,218:172-181.
[20]Dubuc AM,Northcott PA,Mack S,et al.The genetics of pediatric brain tumors[J].Curr Neurol Neurosci Rep,2010,10:215-223.
[21]Rodriguez EF,Scheithauer BW,Giannini C,et al.PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma[J].Acta Neuropathol,2011,121:407-420.
[22]Lellouch-Tubiana A,Boddaert N,Bourgeois M,et al.Angiocentric neuroepithelial tumor(ANET):a new epilepsy-related clinicopathological entity with distinctive MRI[J].Brain Pathol,2010,15:281-286.
[23]Wang M,Tihan T,Rojiani AM,et al.Monomorphous angiocentric gli-395oma:a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma[J].J Neuropathol Exp Neurol,2005,64:875-881.
[24]Ni HC,Chen SY,Chen L,et al.Angiocentric glioma:a report of nine new cases,including four with atypical histological features[J].Neuropathol Appl Neurobiol,2015,41:333-346.
[25]Preusser M,Hoischen A,Novak K,et al.Angiocentric glioma:report of clinico-pathologic and genetic findings in 8 cases[J].Am J Surg Pathol,2007,31:1709-1718.
[26]Tatevossian RG,Tang B,Dalton J,et al.MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas[J].Acta Neuropathol,2010,120:731-743.
[27]Ramkissoon LA,Horowitz PM,Craig JM,et al.Genomic analysis of396diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1[J].Proc Natl Acad Sci U S A,2013,110:8188-8193.
[28]Bandopadhayay P,Ramkissoon LA,Jain P,et al.MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism[J].Nat Genet,2016,48:273-282.
[29]Huse JT,Snuderl M,Jones DTW,et al.Polymorphous low-grade neuroepithelial tumor of the young(PLNTY):an epileptogenic neoplasm with oligodendroglioma-like components,aberrant CD34 expression,and genetic alterations involving the MAP kinase pathway[J].Acta Neuropathol,2017,133:417-429.