彌漫性腦干膠質瘤研究現狀_West China Medical Journal

Authors：

 任艷明 , 肖安琪 , 楊翔 , 劉曉薇 ,  張躍康

四川大學華西醫院神經外科 (成都 610041);

Corresponding?author：

張躍康, Email: 2012zykyx@sina.cn

Keywords：

彌漫性腦干膠質瘤; 分子生物學; 基因測序

DOI：

10.7507/1002-0179.201600212

Video：

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彌漫性腦干膠質瘤（DIPG）占兒童中樞神經系統腫瘤的10%～15%，盡管經過國內外學者幾十年的不斷努力，但這種疾病一經診斷其病死率仍為100%。由于腦干內布滿重要神經核團和纖維，周圍血管眾多，且腦干膠質瘤呈浸潤性生長，所以手術不能給患者帶來好處，往往可能加重神經廢損。越來越多的化學療法（化療）同樣被證實對提高DIPG的預后并無幫助，其中包括常規用于幕上膠質瘤的標準化療藥物替莫唑胺。目前國際認可的標準治療方案是傳統的放射治療，但治療效果也僅限于暫時緩解癥狀。最新的研究利用全基因測序將DIPG細分為3種分子亞型（H3-K27M、silent、MYCN），使人們在認識該疾病上又有了更進一步提高。

Citation： 任艷明, 肖安琪, 楊翔, 劉曉薇, 張躍康. 彌漫性腦干膠質瘤研究現狀. West China Medical Journal, 2016, 31(4): 775-779. doi: 10.7507/1002-0179.201600212 Copy

1.	?Kebudi R, Cakir FB. Management of diffuse pontine gliomas in children: recent developments[J]. Paediatr Drugs, 2013, 15(5): 351-362.
2.	Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials[J]. Lancet Oncol, 2006, 7(3): 241-248.
3.	Jansen MH, van Vuurden DG, Vandertop WP, et al. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology[J]. Cancer Treat Rev, 2012, 38(1): 27-35.
4.	Guillamo JS, Monjour A, Taillandier L, et al. Brainstem gliomas in adults: prognostic factors and classification[J]. Brain, 2001, 124(Pt 12): 2528-2539.
5.	Rubin G, Michowitz S, Horev G, et al. Pediatric brain stem gliomas: an update[J]. Childs Nerv Syst, 1998, 14(4/5): 167-173.
6.	Fisher PG, Breiter SN, Carson BS, et al. A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities[J]. Cancer, 2000, 89(7): 1569-1576.
7.	Gururangan S, Mclaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma[J]. J Neurooncol, 2006, 77(2): 207-212.
8.	Epstein F, Constantini S. Practical decisions in the treatment of pediatric brain stem tumors[J]. Pediatr Neurosurg, 1996, 24(1): 24-34.
9.	Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children[J]. J Neurosurg, 2007, 107(1 Suppl): 1-4.
10.	Walker DA, Liu JF, Kieran M, et al. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method[J]. Neuro Oncol, 2013, 15(4): 462-468.
11.	Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review[J]. Int J Radiat Oncol Biol Phys, 1998, 40(2): 265-271.
12.	Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis[J]. Int J Radiat Oncol Biol Phys, 2013, 85(2): 315-320.
13.	Chassot A, Canale S, Varlet P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma[J]. J Neurooncol, 2012, 106(2): 399-407.
14.	Bailey S, Howman A, Wheatley K, et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy-results of a United Kingdom phase Ⅱ trial (CNS 2007 04)[J]. Eur J Cancer, 2013, 49(18): 3856-3862.
15.	Caretti V, Hiddingh L, Lagerweij T, et al. WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas[J]. Mol Cancer Ther, 2013, 12(2): 141-150.
16.	Mueller S, Hashizume R, Yang XD, et al. Targeting wee1 for the treatment of pediatric high-grade gliomas[J]. Neuro Oncol, 2013, 15(1): 17.
17.	梅國順, 杜建新. 腦膠質瘤治療的新途徑——增強對流輸送[J]. 中華神經外科雜志, 2008, 24(4): 314-316.
18.	Sandberg DI, Edgar MA, Souweidane MM. Convection-enhanced delivery into the rat brainstem[J]. J Neurosurg, 2002, 96(5): 885-891.
19.	Lonser RR, Warren KE, Butman JA, et al. Real-time image-guided direct convective perfusion of intrinsic brainstem lesions[J]. J Neurosurg, 2007, 107(1): 190-197.
20.	Luther N, Zhou Z, Zanzonico P, et al. The potential of theragnostic 124I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma[J]. Neuro Oncol, 2014, 16(6): 800-806.
21.	Thomale UW, Tyler B, Renard V, et al. Neurological grading, survival, Mr imaging, and histological evaluation in the rat brainstem glioma model[J]. Childs Nerv Syst, 2009, 25(4): 433-441.
22.	Yang BJ, Wu X, Mao Y, et al. Dual-targeted antitumor effects against brainstem glioma by intravenous delivery of tumor necrosis factor-related, apoptosis-inducing, ligand-engineered human mesenchymal stem cells[J]. Neurosurgery, 2009, 65(3): 610-624.
23.	Hashizume R, Smirnov I, Liu S, et al. Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment[J]. J Neurooncol, 2012, 110(3): 305-313.
24.	Becher OJ, Hambardzumyan D, Walker TR, et al. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma[J]. Cancer Res, 2010, 70(6): 2548-2557.
25.	Barton KL, Misuraca K, Cordero F, et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma[J]. PLoS One, 2013, 8(10): e77639.
26.	Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem gliomas[J]. J Clin Oncol, 2006, 24(8): 1266-1272.
27.	Schroeder KM, Hoeman CM, Becher OJ. Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology[J]. Pediatr Res, 2014, 75(1/2): 205-209.
28.	Paugh BS, Broniscer A, Qu CX, et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma[J]. J Clin Oncol, 2011, 29(30): 3999-4006.
29.	Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma[J]. Nat Genet, 2014, 46(5): 444-450.
30.	Puget S, Philippe C, Bax DA, et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas[J]. PLoS One, 2012, 7(2): e30313.
31.	Grill J, Puget S, Andreiuolo F, et al. Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma[J]. Pediatr Blood Cancer, 2012, 58(4): 489-491.
32.	Khuong-Quang D, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas[J]. Acta Neuropathol, 2012, 124(3): 439-447.
33.	Taylor KR, Mackay A, Truffaux N, et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma[J]. Nat Genet, 2014, 46(5): 457-461.
34.	Buczkowicz P, Hoeman C, Rakopoulos P, et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations[J]. Nat Genet, 2014, 46(5): 451-456.
35.	Song GA, Kim HJ, Woo KM, et al. Molecular consequences of the ACVR1 (R206H) mutation of fibrodysplasia ossificans progressiva[J]. J Biol Chem, 2010, 285(29): 22542-22553.
36.	Shimasaki S, Moore RK, Otsuka F, et al. The bone morphogenetic protein system in mammalian reproduction[J]. Endocr Rev, 2004, 25(1): 72-101.
37.	Zurawel RH, Allen C, Chiappa S, et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma[J]. Genes Chromosomes Cancer, 2000, 27(1): 44-51.
38.	Monje M, Mitra SS, Freret ME, et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma[J]. Proc Natl Acad Sci USA, 2011, 108(11): 4453-4458.
39.	Wang D, Xia X, Weiss RE, et al. Distinct and histone-specific modifications mediate positive versus negative transcriptional regulation of TSHalpha promoter[J]. PLoS One, 2010, 5(3): e9853.
40.	Schwartz YB, Kahn TG, Stenberg P, et al. Alternative epigenetic chromatin states of polycomb target genes[J]. PLoS Genet, 2010, 6(1): e1000805.
41.	Smith SE, Waller JC, Bingham IA, et al. A diffuse intrinsic pontine glioma roadmap: guiding research toward a cure[J]. Pediatr Blood Cancer, 2014, 61(5): 765-767.

1. ?Kebudi R, Cakir FB. Management of diffuse pontine gliomas in children: recent developments[J]. Paediatr Drugs, 2013, 15(5): 351-362.
2. Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials[J]. Lancet Oncol, 2006, 7(3): 241-248.
3. Jansen MH, van Vuurden DG, Vandertop WP, et al. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology[J]. Cancer Treat Rev, 2012, 38(1): 27-35.
4. Guillamo JS, Monjour A, Taillandier L, et al. Brainstem gliomas in adults: prognostic factors and classification[J]. Brain, 2001, 124(Pt 12): 2528-2539.
5. Rubin G, Michowitz S, Horev G, et al. Pediatric brain stem gliomas: an update[J]. Childs Nerv Syst, 1998, 14(4/5): 167-173.
6. Fisher PG, Breiter SN, Carson BS, et al. A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities[J]. Cancer, 2000, 89(7): 1569-1576.
7. Gururangan S, Mclaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma[J]. J Neurooncol, 2006, 77(2): 207-212.
8. Epstein F, Constantini S. Practical decisions in the treatment of pediatric brain stem tumors[J]. Pediatr Neurosurg, 1996, 24(1): 24-34.
9. Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children[J]. J Neurosurg, 2007, 107(1 Suppl): 1-4.
10. Walker DA, Liu JF, Kieran M, et al. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method[J]. Neuro Oncol, 2013, 15(4): 462-468.
11. Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review[J]. Int J Radiat Oncol Biol Phys, 1998, 40(2): 265-271.
12. Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis[J]. Int J Radiat Oncol Biol Phys, 2013, 85(2): 315-320.
13. Chassot A, Canale S, Varlet P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma[J]. J Neurooncol, 2012, 106(2): 399-407.
14. Bailey S, Howman A, Wheatley K, et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy-results of a United Kingdom phase Ⅱ trial (CNS 2007 04)[J]. Eur J Cancer, 2013, 49(18): 3856-3862.
15. Caretti V, Hiddingh L, Lagerweij T, et al. WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas[J]. Mol Cancer Ther, 2013, 12(2): 141-150.
16. Mueller S, Hashizume R, Yang XD, et al. Targeting wee1 for the treatment of pediatric high-grade gliomas[J]. Neuro Oncol, 2013, 15(1): 17.
17. 梅國順, 杜建新. 腦膠質瘤治療的新途徑——增強對流輸送[J]. 中華神經外科雜志, 2008, 24(4): 314-316.
18. Sandberg DI, Edgar MA, Souweidane MM. Convection-enhanced delivery into the rat brainstem[J]. J Neurosurg, 2002, 96(5): 885-891.
19. Lonser RR, Warren KE, Butman JA, et al. Real-time image-guided direct convective perfusion of intrinsic brainstem lesions[J]. J Neurosurg, 2007, 107(1): 190-197.
20. Luther N, Zhou Z, Zanzonico P, et al. The potential of theragnostic 124I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma[J]. Neuro Oncol, 2014, 16(6): 800-806.
21. Thomale UW, Tyler B, Renard V, et al. Neurological grading, survival, Mr imaging, and histological evaluation in the rat brainstem glioma model[J]. Childs Nerv Syst, 2009, 25(4): 433-441.
22. Yang BJ, Wu X, Mao Y, et al. Dual-targeted antitumor effects against brainstem glioma by intravenous delivery of tumor necrosis factor-related, apoptosis-inducing, ligand-engineered human mesenchymal stem cells[J]. Neurosurgery, 2009, 65(3): 610-624.
23. Hashizume R, Smirnov I, Liu S, et al. Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment[J]. J Neurooncol, 2012, 110(3): 305-313.
24. Becher OJ, Hambardzumyan D, Walker TR, et al. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma[J]. Cancer Res, 2010, 70(6): 2548-2557.
25. Barton KL, Misuraca K, Cordero F, et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma[J]. PLoS One, 2013, 8(10): e77639.
26. Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem gliomas[J]. J Clin Oncol, 2006, 24(8): 1266-1272.
27. Schroeder KM, Hoeman CM, Becher OJ. Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology[J]. Pediatr Res, 2014, 75(1/2): 205-209.
28. Paugh BS, Broniscer A, Qu CX, et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma[J]. J Clin Oncol, 2011, 29(30): 3999-4006.
29. Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma[J]. Nat Genet, 2014, 46(5): 444-450.
30. Puget S, Philippe C, Bax DA, et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas[J]. PLoS One, 2012, 7(2): e30313.
31. Grill J, Puget S, Andreiuolo F, et al. Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma[J]. Pediatr Blood Cancer, 2012, 58(4): 489-491.
32. Khuong-Quang D, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas[J]. Acta Neuropathol, 2012, 124(3): 439-447.
33. Taylor KR, Mackay A, Truffaux N, et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma[J]. Nat Genet, 2014, 46(5): 457-461.
34. Buczkowicz P, Hoeman C, Rakopoulos P, et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations[J]. Nat Genet, 2014, 46(5): 451-456.
35. Song GA, Kim HJ, Woo KM, et al. Molecular consequences of the ACVR1 (R206H) mutation of fibrodysplasia ossificans progressiva[J]. J Biol Chem, 2010, 285(29): 22542-22553.
36. Shimasaki S, Moore RK, Otsuka F, et al. The bone morphogenetic protein system in mammalian reproduction[J]. Endocr Rev, 2004, 25(1): 72-101.
37. Zurawel RH, Allen C, Chiappa S, et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma[J]. Genes Chromosomes Cancer, 2000, 27(1): 44-51.
38. Monje M, Mitra SS, Freret ME, et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma[J]. Proc Natl Acad Sci USA, 2011, 108(11): 4453-4458.
39. Wang D, Xia X, Weiss RE, et al. Distinct and histone-specific modifications mediate positive versus negative transcriptional regulation of TSHalpha promoter[J]. PLoS One, 2010, 5(3): e9853.
40. Schwartz YB, Kahn TG, Stenberg P, et al. Alternative epigenetic chromatin states of polycomb target genes[J]. PLoS Genet, 2010, 6(1): e1000805.
41. Smith SE, Waller JC, Bingham IA, et al. A diffuse intrinsic pontine glioma roadmap: guiding research toward a cure[J]. Pediatr Blood Cancer, 2014, 61(5): 765-767.

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