J Korean Neurosurg Soc.  2018 May;61(3):319-332. 10.3340/jkns.2018.0031.

Pediatric High Grade Gliomas in the Context of Cancer Predisposition Syndromes

• Michaeli O
• Tabori U

• KMID: 2417357
• DOI: http://doi.org/10.3340/jkns.2018.0031

Abstract

Germline mutations in cancer causing genes result in high risk of developing cancer throughout life. These cancer predisposition syndromes (CPS) are especially prevalent in childhood brain tumors and impact both the patient's and other family members' survival. Knowledge of specific CPS may alter the management of the cancer, offer novel targeted therapies which may improve survival for these patients, and enables early detection of other malignancies. This review focuses on the role of CPS in pediatric high grade gliomas (PHGG), the deadliest group of childhood brain tumors. Genetic aspects and clinical features are depicted, allowing clinicians to identify and diagnose these syndromes. Challenges in the management of PHGG in the context of each CPS and the promise of innovative options of treatment and surveillance guidelines are discussed with the hope of improving outcome for individuals with these devastating syndromes.

Keyword

Cancer predisposition syndrome; High grade glioma; Li fraumeni syndrome; Constitutional mismatch repair deficiency; Neurofibromatosis 1; Surveillance

MeSH Terms

Brain Neoplasms
Germ-Line Mutation
Glioma*
Hope
Humans
Li-Fraumeni Syndrome
Neurofibromatosis 1

Figure

• 

  Fig. 1. Transformation of a low grade to high grade glioma in a patient with Li Fraumeni. A low grade glioma was diagnosed in a known LFS patient (A). Three years following the initial diagnosis, a sudden dramatic growth was observed (B). Biopsy confirmed the diagnosis of anaplastic astrocytoma (WHO grade III). LFS : Li Fraumeni syndrome, WHO : World Health Organization.

• 

  Fig. 2. Surveillance imaging reveals asymptomatic glioma in a Li Fraumeni patient. A routine surveillance imaging in an LFS patient reveals an intra-axial lesion within the inferior left frontal lobe. The lesion was fully resected, and the pathology revealed diffuse astrocytoma, WHO stage II. LFS : Li Fraumeni syndrome, WHO : World Health Organization.

• 

  Fig. 3. Bifocal glioblastoma in a CMMRD patient. Two separate lesions uncovered in an infant with CMMRD. Molecular and genetic analysis confirmed two different glioblastomas and not metastatic disease. CMMRD : constitutional mismatch repair deficiency.

• 

  Fig. 4. Malignant glioma in a NF-1 patient. Rapidly growing thalamic lesion in a patient with NF-1 exhibiting significant mass effect and edema. Pathology confirmed PHGG. NF-1 : neurofibromatosis-1, PHGG : pediatric high grade gliomas.

Reference

References

1. Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, et al. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 99:337–351. 2016.

2. Albers AC, Gutmann DH. Gliomas in patients with neurofibromatosis type 1. Expert Rev Neurother. 9:535–539. 2009.

3. Amayiri N, Tabori U, Campbell B, Bakry D, Aronson M, Durno C, et al. High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan. Int J Cancer. 138:380–385. 2016.

4. de Andrade KC, Mirabello L, Stewart DR, Karlins E, Koster R, Wang M, et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat. 38:1723–1730. 2017.

5. Andrianova MA, Chetan GK, Sibin MK, Mckee T, Merkler D, Narasinga RK, et al. Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours. J Pathol. 243:331–341. 2017.

6. Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 6:a026062. 2016.

7. Baas AF, Gabbett M, Rimac M, Kansikas M, Raphael M, Nievelstein RAJ, et al. Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome. Eur J Hum Genet. 21:55–61. 2013.

8. Bainbridge MN, Armstrong GN, Gramatges MM, Bertuch AA, Jhangiani SN, Doddapaneni H, et al. Germline mutations in shelterin complex genes are associated with familial glioma. J Natl Cancer Inst. 107:384. 2015.

9. Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK, et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer. 50:987–996. 2014.

10. Ballinger ML, Best A, Mai PL, Khincha PP, Loud JT, Peters JA, et al. Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging. JAMA Oncol. 3:1634–1639. 2017.

11. Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T, et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol. 19:1135–1144. 2017.

12. Bleeker FE, Hopman SMJ, Merks JHM, Aalfs CM, Hennekam RC. Brain tumors and syndromes in children. Neuropediatrics. 45:137–161. 2014.

13. Bögler O, Su Huang HJ, Kleihues P, Cavenee WK. The p53 gene and its role in human brain tumors. Glia. 15:308–327. 1995.

14. Bojadzieva J, Amini B, Day SF, Jackson TL, Thomas PS, JWillis BJ, et al. Whole body magnetic resonance imaging (WB-MRI) and brain MRI baseline surveillance in TP53 germline mutation carriers: experience from the Li-Fraumeni Syndrome Education and Early Detection (LEAD) clinic. Fam Cancer. 2017; [Epub ahead of print].

15. Bouffet E, Larouche V, Campbell BB, Merico D, De Borja R, Aronson M, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 34:2206–2211. 2016.

16. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 33:2345–2352. 2015.

17. Brodeur GM, Nichols KE, Plon SE, Schiffman JD, Malkin D. Pediatric cancer predisposition and surveillance: an overview, and a tribute to Alfred G. Knudson Jr. Clin Cancer Res. 23:e1–e5. 2017.

18. Broekman ML, Risselada R, Engelen-Lee J, Spliet WG, Verweij BH. Glioblastoma multiforme in the posterior cranial fossa in a patient with neurofibromatosis type I. Case Rep Med. 2009:757898. 2009.

19. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 171:1042–1056.e10. 2017.

20. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008.

21. Cruz GR, Dias Oliveira I, Moraes L, Del Giudice Paniago M, De Seixas Alves MT, Capellano AM, et al. Analysis of KIAA1549-BRAF fusion gene expression and IDH1/IDH2 mutations in low grade pediatric astrocytomas. J Neurooncol. 117:235–242. 2014.

22. Distelmaier F, Fahsold R, Reifenberger G, Messing-Juenger M, Schaper J, Schneider DT, et al. Fatal glioblastoma multiforme in a patient with neurofibromatosis type I: the dilemma of systematic medical follow-up. Child’s Nerv Syst. 23:343–347. 2007.

23. Dodgshun AJ, Sexton-Oates A, Saffery R, Sullivan MJ. Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. Cancer Genet. 209:53–56. 2016.

24. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 22:813–820. 2016.

25. Durno C, Boland CR, Cohen S, Dominitz JA, Giardiello FM, Johnson DA, et al. Recommendations on surveillance and management of biallelic mismatch repair deficiency (BMMRD) syndrome: a consensus statement by the US multi-society task force on colorectal cancer. Gastroenterology. 152:1605–1614. 2017.

26. Eaton KW, Tooke LS, Wainwright LM, Judkins AR, Biegel JA. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer. 56:7–15. 2011.

27. Eisenstat DD, Pollack IF, Demers A, Sapp MV, Lambert P, Weisfeld-Adams JD, et al. Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children’s Cancer Group high-grade glioma study CCG-945. J Neurooncol. 121:573–581. 2015.

28. Elmariah SB, Huse J, Mason B, Leroux P, Lustig RA. Multicentric glioblastoma multiforme in a patient with BRCA-1 invasive breast cancer. Breast J. 12:470–474. 2006.

29. Esteban-Jurado C, Giménez-Zaragoza D, Muñoz J, Franch-Expósito S, Álvarez-Barona M, Ocaña T, et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget. 8:26732–26743. 2017.

30. Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Schneide KW, et al. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 1. Clin Cancer Res. 23:e46–e53. 2017.

31. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 44:81–88. 2006.

32. Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 14:790–797. 2012.

33. Girardstein-Boccara L, Mari V, Met-Domestici M, Burel-Vandenbos F, Berthet P, Paquis P, et al. Gliomas and BRCA genes mutations: fortuitous association or imputability? Bull Cancer 101. 14:795–802. 2014.

34. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 27:1250–1256. 2009.

35. Goudie C, Coltin H, Witkowski L, Mourad S, Malkin D, Foulkes WD. The McGill Interactive Pediatric OncoGenetic Guidelines: an approach to identifying pediatric oncology patients most likely to benefit from a genetic evaluation. Pediatr Blood Cancer. 64:e26441. 2017.

36. Gozali AE, Britt B, Shane L, Gonzalez I, Gilles F, McComb JG, et al. Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children’s Hospital Los Angeles (CHLA) experience, 1991-2010. Pediatr Blood Cancer. 58:905–909. 2012.

37. Grill J, Laithier V, Rodriguez D, Raquin MA, Pierre-Kahn A, Kalifa C. When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre. Eur J Pediatr. 159:692–696. 2000.

38. Guillamo JS, Créange A, Kalifa C, Grill J, Rodriguez D, Doz F, et al. Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain. 126(Pt 1):152–160. 2003.

39. Gutmann DH, James CD, Poyhonen M, Louis DN, Ferner R, Guha A, et al. Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology. 61:1397–1400. 2003.

40. Hakan T, Aker FV. Case report on a patient with neurofibromatosis type 1 and a frontal cystic glioblastoma. Neurol Neurochir Pol. 42:362–365. 2008.

41. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011.

42. Henry E, Villalobos V, Million L, Jensen KC, West R, Ganjoo K, et al. Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome. J Natl Compr Canc Netw. 10:939–942. 2012.

43. Hersh JH; American Academy of Pediatrics Committee on Genetics, American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 121:633–642. 2008.

44. Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol. 5:104. 2010.

45. Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol. 19:1047–1057. 2017.

46. Huttner AJ, Kieran MW, Yao X, Cruz L, Ladner J, Quayle K, et al. Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1. Pediatr Blood Cancer. 54:890–896. 2010.

47. Jalali A, Amirian ES, Bainbridge MN, Armstrong GN, Liu Y, Tsavachidis S, et al. Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene consortium. Sci Rep. 5:8278. 2015.

48. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 12:1–11. 2010.

49. Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 6:1230–1236. 2016.

50. Kandoth C, Mclellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 502:333–339. 2013.

51. Kaufman DK, Kimmel DW, Parisi JE, Michels VV. A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma. Neurology. 43:1728–1731. 1993.

52. Khatua S, Gutmann DH, Packer RJ. Neurofibromatosis type 1 and optic pathway glioma: molecular interplay and therapeutic insights. Pediatr Blood Cancer. 65:e26838. 2017.

53. King A, Listernick R, Charrow J, Piersall L, Gutmann DH. Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am J Med Genet 122A. 122A:95–99. 2003.

54. Kinsella TJ. Coordination of DNA mismatch repair and base excision repair processing of chemotherapy and radiation damage for targeting resistant cancers. Clin Cancer Res. 15:1853–1859. 2009.

55. Kleihues P, Schäuble B, zur Hausen A, Estève J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 150:1–13. 1997.

56. Knapke S, Nagarajan R, Correll J, Kent D, Burns K. Hereditary cancer risk assessment in a pediatric oncology follow‐up clinic. Pediatr Blood Cancer. 58:85–89. 2012.

57. Kratz CP, Achatz MI, Brugières I, Frebourg T, Garber JE, Greer MC, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 23:e38–e45. 2017.

58. Kyritsis AP, Bondy ML, Rao JS, Sioka C. Inherited predisposition to glioma. Neuro Oncol. 12:104–113. 2010.

59. Lalloo F, Varley J, Ellis D, Moran A, O’Dair L, Pharoah P, et al. Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet. 361:1101–1102. 2003.

60. Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N, et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 52:770–778. 2015.

61. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015.

62. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site - when a biomarker defines the indication. N Engl J Med. 377:1409–1412. 2017.

63. Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 48:5358–5362. 1988.

64. Ligtenberg MJL, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet. 41:112–117. 2009.

65. Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer. 96:238–242. 2001.

66. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 61:189–198. 2007.

67. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system, ed 4. Lyon: International Agency for Research on Cancer Publications;2016.

68. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131:803–820. 2016.

69. Mai P, Malkin D, Garber JE, Schiffman JD Weitzel JN, Strong LC, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 205:479–487. 2012.

70. Malkin D. Li-Fraumeni syndrome. Genes Cancer. 2:475–484. 2011.

71. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 250:1233–1238. 1990.

72. Malmer B, Adatto P, Armstrong G, Barnholtz-Sloan J, Bernstein JL, Claus E, et al. GLIOGENE an international consortium to understand familial glioma. Cancer Epidemiol Biomarkers Prev. 16:1730–1734. 2007.

73. McKeever K, Shepherd CW, Crawford H, Morrison PJ. An epidemiological, clinical and genetic survey of neurofibromatosis type 1 in children under sixteen years of age. Ulster Med J. 77:160–163. 2008.

74. Menor F, Martí-Bonmatí L, Mulas F, Cortina H, Olagüe R. Imaging considerations of central nervous system manifestations in pediatric patients with neurofibromatosis type 1. Pediatr Radiol. 21:389–394. 1991.

75. Miaux Y, Guermazi A, Cornu P, Mokhtari K, Singer B, Chiras J, et al. Highintensity lesion on T1-weighted MR images in neurofibromatosis type 1: a case of premalignant lesion. Acta Neurochir (Wien). 139:1085–1087. 1997.

76. Mody RJ, Wu YM, Lonigro RJ, Cao X, Roychowdhury S, Vats P, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA. 314:913–925. 2015.

77. Nebot-Bral L, Brandao D, Verlingue L, Rouleau E, Caron O, Despras E, et al. Hypermutated tumours in the era of immunotherapy: the paradigm of personalised medicine. Eur J Cancer. 84:290–303. 2017.

78. Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 63:6643–6650. 2003.

79. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008.

80. Parsons DW, Roy A, Yang Y, Wang T, Scollon S, Bergstrom K, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2:616–624. 2016.

81. Patil S, Chamberlain RS. Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist. 17:101–116. 2012.

82. Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol. 28:3061–3068. 2010.

83. Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, et al. Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med. 346:420–427. 2002.

84. Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 10:55–62. 2001.

85. Ranger A, Szymczak A, Hammond RR, Zelcer S. Pediatric thalamic glioblastoma associated with Ollier disease (multiple enchondromatosis): a rare case of concurrence. J Neurosurg Pediatr. 4:363–367. 2009.

86. Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, et al. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23:e68–e75. 2017.

87. Reyes D, Prayson R. Glioblastoma in the setting of tuberous sclerosis. J Clin Neurosci. 22:907–908. 2015.

88. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 348:124–128. 2015.

89. Rosenfeld A, Listernick R, Charrow J, Goldman S. Neurofibromatosis type 1 and high-grade tumors of the central nervous system. Childs Nerv Syst. 26:663–667. 2010.

90. Rosser T, Packer RJ. Intracranial neoplasms in children with neurofibromatosis 1. J Child Neurol. 17:630–637; discussion 646-651. 2002.

91. Santin AD, Bellone S, Buza N, Choi J, Schwartz PE, Schlessinger J, et al. Regression of chemotherapy-resistant polymerase ϵ (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res. 22:5682–5687. 2016.

92. Saya S, Killick E, Thomas S, Taylor N, Bancroft EK, Rothwell J, et al. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. Fam Cancer. 16:433–440. 2017.

93. Scheffzek K, Ahmadian MR, Wiesmüller L, Kabsch W, Stege P, Schmitz F, et al. Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J. 17:4313–4327. 1998.

94. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni syndrome in Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds). GeneReviews®. Seattle: University of Washington;1993.

95. Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 24:2570–2575. 2006.

96. Sherborne AL, Lavergne V, Yu K, Lee L, Davidson PR, Mazor T, et al. Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. Clin Cancer Res. 23:1852–1861. 2017.

97. Shete S, Lau CC, Houlston RS, Claus EB, Barnholtz-Sloan J, Lai R, et al. Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the gliogene consortium. Cancer Res. 71:7568–7575. 2011.

98. Shibahara I, Sonoda Y, Suzuki H, Mayama A, Kanamori M, Saito R, et al. Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations. Brain Tumor Pathol. 1:10–18. 2018.

99. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet. 47:257–262. 2015.

100. Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, et al. Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol. 28:1345–1350. 2010.

101. Tabori U, Hansford JR, Achatz MI, Kratz CP, Plon SE, Frebourg T, et al. Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood. Clin Cancer Res. 23:e32–e37. 2017.

102. Tabori U, Laberge AM, Ellezam B, Carret AS. Cancer Predisposition in Children with Brain Tumors : Pediatric Neuro-oncology. New York: Springer New York;2015. p. 69–89.

103. Tabori U, Shlien A, Baskin B, Levitt S, Ray P, Alon N, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol. 28:1995–2001. 2010.

104. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 27:e108–e109; author reply e110. 2009.

105. Unger PD, Taff ML, Song S, Schwartz IS. Sudden death in a patient with Von Recklinghausen’s neurofibromatosis. Am J Forensic Med Pathol. 5:175–179. 1984.

106. Uyttebroeck A, Legius E, Brock P, Van de Cassey W, Casaer P, Casteels-Van Daele M. Consecutive glioblastoma and B cell non-Hodgkin’s lymphoma in a young child with von Recklinghausen’s neurofibromatosis. Med Pediatr Oncol. 24:46–49. 1995.

107. Varan A, Şen H, Aydin B, Yalçın B, Kutluk T, Akyüz C. Neurofibromatosis type 1 and malignancy in childhood. Clin Genet. 89:341–345. 2016.

108. Villani A, Malkin D, Tabori U. Syndromes predisposing to pediatric central nervous system tumors: lessons learned and new promises. Curr Neurol Neurosci Rep. 12:153–164. 2012.

109. Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17:1295–1305. 2016.

110. Wasserman JD, Novokmet A, Eichler-Jonsson C, Ribeiro RC, Rodriguez-Galindo C, Zambetti GP, et al. Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children’s oncology group study. J Clin Oncol. 33:602–609. 2015.

111. Watanabe T, Vital A, Nobusawa S, Kleihues P, Ohgaki H. Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol. 117:653–656. 2009.

112. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet. 124:105–122. 2008.

113. Wimmer K, Kratz CP, Vasen HF, Caron O, Colas C, Entz-Werle N, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “Care for CMMRD” (C4CMMRD). J Med Genet. 51:355–365. 2014.

114. Wimmer K, Rosenbaum T, Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet. 91:507–519. 2017.

115. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 373:2336–2346. 2015.

116. Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol. 31:2927–35. 2013.