Methylation pattern in the diagnosis and prognosis of brain cancer

Czech version

Authors: Aleš Vícha ^1,4; Lucie Štolová ¹; Pavla Jenčová ¹; Michal Zápotocký ^1,4; David Sumerauer ^1,4; Adéla Mišove ^1,4; Miroslav Koblížek ^2,4; Petr Brož ^1,3; Josef Zámečník ^2,4; Martin Kynčl ⁵; Petr Libý ⁶; Lenka Krsková ^2,4
Authors‘ workplace: Klinika dětské hematologie a onkologie 2. LF UK a FN Motol, Praha ¹; Ústav patologie a molekulární medicíny 2. LF UK a FN Motol, Praha ²; Bioxsys, Ústí nad Labem ³; Prague Brain Tumour Research Group ⁴; Klinika zobrazovacích metod 2. LF UK a FN Motol, Praha ⁵; Neurochirurgická klinika dětí a dospělých 2. LF UK a FN Motol, Praha ⁶
Published in: Čes.-slov. Patol., 57, 2021, No. 3, p. 154-160
Category: Reviews Article

Overview

Examination of changes in the methylation profile of DNA in cancer is currently used to determine the diagnosis or prognostic and predictive biomarkers. It complements histological or molecular biological examinations. At the same time, it helps to identify new diagnostic groups and subgroups. Currently, this diagnosis is most common in brain tumors, where it has become a routine examination. The established methylation profile may help even where the diagnosis or subgroup classification of the disease cannot be determined in any other way, as is the case with medulloblastoma.

Keywords:

Methylation – SNP array – brain tumors – classification

Sources

1. Pickles JC, Fairchild AR, Stone TJ, et al. DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. Lancet Child Adolesc Heal 2020; 4:121–30. doi:10.1016/S2352- 4642(19)30342-6.

2. Anvar Z, Acurzio B, Roma J, Cerrato F, Verde G. Origins of DNA methylation defects in Wilms tumors. Cancer Letters 2019; 457: 119–128.

3. Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature 2018; 555: 469–474.

4. Koelsche C, Schrimpf D, Stichel D, et al. Sarcoma classification by DNA methylation profiling. Nat Commun 2021; 12. doi:10.1038/ s41467-020-20603-4.

5. Nobre L, Zapotocky M, Khan S, et al. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma. Cell Reports Med 2020; 1(3): 100038.

6. Sievers P, Sill M, Blume C, et al. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1. Acta Neuropathol 2021; 141: 281– 290.

7. Sievers P, Appay R, Schrimpf D, et al. Rosette- forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol 2019; 138: 497–504.

8. Sumerauer D, Krskova L, Vicha A, et al. Rare IDH1 variants are common in pediatric hemispheric diffuse astrocytomas and frequently associated with Li-Fraumeni syndrome. Acta Neuropathol 2020; 139: 795–7.

9. Van Paemel R, De Koker A, Vandeputte C, et al. Minimally invasive classification of paediatric solid tumours using reduced representation bisulphite sequencing of cell-free DNA: a proof-of-principle study. Epigenetics 2020; 16: 1–13.

10. Witt H, Gramatzki D, Hentschel B, et al. DNA methylation-based classification of ependymomas in adulthood: Implications for diagnosis and treatment. Neuro Oncol 2018; 20: 1616–1624.

11. Mancarella D, Plass C. Epigenetic signatures in cancer: proper controls, current challenges and the potential for clinical translation. Genome Medicine 2021; 3(1): 23.

12. Machnik M, Oleksiewicz U. Dynamic Signatures of the Epigenome: Friend or Foe? Cells 2020; 9(3): 653.

13. Corley J, Cox SR, Harris SE, et al. Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936. Transl Psychiatry 2019; 9(1): 248.

14. Hillary RF, Stevenson AJ, Cox SR, et al. An epigenetic predictor of death captures multi-modal measures of brain health. Mol Psychiatry 2019, In Print.

15. Fernandez AF, Assenov Y, Martin-Subero JI, et al. A DNA methylation fingerprint of 1628 human samples. Genome Res 2012; 22: 407–419.

16. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics 2009; 1: 239–259.

17. Hovestadt V, Remke M, Kool M, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathologica 2013; 125: 913–916.

18. Korshunov A, Chavez L, Northcott PA, et al. DNA-methylation profiling discloses significant advantages over NanoString method for molecular classification of medulloblastoma. Acta Neuropathologica 2017; 134: 965–967.

19. Sahm F, Schrimpf D, Stichel D, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 2017; 18: 682–694.

20. Sexton-Oates A, Dodgshun A, Hovestadt V, et al. Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence. Mol Oncol 2018; 12: 1219–1232.

21. Hovestadt V, Jones DTW, Picelli S, et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 2014; 510: 537–541.

22. Koelsche C, Hartmann W, Schrimpf D, et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod Pathol 2018; 31: 1246–1256.

23. Sievers P, Sill M, Schrimpf D, et al. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol 2021; 23: 34–43.

24. Binder H, Willscher E, Loeffler-Wirth H, et al. DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development. Acta Neuropathol Commun 2019; 7: 59.

25. Braczynski AK, Capper D, Jones DTW, et al. High density DNA methylation array is a reliable alternative for PCR-based analysis of the MGMT promoter methylation status in glioblastoma. Pathol Res Pract 2020; 216(1): 152728.

26. Koelsche C, Kriegsmann M, Kommoss FKF, et al. DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1–NFATc2 fusion from Ewing sarcoma. J Cancer Res Clin Oncol 2019; 145(5): 1273-1281.

27. Capper D, Engel NW, Stichel D, et al. DNA methylation-based reclassification of olfactory neuroblastoma. Acta Neuropathol 2018; 136: 255–271.

28. Capper D, Engel NW, Stichel D, et al. Correction to: DNA methylation-based reclassification of olfactory neuroblastoma (Acta Neuropathologica, (2018), 136, 2, (255-271), 10.1007/ s00401-018-1854-7). Acta Neuropathologica 2018; 136: 505.

29. Capper D, Stichel D, Sahm F, et al. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol 2018; 136: 181–210. 3

0. Pagès M, Pajtler KW, Puget S, et al. Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging. Brain Pathol 2019; 29: 325–335.

31. Moran S, Martínez-Cardús A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 2016; 17: 1386–1395.

32. Pickles JC, Fairchild AR, Stone TJ, et al. DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population- based study. Lancet Child Adolesc Heal 2020; 4: 121–130.

33. Stichel D, Schrimpf D, Sievers P, et al. Accurate calling of KIAA1549-BRAF fusions from DNA of human brain tumours using methylation array-based copy number and gene panel sequencing data. Neuropathol Appl Neurobiol 2021; 47: 406–414.

34. Korshunov A, Sahm F, Zheludkova O, et al. DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas. Neuro Oncol 2019; 21: 214–221.

35. Ellison DW, Aldape KD, Capper D, et al. cIMPACT- NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathology 2020; 30: 863–866.

36. Fukuoka K, Mamatjan Y, Tatevossian R, et al. Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas. Neuro Oncol 2020; 22: 1474–1483.

37. Halliday GC, Junckerstorff RC, Bentel JM, et al. The case for DNA methylation based molecular profiling to improve diagnostic accuracy for central nervous system embryonal tumors (not otherwise specified) in adults. J Clin Neurosci 2018; 47: 163–167.

38. Hou Y, Pinheiro J, Sahm F, et al. Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. Acta Neuropathol 2019; 137: 837–846.

39. Jaunmuktane Z, Capper D, Jones DTW, et al. Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre. Acta Neuropathol Commun 2019; 7: 24.

40. Koch A, Joosten SC, Feng Z, et al. Analysis of DNA methylation in cancer: Location revisited. Nature Reviews Clinical Oncology 2018; 15: 459–466.

41. Lambert SR, Witt H, Hovestadt V, et al. Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma. Acta Neuropathol 2013; 126: 291–301.

42. Petruzzellis G, Alessi I, Colafati GS, et al. Role of DNA methylation profile in diagnosing astroblastoma: A case report and literature review. Front Genet 2019; 10: 391.

43. Sievers P, Stichel D, Hielscher T, et al. Chordoid meningiomas can be sub-stratified into prognostically distinct DNA methylation classes and are enriched for heterozygous deletions of chromosomal arm 2p. Acta Neuropathologica 2018; 136: 975–978.

44. Pajtler KW, Witt H, Sill M, et al. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 2015; 27: 728–743.

45. Sharma T, Schwalbe EC, Williamson D, et al. Second-generation molecular subgrouping of medulloblastoma: an international meta- analysis of Group 3 and Group 4 subtypes. Acta Neuropathol 2019; 138: 309–326.

46. Wesseling P, Capper D. WHO 2016 Classification of gliomas. Neuropathology and Applied Neurobiology 2018; 44: 139–150.

47. Orr BA. Pathology, diagnostics, and classification of medulloblastoma. Brain Pathology 2020; 30: 664–678.

48. Ramaswamy V, Remke M, Bouffet E, et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 2016; 131: 821–831.

49. Thompson MC, Fuller C, Hogg TL, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006; 24: 1924–1931.

50. Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 2008; 3(8): e3088.

51. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: An international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012; 123: 473–484.

52. Cho YJ, Tsherniak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 2011; 29: 1424–1430.

53. Zou H, Poore B, Broniscer A, Pollack IF, Hu B. Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma. Cancers (Basel) 2020; 12(3): 643.

54. Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol 2012; 123: 465–472.

55. Hovestadt V, Ayrault O, Swartling FJ, Robinson GW, Pfister SM, Northcott PA. Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nature Reviews Cancer 2020; 20: 42–56.

56. Northcott PA, Jones DTW, Kool M, et al. Medulloblastomics: The end of the beginning. Nature Reviews Cancer 2012; 12: 818–834.

57. Schwalbe EC, Hicks D, Rafiee G, et al. Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures. Sci Rep. 2017; 7(1): 13421.

58. Schwalbe EC, Williamson D, Lindsey JC, et al. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin- fixed biopsies. Acta Neuropathol 2013; 125: 359–371.

59. Cavalli FMG, Remke M, Rampasek L, et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 2017; 31: 737-754.e6.

60. Nobre L, Zapotocky M, Khan S, et al. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma. Cell Reports Med 2020; 1(3):100038.

61. Jabarkheel R, Amayiri N, Yecies D, et al. Molecular correlates of cerebellar mutism syndrome in medulloblastoma. Neuro Oncol 2020; 22: 290–297.

62. Zschernack V, Jünger ST, Mynarek M, et al. Supratentorial ependymoma in childhood: more than just RELA or YAP. Acta Neuropathol 2021; 141: 455–466.

63. Fukuoka K, Mamatjan Y, Tatevossian R, et al. Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas. Neuro Oncol 2020; 22: 1474–1483.

64. Jeyapalan JN, Doctor GT, Jones TA, et al. DNA methylation analysis of paediatric lowgrade astrocytomas identifies a tumour-specific hypomethylation signature in pilocytic astrocytomas. Acta Neuropathol Commun 2016; 4: 54.

65. 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. Acta Neuropathol 2016; 131: 833–845.

66. Stone TJ, Keeley A, Virasami A, et al. Comprehensive molecular characterisation of epilepsy- associated glioneuronal tumours. Acta Neuropathol 2018; 135: 115–129.

67. Aran D, Sirota M, Butte AJ. Systematic pan-cancer analysis of tumour purity. Nat Commun 2015; 6: 8971.