Brain Tumors: Development, Drug Resistance, and Sensitization – An Epigenetic Approach

Figures & data

Table 1. The table describes different types of paediatric and adult brain tumours both benign and malignant, their location, treatability, age group, and mutations observed in those types of brain tumours.

Type of Brain Tumour	Location	Age	Benign and/or Malignant	Treatability	Mutations
Pituitary Adenomas	Pituitary Glands	Most often seen in 30–40-y-old adults. Possible in children	Usually benign, rarely malignant	Highly treatable problems are caused by hormone irregularities and pressure on major nerves	MEN1, CDKN1B, CDKN2C, AIP, PRKAR1A mutations are seen [3]
Craniopharyngiomas	Pituitary Gland region	Most common in children ages 5–14 Adults >50 have been diagnosed	Benign	Highly treatable Hormone dysfunction, not usually harmful	~70% of cases have mutations in CTNNB1 and APC gene (embryonic protein) [4]
Chordomas	Bone at the base of the skull and lower spine	Elder population	Benign, does become malignant if not removed	Slow growing, larger size can cause damage from healthy tissue compression Medial survival rate is 7 y, life threatening	PBRM1 mutation and Chromosome 22q deletion both SWI/SNF complex subunit genes are observed to lower survival rates [5]
Pineocytomas	Pineal Gland Cells	Paediatric, male	Benign until grade IV where they become pineoblastomas	Majority in this region are malignant but they are called pineoblastomas Poor sleep or irregular sleep due to melatonin disruptions	Pineoblastoma genetics: mutation of DICER1 or DROSHA Homo-deletion [6]
Gangliocytomas	Mature Nerve Cells	All ages are affected but most commonly between 10 and 30 y of age	Benign and usually not malignant.	Most commonly associated with epilepsy Slow-growing and surgically treatable in most cases	Loss of PTEN function and activated AKT [7]
Schwannomas	Schwann Cells (myelin sheath producers) *Schwannomatosis: multiple tumours	Can occur in all ages.	Benign	Pressure on the cranial nerves causing malfunction.	NF2 Mutation or deletion is most common; with schwannomatosis, there are early mutations in SMARCB1 and LZTR1 [8]
Glomus Jugulare	Base of Skull/Top of Jugular Vein	Uncommon in adults and rare in children.	Malignant when found? Benign in children?	Rare.	PGL1 and PGL2 mutations in germline as well as sporadic mutations in SDHB and SDHD [9]
Meningiomas	Meninges Membrane, Lining the Skull	Most commonly found in adults ages 40–70.	Benign	Spreads to the brain and spinal cord Can become malignant	Monosomy 22 and inactivating mutation of NF2 are common [10]
Ependymomas	Ventricular System	Found in both adults and children, one of the higher percentages in children.	Malignant	Children have a 5-y survival rate. Adults have a better survival rate than children.	ADM1 and CDK11 under expression DUSP12 overexpression [11]
Gliomas	Glial Cells	Common to both	Malignant, poor prognosis.	About 78% of malignant brain tumours	See below for individual types.
Oligodendrogliomas	Oligodendrocytes Cells (myelin sheath in the brain)	Both adults and children Low percentage in general	Subdivision of Glioma	Grade dependent: 3–12-y-old individuals.	1p and 19p loss demonstrates a better prognosis [12]
Astrocytoma	Astrocytes Adults – Cerebellum Paediatric – Base of Brain	All ages, most common in middle-aged men – high grade Children present as low grade	Subdivision of Glioma	About half of neurological tumours	IDH1 mutations were co-present with TP53 mutations in majority of cases [13]
Glioblastoma Multiforme	Cerebellum and cerebrum	Mostly seen in 50–70-y-old individuals; more commonly found in men.	Subdivision of Glioma Malignant	Poor as they are aggressive, fast growing, and highly metastatic	IDH mutants have better prognosis than wild type (adults) [14]
Medulloblastomas	Cerebellum	Occurs in the paediatric population and is rarely seen in adults.	Subdivision of Glioma Malignant	Success through chemotherapy and radiology	Genetic mutations: CTNNB1 and SHH WNT activated is common in young [15]
Paediatric Gliomas	Brain stem	Paediatric only 25% of childhood cancers	Malignant; however, flexible due to young brain	Highly treatable with good outcome	H3K27Me3 mutation for diffuse intrinsic pontine glioma(DIPG) – presence is automatic grade IV [16,17]

Table 1 is prepared from information listed in the references cited in the paper.

Figure 1. Figure 1 describes the regions of brain and their functions. (a) Upper Brain, (b) Mid-Brain, and (c) Lower Brain.

Figure 2. (continued).

Figure 2. This diagram shows the change in methylation at the enhancer and the promoter regions. With no methylation at the enhancer region, the folding will not occur. (a, c). This will limit the amount transcribed (a), with methylation at the enhancer CCCTC motif, CTCF protein is prevented from binding and the enhancer region will fold over to the promoter to encourage transcription (b, d). Methylation by DNMT1 at the promoter region prevents transcription by not allowing POL II to bind to the region (c, d). When the promoter is not methylated, POL II is able to bind to the sequence and transcribe the genes (a, b).

Figure 3. (a) Pediatric Brain Tumour Development. (I) Pluripotent Brain Cells. (II) Differentiation of cells to many specific types of brain cells, (III) One differentiated cells becomes a cancer progenitor cell, and (IV) Rapid growth of this cancer progenitor cell becomes a full-fledged tumour. (b) Adult Brain Tumour Development. (I) Normal differentiated adult cells. (II) One of the differentiated cells become cancer progenitor cells, (III) Rapid growth forming a group of cancer cells, and (IV) Brain tumour including heterogenous call population formed. EMT-epithelial mesenchymal transition, MET-mesenchymal epithelial transition.

Figure 4. Comparison of Standard Chemotherapy with Combination Therapy. a) Standard Chemo Therapy. (I) Standard chemotherapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with epigenetic Drugs. b) Combination Therapy (I) Surgery, Radiation, Chemo Therapy, Standard therapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with Epigenetic Drugs.

Stratakis CA, Tichomirowa MA, Boikos S, et al. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet. 2010;78(5):457–463. doi: 10.1111/j.1399-0004.2010.01406.x PMID: 20507346; PMCID: PMC3050035

 PubMed Web of Science ®Google Scholar

Onilude OE, Lusher ME, Lindsey JC, et al. APC and CTNNB1 mutations are rare in sporadic ependymomas. Cancer Genet Cytogenet. 2006;168(2):158–161. doi: 10.1016/j.cancergencyto.2006.02.019 PMID: 16843107

 PubMedGoogle Scholar

Bai J, Shi J, Li C, et al. Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival. Nat Commun. 2021;12(1):757. doi: 10.1038/s41467-021-21026-5 PMID: 33536423; PMCID: PMC7859411.

 PubMed Web of Science ®Google Scholar

Snuderl M, Kannan K, Pfaff E, et al. Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun. 2018;9(1):2868. doi: 10.1038/s41467-018-05029-3 PMID: 30030436; PMCID: PMC6054684.

 PubMedGoogle Scholar

Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;1111(4):289–301. doi: 10.1038/nrc3037 Erratum in: Nat Rev Cancer. 2011 Jun;11(6):458. PMID: 21430697; PMCID: PMC6946181.

 PubMed Web of Science ®Google Scholar

Kehrer-Sawatzki H, Farschtschi S, Mautner VF, et al. The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet. 2017;136(2):129–148. doi: 10.1007/s00439-016-1753-8 Epub 2016 Dec 5. PMID: 27921248; PMCID: PMC5258795.

 PubMed Web of Science ®Google Scholar

Guha A, Vicha A, Zelinka T, et al. Genetic variants in patients with multiple head and neck paragangliomas: dilemma in management. Biomedicines. 2021;9(6):626. doi: 10.3390/biomedicines9060626 PMID: 34072806; PMCID: PMC8226913

 PubMed Web of Science ®Google Scholar

Domingues P, González-Tablas M, Otero Á, et al. Genetic/Molecular alterations of meningiomas and the signaling pathways targeted. Oncotarget. 2015;6(13):10671–10688. doi: 10.18632/oncotarget.3870 PMID: 25965831; PMCID: PMC4484411.

 PubMed Web of Science ®Google Scholar

Yang I, Nagasawa DT, Kim W, et al. Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas. J Clin Neurosci. 2012;19(6):779–785. doi: 10.1016/j.jocn.2011.11.004 Epub 2012 Apr 18. PMID: 22516549; PMCID: PMC3615711

 PubMed Web of Science ®Google Scholar

Smith JS, Perry A, Borell TJ, et al. 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol. 2000;18(3):636–636. doi: 10.1200/JCO.2000.18.3.636

 PubMed Web of Science ®Google Scholar

Watanabe T, Nobusawa S, Kleihues P, et al. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–1153. doi: 10.2353/ajpath.2009.080958 Epub 2009 Feb 26. PMID: 19246647; PMCID: PMC2671348

 PubMed Web of Science ®Google Scholar

Turkalp Z, Karamchandani J, Das S. IDH mutation in glioma: new insights and promises for the future. JAMA Neurol. 2014;71(10):1319–1325. doi: 10.1001/jamaneurol.2014.1205

 PubMed Web of Science ®Google Scholar

Richardson S, Hill RM, Kui C, et al. Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Neuro Oncol. 2022;2424(11):153–165. doi: 10.1093/neuonc/noab178

 PubMed Web of Science ®Google Scholar

Zhang X, Zhang Z. Oncohistone mutations in diffuse intrinsic pontine glioma. Trends Cancer. 2019;5(12):799–808. doi: 10.1016/j.trecan.2019.10.009 Epub 2019 Nov 9. PMID: 31813457; PMCID: PMC6986369.

 PubMed Web of Science ®Google Scholar

Lewis NA, Klein RH, Kelly C, et al. Histone H3.3 K27M chromatin functions implicate a network of neurodevelopmental factors including ASCL1 and NEUROD1 in DIPG. Epigenet Chromatin. 2022;15(1):18. doi: 10.1186/s13072-022-00447-6 PMID: 35590427; PMCID: PMC9121554

 PubMed Web of Science ®Google Scholar