SEARCH

SEARCH BY CITATION

Keywords:

  • Biomarker;
  • Epilepsy;
  • Brain tumor;
  • O6-methylguanine methyltranferase ;
  • Isocitrate dehydrogenase 1;
  • Isocitrate dehydrogenase 2;
  • Long-term epilepsy associated tumors ;
  • Glioma-CpG island DNA methylator phenotype

Summary

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

Gene markers or biomarkers can be used for diagnostic or prognostic purposes for all different types of complex disease, including brain tumors. Prognostic markers can be useful to explain differences not only in overall survival but also in response to treatment and for development of targeted therapies. Multiple genes with specific types of alterations have now been identified that are associated with improved response to chemotherapy and radiotherapy, such as O6-methylguanine methyltranferase (MGMT) or loss of chromosomes 1p and/or 19q. Other alterations have been identified that are associated with improved overall survival, such as mutations in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2) or having the glioma CpG island DNA methylator phenotype (G-CIMP). There are many biomarkers that may have relevance in brain tumor–associated epilepsy that do not respond to treatment. Given the rapidly changing landscape of high throughput “omics” technologies, there is significant potential for gaining further knowledge via integration of multiple different types of high genome-wide data. This knowledge can be translated into improved therapies and clinical outcomes for patients with brain tumors.

A biomarker is a biochemical or genetic feature that can be assessed in a biospecimen to indicate a particular diagnosis, prognosis, or response to treatment. Biomarkers can be used for diagnostic, prognostic, or predictive purposes for many complex diseases, including gliomas, the most common malignant brain tumor in adults (World Health Organization [WHO] grades II, III, or IV) (Olar & Aldape, 2012). Prognostic biomarkers are those used to assess differences in overall disease course (i.e., overall survival time) or time to recurrence, whereas predictive biomarkers are those that can be used to assess the likelihood of response to a particular treatment (Fischer & Aldape, 2010; De Groot et al., 2011). Predictive biomarkers may also suggest new drug targets for disease. Several biomarkers have been described in brain tumors that may be relevant in epilepsy (as shown in Table 1), especially for long-term epilepsy–associated tumors (LEATs).

Table 1. Summary of most clinically relevant biomarkers in brain tumors
BiomarkerAssociated brain tumor type(s)FrequencyEffect on prognosisRelevant references
Methylation of O6-methylguanine methyltranferase (MGMT)Glioblastoma (GBM) (grade IV)20–40% of GBMs

Hypermethylation increases responsiveness to alkylating chemotherapeutic agents, by silencing DNA repair mechanism

Enhances the effectiveness of temozolomide chemotherapy and radiation

Hegi et al. (2005), Brandes et al. (2009), Everhard et al. (2009), and Kreth et al. (2011)
Loss of chromosomes 1p and/or 19qAnaplastic oligodendroglioma (grade III)50–70% of grade III oligodendrogliomasIncrease responsiveness to temozolomide chemotherapy. Significantly increased survival and progression-free survival after treatment with temozolomideCairncross et al. (1998)
Mutation in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2)Oligodendrogliomas and oligoastrocytomas (grades II and III)

91% of grade II oligodendrogliomas, 94% of grade III oligodendrogliomas, 79% of grade II oligoastrocytomas, and 91% of grade III oligoastrocytomas

0% of GBMs

Increases overall survival, 1-year overall survival, and recurrence-free survivalYan et al. (2009), Capper et al. (2011), and Pollack et al. (2011)
Gene expression based subtypesGBM (grade IV)

~25% Proneural

~17% Neural

~26% Classical

~29% Mesenchymal

Proneural subtype was originally found to be associated with improved survival, but in a recent update analysis this survival advantage is no longer presentNoushmehr et al. (2010) and Brennan et al. (2013)
Glioma-CpG island DNA methylator phenotype (G-CIMP)Adult low grade gliomas (LGGs) (grades II and III), and secondary GBMs (grade IV, derived from LGGs)~10% of GBMsIncreased overall survival. Strongly associated with IDH1/IDH2 mutationsYan et al. (2009), Noushmehr et al. (2010), and Brennan et al. (2013)

Biomarkers in Brain Tumors

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations

IDH1 mutations are common in infiltrating lower grade (WHO II and III) and secondary high grade (WHO IV) glioblastomas (GBMs), where the most common mutation in this gene is R132H (Yan et al., 2009). Primary GBMs arise with no prior glioma diagnosis, whereas secondary GBMs represent malignant transformation in preexisting lower grade gliomas. A review of specimens from adult cases that were immunohistochemically stained for IDH1-R132H found that 91% of grade II oligodendrogliomas, 94% of grade III oligodendrogliomas, 79% of grade II oligoastrocytomas, and 91% of grade III oligoastrocytomas were positive for this mutation. Neurocytomas, meningiomas, primary GBMs with oligodendroglial component, and pilocytic astrocytomas with oligodendroglioma-like differentiation stained negative, as did all pediatric gliomas (Capper et al., 2011). Other studies have reported similar rates of mutation in adult glioma brain tumors. In a polymerase chain reaction (PCR)–based analyses of pediatric malignant gliomas, IDH1 mutations were found in 16.3% of tumors and IDH2 mutations were found in none (Pollack et al., 2011).

These mutations are useful for diagnosis of low grade malignant adult gliomas, but are of little utility in diagnosis of other adult tumors or pediatric gliomas. Mutations in IDH1 and IDH2 have been associated with improved overall survival (Yan et al., 2009). In adolescents that had ID1H mutation, 1 year overall and recurrence-free survival was significantly improved (p = 0.035 and p = 0.03, respectively) (Pollack et al., 2011).

Gene expression–based subtypes of glioblastoma and the glioma-CpG island DNA methylator phenotype (G-CIMP)

The Cancer Genome Atlas (TCGA) is a National Cancer Institute–funded effort to fully molecularly characterize multiple different cancer types including GBM (WHO grade IV) and lower grade gliomas (WHO grades II and III). Using an unsupervised clustering approach with genome-wide gene expression array data, four clusters of GBMs were determined, denoting four gene expression–based subtypes of GBMs: proneural, neural, classical, and mesenchymal (Verhaak et al., 2010). The proneural subtype was originally found to be associated with improved survival, but in a recent update analysis of the TCGA GBM data, this survival advantage is no longer present (Brennan et al., 2013).

Another analysis of the TCGA GBM data using DNA methylation array data, revealed a tightly clustered DNA methylation subtype that comprised 8.8% of all samples. Tumors positive for the glioma CpG island DNA methylator phenotype (G-CIMP) phenotype most often clustered into the proneural tumor subtype (Noushmehr et al., 2010). Compared to non–G-CIMP proneural tumors, patients with G-CIMP tumors were significantly younger at time of diagnosis (p < 0.0001), and showed significantly longer survival (p = 0.0165) after adjusting for age, recurrence status, and primary versus secondary GBM status.

Further analyses conducted in low grade gliomas and GBMs suggest that the G-CIMP phenotype is associated with secondary rather than primary GBMs. Positive G-CIMP status is tightly associated with IDH1 mutation in low grade glioma. G-CIMP was also a significant independent predictor of survival in low grade glioma, after adjusting for age and tumor grade (Noushmehr et al., 2010).

However, the most recently updated analysis of the TCGA data do not show a survival advantage by gene expression subtype class (Brennan et al., 2013), but do continue to show an overall survival advantage for patients who are G-CIMP positive and have IDH1 mutations (who are also more likely to be proneural) (Yan et al., 2009; Noushmehr et al., 2010; Verhaak et al., 2010), although this is a small proportion of all GBM patients (~10%).

O6-methylguanine methyltranferase (MGMT) methylation in glioma

Many of the common chemotherapeutic agents used for brain tumors are alkylating agents. The effectiveness of these agents is compromised by direct DNA repair via the MGMT DNA repair gene. When this gene is silenced by promoter methylation, it cannot repair damaged DNA, hence chemotherapy and radiation treatment is significantly more effective and survival is improved. Hypermethylation has been found in a significant number of patients with GBM (20–40%). Patients with MGMT methylation had a significant survival benefit from concurrent temozolomide (TMZ) chemotherapy and radiotherapy as compared to radiotherapy alone, whereas those who did not have methylation of the MGMT promoter had a statistically insignificant gain in survival from the addition of chemotherapy (Hegi et al., 2005). However, clinical utility of MGMT promoter methylation determinations is confounded by the controversy regarding how best to measure it (Suri et al., 2011), the absence of a direct one-to-one correspondence between MGMT promoter methylation and response to TMZ (Brandes et al., 2009), and a growing appreciation that methylation-independent pathways of MGMT expression regulation are in operation (Everhard et al., 2009; Kreth et al., 2011).

Loss of chromosomes 1p and/or 19q in glioma

In patients with WHO grade III anaplastic oligodendroglioma, coincident loss of chromosomal arms 1p and 19q is a commonly occurring phenotype, seen in 50–70% of tumors (Cairncross et al., 1998). Loss of 1p has been associated significantly with response to TMZ chemotherapy, with all tumors who expressed this phenotype responding positively to chemotherapy in one analysis (p < 0.001). In patients whose tumors lost both 1p and 19q, there was also a significantly increased likelihood of response to chemotherapy (p < 0.001), and a significantly longer progression-free survival after chemotherapy. Loss of either 1p alone or both 1p and 19q was also a significant predictor of improved survival, even after adjustment for other clinical features (Cairncross et al., 1998).

Brain Tumors and Epilepsy

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

Any type of brain tumor can potentially cause seizures, and some may cause long-term drug-resistant epilepsy (LEATs). The tumors most frequently reported as causing this outcome are circumscribed and lower grade infiltrating gliomas (WHO grades I and III) and glioneuronal neoplasms, especially dysembryoplastic neuroepithelial tumors and gangliogliomas. In some tumor types, such as astrocytoma, presentation with chronic epilepsy predicts better prognosis (Thom et al., 2012). Presenting with seizure as first symptom is significantly associated with IDH1 or IDH2 mutation in lower grade glioma (Stockhammer et al., 2012). In addition, v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutations have been found in gangliogliomas, pilocytic astrocytomas, and pleomorphic xanthoastrocytomas (PXA), but not in diffuse glioma (as reviewed in Thom et al., 2012). Assessment of this mutation, along with IDH1 mutation, could be useful for distinguishing between diffuse glioma and PXAs.

There is a strong association between specific histologic types of brain tumors and chronic seizures, and some studies have suggested that this may be due to the cellular composition and neurochemical profile of these tumor types. Studies of glioneuronal tumors have suggested that high neuronal density may be associated with epileptiform discharge patterns. Gangliogliomas have been reported to have increased expression of sodium-potassium chloride cotransporter expression and decreased expression of potassium-chloride cotransporter. Decreased expression of glial glutamate transporters may also contribute to epileptogenesis. Tumors may also disturb intercellular communication, damage surrounding tissue, and effect enzymatic changes that may result in epilepsy (Thom et al., 2012).

Biomarkers in Epilepsy

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

There are currently no reliable biomarkers for epilepsy, although potential biomarkers are currently being investigated and multiple markers are used as part of standard diagnosis of brain tumors of different histologic types that have implications in epilepsy (Kaye & Laws, 2001; Sulman et al., 2009; Engel, 2011). Biomarkers are needed to predict both epileptogenesis and epileptogenicity.

Currently, pharmacologic treatment for existing epilepsy is determined by acceptability of side effects, drug interactions, and patient tolerance for dosing interval. Development of biomarkers could assist physicians in determining appropriate antiepileptic drugs for each patient. Biomarkers could also be beneficial in predicting patients with drug-resistant epilepsy who would benefit most from surgical intervention, and allow these patients to receive surgical therapy earlier and prevent irreversible morbidity from recurrent seizures. Because there are numerous types of seizures and epileptic conditions, there may be different biomarkers for each. Being able to predict epileptic conditions prior to onset, or shortly after onset, would allow physicians the opportunity to prevent progression of disease.

Current areas of research into genetic biomarkers for epilepsy include identification of cellular changes causing neuronal death and synaptic reorganization, potential measures of gene expression alterations via positron emission tomography (PET) or peripheral blood tests, and exploration of inflammatory changes (Engel, 2011).

Looking Forward

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

Given the rapidly changing landscape of high throughput “omics” technologies, significant further knowledge is to be gained via integration of multiple different types of high genome wide data in order to translate this knowledge into improved therapies and clinical outcomes for brain tumor and epilepsy patients.

Acknowledgments

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

The authors would like to thank Samden Lhatoo, MD. This work was supported in part by the Case Comprehensive Cancer Center Support Grant (NIH/NCI P30 CA043703).

Disclosures

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References

The authors do not have anything to disclose. The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Biomarkers in Brain Tumors
  4. Brain Tumors and Epilepsy
  5. Biomarkers in Epilepsy
  6. Looking Forward
  7. Acknowledgments
  8. Disclosures
  9. References
  • Brandes AA, Tosoni A, Franceschi E, Sotti G, Frezza G, Amista P, Morandi L, Spagnolli F, Ermani M. (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol 27:12751279.
  • Brennan C, Verhaak RGW, Mckenna A, Campos B, Noushmehr H, Salama S, Zheng S, Chakarvarti D, Sanborn JZ, Berman S, Beroukhim R, Bernard B, Wu C-J, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla S, Ciriello G, Lu Y, Yung WK, Zhang W, Kucherlapati R, Perou CM, Gibbs R, Marra M, Gastier-Foster JM, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Laird PW, Haussler D, Gabriel S, Getz G, Chin L, on behalf of the TCGA Research Network. (2013) The somatic genomic landscape of glioblastoma. Cell. 10:462477.
  • Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN. (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:14731479.
  • Capper D, Reuss D, Schittenhelm J, Hartmann C, Bremer J, Sahm F, Harter PN, Jeibmann A, Von Deimling A. (2011) Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol 121:241252.
  • De Groot JF, Sulman EP, Aldape KD. (2011) Multigene sets for clinical application in glioma. J Natl Compr Canc Netw 9:449456; quiz 457.
  • Engel J Jr. (2011) Biomarkers in epilepsy: introduction. Biomark Med 5:537544.
  • Everhard S, Tost J, El Abdalaoui H, Criniere E, Busato F, Marie Y, Gut IG, Sanson M, Mokhtari K, Laigle-Donadey F, Hoang-Xuan K, Delattre JY, Thillet J. (2009) Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro Oncol 11:348356.
  • Fischer I, Aldape K. (2010) Molecular tools: biology, prognosis, and therapeutic triage. Neuroimaging Clin N Am 20:273282.
  • Hegi ME, Diserens AC, Gorlia T, Hamou MF, De Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:9971003.
  • Kaye AH, Laws ER. (2001) Brain tumors: an encyclopedic approach. 2nd ed. Harcourt International, London.
  • Kreth S, Thon N, Eigenbrod S, Lutz J, Ledderose C, Egensperger R, Tonn JC, Kretzschmar HA, Hinske LC, Kreth FW. (2011) O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation. PLoS ONE 6:e17156.
  • Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K. (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510522.
  • Olar A, Aldape KD. (2012) Biomarkers classification and therapeutic decision-making for malignant gliomas. Curr Treat Options Oncol 13:417436.
  • Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Lyons-Weiler MA, Laframboise WA, Burger PC, Brat DJ, Rosenblum MK, Holmes EJ, Zhou T, Jakacki RI, Children's Oncology G. (2011) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst 27:8794.
  • Stockhammer F, Misch M, Helms HJ, Lengler U, Prall F, Von Deimling A, Hartmann C. (2012) IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom. Seizure 21:194197.
  • Sulman EP, Guerrero M, Aldape K. (2009) Beyond grade: molecular pathology of malignant gliomas. Semin Radiat Oncol 19:142149.
  • Suri V, Jha P, Sharma MC, Sarkar C. (2011) O6-methylguanine DNA methyltransferase gene promoter methylation in high-grade gliomas: a review of current status. Neurol India 59:229235.
  • Thom M, Blumcke I, Aronica E. (2012) Long-term epilepsy-associated tumors. Brain Pathol 22:350379.
  • Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98110.
  • Yan H, Parsons DW, Jin G, Mclendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765773.