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Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor-related epilepsy: a whole transcriptome sequencing analysis

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Abstract

The majority of patients with low-grade glioma (LGG) experience epileptic seizures as their initial symptom, while the underlying mechanisms of tumor-related seizures are still far from being fully understood. In addition to tumor type and location, genetic changes of LGGs are considered to be influential factors in causing epileptic seizures. Nevertheless, the molecular biomarkers associated with tumor-related epilepsy have rarely been identified. RNA sequence data from 80 patients with histologically confirmed LGG were collected from the Chinese glioma genome atlas database and significant differences in expression levels of 33 genes were found. One of the genes, Very large G-protein-coupled receptor-1 (VLGR1), had been previously associated with seizures. Therefore, we investigated the association between LGG-related epilepsy and VLGR1, which played a role in idiopathic epilepsy. The level of VLGR1 expression was compared between patients with epileptic seizures and those without using the reads per kilobase transcriptome per million method. To evaluate the prognostic role of VLGR1 gene expression, the progression-free survival was determined by the Kaplan–Meier method and a multivariate Cox model. We demonstrated that VLGR1 had a significantly lower expression level in patients with epileptic seizures compared to seizure-free patients (p = 0.003). Furthermore, VLGR1 was highly associated with the presence of seizures in a multivariate statistical model. However, VLGR1 could not serve as an independent prognostic factor to determine progression-free survival of LGG patients. Based on RNA sequence data analysis, our results suggest that low expression of VLGR1 is a significant risk factor of epileptic seizures in patients with LGG.

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References

  1. Japp A, Gielen GH, Becker AJ (2013) Recent aspects of classification and epidemiology of epilepsy-associated tumors. Epilepsia 54(Suppl 9):5–11. doi:10.1111/epi.12436

    Article  PubMed  Google Scholar 

  2. Lhatoo SD, Moghimi N, Schuele S (2013) Tumor-related epilepsy and epilepsy surgery. Epilepsia 54(Suppl 9):1–4. doi:10.1111/epi.12435

    Article  PubMed  Google Scholar 

  3. Lynam LM, Lyons MK, Drazkowski JF, Sirven JI, Noe KH, Zimmerman RS, Wilkens JA (2007) Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review. Clin Neurol Neurosurg 109(7):634–638. doi:10.1016/j.clineuro.2007.05.017

    Article  PubMed  Google Scholar 

  4. van Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6(5):421–430. doi:10.1016/S1474-4422(07)70103-5

    Article  PubMed  Google Scholar 

  5. Danfors T, Ribom D, Berntsson SG, Smits A (2009) Epileptic seizures and survival in early disease of grade 2 gliomas. Eur J Neurol 16(7):823–831. doi:10.1111/j.1468-1331.2009.02599.x

    Article  CAS  PubMed  Google Scholar 

  6. Pallud J, Audureau E, Blonski M, Sanai N, Bauchet L, Fontaine D, Mandonnet E, Dezamis E, Psimaras D, Guyotat J, Peruzzi P, Page P, Gal B, Parraga E, Baron MH, Vlaicu M, Guillevin R, Devaux B, Duffau H, Taillandier L, Capelle L, Huberfeld G (2014) Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137(Pt 2):449–462. doi:10.1093/brain/awt345

    Article  PubMed  Google Scholar 

  7. Prakash O, Lukiw WJ, Peruzzi F, Reiss K, Musto AE (2012) Gliomas and seizures. Med Hypotheses 79(5):622–626. doi:10.1016/j.mehy.2012.07.037

    Article  CAS  PubMed  Google Scholar 

  8. Ruda R, Bello L, Duffau H, Soffietti R (2012) Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro-oncology 14(Suppl 4):iv55–64. doi:10.1093/neuonc/nos199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Smits A, Duffau H (2011) Seizures and the natural history of World Health Organization grade II gliomas: a review. Neurosurgery 68(5):1326–1333. doi:10.1227/NEU.0b013e31820c3419

    PubMed  Google Scholar 

  10. Englot DJ, Berger MS, Chang EF, Garcia PA (2012) Characteristics and treatment of seizures in patients with high-grade glioma: a review. Neurosurg Clin N Am 23 (2): 227–235, vii–viii. doi: 10.1016/j.nec.2012.01.009

  11. Kim YH, Park CK, Kim TM, Choi SH, Kim YJ, Choi BS, Han JH, Lee SH, Kim CY, Kim IA, Heo DS, Kim IH, Kim DG, Jung HW (2013) Seizures during the management of high-grade gliomas: clinical relevance to disease progression. J Neurooncol 113(1):101–109. doi:10.1007/s11060-013-1094-6

    Article  PubMed  Google Scholar 

  12. Kerkhof M, Vecht CJ (2013) Seizure characteristics and prognostic factors of gliomas. Epilepsia 54(Suppl 9):12–17. doi:10.1111/epi.12437

    Article  PubMed  Google Scholar 

  13. van Dellen E, Douw L, Hillebrand A, Ris-Hilgersom IH, Schoonheim MM, Baayen JC, De Witt Hamer PC, Velis DN, Klein M, Heimans JJ, Stam CJ, Reijneveld JC (2012) MEG network differences between low- and high-grade glioma related to epilepsy and cognition. PLoS One 7(11):e50122. doi:10.1371/journal.pone.0050122

    Article  PubMed Central  PubMed  Google Scholar 

  14. Berntsson SG, Malmer B, Bondy ML, Qu M, Smits A (2009) Tumor-associated epilepsy and glioma: are there common genetic pathways? Acta Oncol 48(7):955–963. doi:10.1080/02841860903104145

    Article  PubMed  Google Scholar 

  15. Huang L, You G, Jiang T, Li G, Li S, Wang Z (2011) Correlation between tumor-related seizures and molecular genetic profile in 103 Chinese patients with low-grade gliomas: a preliminary study. J Neurol Sci 302(1–2):63–67. doi:10.1016/j.jns.2010.11.024

    Article  CAS  PubMed  Google Scholar 

  16. Ostrom Q, Cohen ML, Ondracek A, Sloan A, Barnholtz-Sloan J (2013) Gene markers in brain tumors: what the epileptologist should know. Epilepsia 54(Suppl 9):25–29. doi:10.1111/epi.12439

    Article  CAS  PubMed  Google Scholar 

  17. Aronica E, Boer K, Becker A, Redeker S, Spliet WG, van Rijen PC, Wittink F, Breit T, Wadman WJ, Lopes da Silva FH, Troost D, Gorter JA (2008) Gene expression profile analysis of epilepsy-associated gangliogliomas. Neuroscience 151(1):272–292. doi:10.1016/j.neuroscience.2007.10.036

    Article  CAS  PubMed  Google Scholar 

  18. Gu W, Brodtkorb E, Piepoli T, Finocchiaro G, Steinlein OK (2005) LGI1: a gene involved in epileptogenesis and glioma progression? Neurogenetics 6(2):59–66. doi:10.1007/s10048-005-0216-5

    Article  CAS  PubMed  Google Scholar 

  19. Kunapuli P, Kasyapa CS, Hawthorn L, Cowell JK (2004) LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. J Biol Chem 279(22):23151–23157. doi:10.1074/jbc.M314192200

    Article  CAS  PubMed  Google Scholar 

  20. Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay JL, Mariani L (2013) IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro-oncology 15(4):469–479. doi:10.1093/neuonc/nos317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Okita Y, Narita Y, Miyakita Y, Ohno M, Matsushita Y, Fukushima S, Sumi M, Ichimura K, Kayama T, Shibui S (2012) IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy. Int J Oncol 41(4):1325–1336. doi:10.3892/ijo.2012.1564

    CAS  PubMed  Google Scholar 

  22. 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(3):194–197. doi:10.1016/j.seizure.2011.12.007

    Article  PubMed  Google Scholar 

  23. Liang R, Fan Y, Wang X, Mao Q, Liu Y (2013) The significance of IDH1 mutations in tumor-associated seizure in 60 Chinese patients with low-grade gliomas. ScientificWorldJournal 2013:403942. doi:10.1155/2013/403942

    PubMed Central  PubMed  Google Scholar 

  24. Reimers MS, Bastiaannet E, Langley RE, van Eijk R, van Vlierberghe RL, Lemmens VE, van Herk-Sukel MP, van Wezel T, Fodde R, Kuppen PJ, Morreau H, van de Velde CJ, Liefers GJ (2014) Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med 174(5):732–739. doi:10.1001/jamainternmed.2014.511

    Article  PubMed  Google Scholar 

  25. You G, Feng L, Yan W, Zhang W, Wang YZ, Li SW, Li SW, Li GL, Song YJ, Kang CS, You YP, Jiang T (2013) BCL2A1 is a potential biomarker for postoperative seizure control in patients with low-grade gliomas. CNS Neurosci Ther 19(11):882–888. doi:10.1111/cns.12148

    Article  CAS  PubMed  Google Scholar 

  26. Soffietti R, Baumert BG, Bello L, von Deimling A, Duffau H, Frenay M, Grisold W, Grant R, Graus F, Hoang-Xuan K, Klein M, Melin B, Rees J, Siegal T, Smits A, Stupp R, Wick W, European Federation of Neurological Societies (2010) Guidelines on management of low-grade gliomas: report of an EFNS–EANO task force. Eur J Neurol 17(9):1124–1133. doi:10.1111/j.1468-1331.2010.03151.x

    Article  CAS  PubMed  Google Scholar 

  27. de Groot M, Reijneveld JC, Aronica E, Heimans JJ (2012) Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain 135(Pt 4):1002–1016. doi:10.1093/brain/awr310

    Article  PubMed  Google Scholar 

  28. Heuser K, Szokol K, Tauboll E (2014) The role of glial cells in epilepsy. Tidsskr Nor Laegeforen 134(1):37–41. doi:10.4045/tidsskr.12.1344

    Article  PubMed  Google Scholar 

  29. Skradski SL, White HS, Ptacek LJ (1998) Genetic mapping of a locus (mass1) causing audiogenic seizures in mice. Genomics 49(2):188–192. doi:10.1006/geno.1998.5229

    Article  CAS  PubMed  Google Scholar 

  30. Skradski SL, Clark AM, Jiang H, White HS, Fu YH, Ptacek LJ (2001) A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron 31(4):537–544

    Article  CAS  PubMed  Google Scholar 

  31. Scheel H, Tomiuk S, Hofmann K (2002) A common protein interaction domain links two recently identified epilepsy genes. Hum Mol Genet 11(15):1757–1762

    Article  CAS  PubMed  Google Scholar 

  32. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy (1981). Epilepsia 22(4):489–501

  33. Yan L, Yang M, Guo H, Yang L, Wu J, Li R, Liu P, Lian Y, Zheng X, Yan J, Huang J, Li M, Wu X, Wen L, Lao K, Li R, Qiao J, Tang F (2013) Single-cell RNA-seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol 20(9):1131–1139. doi:10.1038/nsmb.2660

    Article  CAS  PubMed  Google Scholar 

  34. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5(7):621–628. doi:10.1038/nmeth.1226

    Article  CAS  PubMed  Google Scholar 

  35. Yagi H, Noguchi Y, Kitamura K, Sato M (2009) Deficiency of Vlgr1 resulted in deafness and susceptibility to audiogenic seizures while the degree of hearing impairment was not correlated with seizure severity in C57BL/6- and 129-backcrossed lines of Vlgr1 knockout mice. Neurosci Lett 461(2):190–195. doi:10.1016/j.neulet.2009.06.012

    Article  CAS  PubMed  Google Scholar 

  36. van Wijk E, van der Zwaag B, Peters T, Zimmermann U, Te Brinke H, Kersten FF, Marker T, Aller E, Hoefsloot LH, Cremers CW, Cremers FP, Wolfrum U, Knipper M, Roepman R, Kremer H (2006) The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum Mol Genet 15(5):751–765. doi:10.1093/hmg/ddi490

    Article  PubMed  Google Scholar 

  37. Nakayama J, Arinami T (2006) Molecular genetics of febrile seizures. Epilepsy Res 70(Suppl 1):S190–S198. doi:10.1016/j.eplepsyres.2005.11.023

    Article  CAS  PubMed  Google Scholar 

  38. Nikkila H, McMillan DR, Nunez BS, Pascoe L, Curnow KM, White PC (2000) Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain. Mol Endocrinol 14(9):1351–1364. doi:10.1210/mend.14.9.0511

    Article  CAS  PubMed  Google Scholar 

  39. McMillan DR, Kayes-Wandover KM, Richardson JA, White PC (2002) Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. J Biol Chem 277(1):785–792. doi:10.1074/jbc.M108929200

    Article  CAS  PubMed  Google Scholar 

  40. Lerche H, Weber YG, Jurkat-Rott K, Lehmann-Horn F (2005) Ion channel defects in idiopathic epilepsies. Curr Pharm Des 11(21):2737–2752

    Article  CAS  PubMed  Google Scholar 

  41. Lerche H, Jurkat-Rott K, Lehmann-Horn F (2001) Ion channels and epilepsy. Am J Med Genet 106(2):146–159. doi:10.1002/ajmg.1582

    Article  CAS  PubMed  Google Scholar 

  42. Olsen ML, Sontheimer H (2008) Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem 107(3):589–601. doi:10.1111/j.1471-4159.2008.05615.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Pallud J, Capelle L, Huberfeld G (2013) Tumoral epileptogenicity: how does it happen? Epilepsia 54(Suppl 9):30–34. doi:10.1111/epi.12440

    Article  CAS  PubMed  Google Scholar 

  44. Campbell SL, Buckingham SC, Sontheimer H (2012) Human glioma cells induce hyperexcitability in cortical networks. Epilepsia 53(8):1360–1370. doi:10.1111/j.1528-1167.2012.03557.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. doi:10.1056/NEJMra0708126

    Article  CAS  PubMed  Google Scholar 

  46. Melom JE, Littleton JT (2013) Mutation of a NCKX eliminates glial microdomain calcium oscillations and enhances seizure susceptibility. J Neurosci 33(3):1169–1178. doi:10.1523/JNEUROSCI.3920-12.2013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310(17):1842–1850. doi:10.1001/jama.2013.280319

    Article  CAS  PubMed  Google Scholar 

  48. Carico C, Nuno M, Mukherjee D, Elramsisy A, Dantis J, Hu J, Rudnick J, Yu JS, Black KL, Bannykh SI, Patil CG (2012) Loss of PTEN is not associated with poor survival in newly diagnosed glioblastoma patients of the temozolomide era. PLoS One 7(3):e33684. doi:10.1371/journal.pone.0033684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Bate L, Gardiner M (1999) Molecular genetics of human epilepsies. Expert Rev Mol Med 1999:1–22. doi:10.1017/S1462399499001349

    CAS  PubMed  Google Scholar 

  50. Youland RS, Schomas DA, Brown PD, Nwachukwu C, Buckner JC, Giannini C, Parney IF, Laack NN (2013) Changes in presentation, treatment, and outcomes of adult low-grade gliomas over the past fifty years. Neuro-oncology 15(8):1102–1110. doi:10.1093/neuonc/not080

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. You G, Sha ZY, Yan W, Zhang W, Wang YZ, Li SW, Sang L, Wang Z, Li GL, Li SW, Song YJ, Kang CS, Jiang T (2012) Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas: a clinicopathological study. Neuro-oncology 14(2):230–241. doi:10.1093/neuonc/nor205

    Article  PubMed Central  PubMed  Google Scholar 

  52. Chang EF, Potts MB, Keles GE, Lamborn KR, Chang SM, Barbaro NM, Berger MS (2008) Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg 108(2):227–235. doi:10.3171/JNS/2008/108/2/0227

    Article  PubMed  Google Scholar 

  53. Wang Y, Qian T, You G, Peng X, Chen C, You Y, Yao K, Wu C, Ma J, Sha Z, Wang S, Jiang T (2014) Localizing seizure-susceptible brain regions associated with low-grade gliomas using voxel-based lesion-symptom mapping. Neuro Oncol. doi:10.1093/neuonc/nou130

    PubMed Central  Google Scholar 

  54. Lee JW, Wen PY, Hurwitz S, Black P, Kesari S, Drappatz J, Golby AJ, Wells WM 3rd, Warfield SK, Kikinis R, Bromfield EB (2010) Morphological characteristics of brain tumors causing seizures. Arch Neurol 67(3):336–342. doi:10.1001/archneurol.2010.2

    Article  PubMed Central  PubMed  Google Scholar 

  55. Yang P, Wang Y, Peng X, You G, Zhang W, Yan W, Bao Z, Wang Y, Qiu X, Jiang T (2013) Management and survival rates in patients with glioma in China (2004–2010): a retrospective study from a single-institution. J Neurooncol 113(2):259–266. doi:10.1007/s11060-013-1103-9

    Article  CAS  PubMed  Google Scholar 

  56. Pallud J, Capelle L, Taillandier L, Fontaine D, Mandonnet E, Guillevin R, Bauchet L, Peruzzi P, Laigle-Donadey F, Kujas M, Guyotat J, Baron MH, Mokhtari K, Duffau H (2009) Prognostic significance of imaging contrast enhancement for WHO grade II gliomas. Neuro-oncology 11(2):176–182. doi:10.1215/15228517-2008-066

    Article  PubMed Central  PubMed  Google Scholar 

  57. Chaichana KL, McGirt MJ, Niranjan A, Olivi A, Burger PC, Quinones-Hinojosa A (2009) Prognostic significance of contrast-enhancing low-grade gliomas in adults and a review of the literature. Neurol Res 31(9):931–939. doi:10.1179/174313209X395454

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by funding from the National High Technology Research and Development Program (No. 2012AA02A508), the National Basic Research Program of China (No. 2015CB755500), and the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No. 2013BAI09B03).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Authors and Affiliations

  1. Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China

    Yinyan Wang & Tao Jiang

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China

    Yinyan Wang, Xing Fan, Wei Zhang, Chuanbao Zhang, Jiangfei Wang, Tao Jiang & Lei Wang

  3. China National Clinical Research Center for Neurological Diseases, Beijing, 100050, China

    Jiangfei Wang & Lei Wang

  4. Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, 100069, China

    Tao Jiang

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  1. Yinyan Wang
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  3. Wei Zhang
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Correspondence to Tao Jiang or Lei Wang.

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Yinyan Wang and Xing Fan contributed equally to this study.

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Wang, Y., Fan, X., Zhang, W. et al. Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor-related epilepsy: a whole transcriptome sequencing analysis. J Neurooncol 121, 609–616 (2015). https://doi.org/10.1007/s11060-014-1674-0

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