TY - JOUR
T1 - Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex
AU - Bongaarts, Anika
AU - Mijnsbergen, Caroline
AU - Anink, Jasper J.
AU - Jansen, Floor E.
AU - Spliet, Wim G. M.
AU - den Dunnen, Wilfred F. A.
AU - Coras, Roland
AU - Blümcke, Ingmar
AU - Paulus, Werner
AU - Gruber, Victoria E.
AU - Scholl, Theresa
AU - Hainfellner, Johannes A.
AU - Feucht, Martha
AU - Kotulska, Katarzyna
AU - Jozwiak, Sergiusz
AU - Grajkowska, Wieslawa
AU - Buccoliero, Anna Maria
AU - Caporalini, Chiara
AU - Giordano, Flavio
AU - Genitori, Lorenzo
AU - Söylemezoğlu, Figen
AU - Pimentel, José
AU - Jones, David T. W.
AU - Scicluna, Brendon P.
AU - Schouten-van Meeteren, Antoinette Y. N.
AU - Mühlebner, Angelika
AU - Mills, James D.
AU - Aronica, Eleonora
N1 - Funding Information: This work was supported by KIKA (Stichting Kinderen Kankervrij; AB, AM, AS, BS, EA); Stichting AMC Foundation (EA); Stichting TSC Fonds (EA); the Austrian Science Fund (FWF, no. J3499; AM); the European Union 7th framework program: acronym EPISTOP (Grant Agreement No. 602391; FJ, VG, TS, MF, SJ, AM, JM, EA) and acronym DESIRE (Grant Agreement No. 602531; IB); the European Union’s Horizon 2020 WIDESPREAD-05-2020–Twinning, (EpiEpiNet; EA,JM), Grant Agreement no. 952455; the Polish Ministerial funds for science (years 2013–2018) for the implementation of international co-financed project (KK, SJ) and internal research project of the Children’s Memorial Health Institute No.S132/2013 (KK, SJ). Publisher Copyright: © 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.
AB - Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.
KW - Low-grade glioma
KW - Methylation
KW - RNA-sequencing
KW - SEGA
KW - TSC
UR - http://www.scopus.com/inward/record.url?scp=85118212684&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s10571-021-01157-5
DO - https://doi.org/10.1007/s10571-021-01157-5
M3 - Article
C2 - 34709498
SN - 0272-4340
JO - Cellular and molecular neurobiology
JF - Cellular and molecular neurobiology
ER -