Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism
Abstract Background Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA met...
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BMC
2020-04-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-020-06802-8 |
| _version_ | 1828768902933381120 |
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| author | Giselle M. Faria Igor D. P. Soares Marcela D’Alincourt Salazar Marcia R. Amorim Bruno L. Pessoa Clovis O. da Fonseca Thereza Quirico-Santos |
| author_facet | Giselle M. Faria Igor D. P. Soares Marcela D’Alincourt Salazar Marcia R. Amorim Bruno L. Pessoa Clovis O. da Fonseca Thereza Quirico-Santos |
| author_sort | Giselle M. Faria |
| collection | DOAJ |
| description | Abstract Background Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment. Methods gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event. Results Most rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = − 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = − 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = − 0,450; p = 0.04) or CT (median = 137.80%; rho = − 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length. Conclusion rGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism. Trial registration CONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004. |
| first_indexed | 2024-12-11T13:38:07Z |
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| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-11T13:38:07Z |
| publishDate | 2020-04-01 |
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| series | BMC Cancer |
| spelling | doaj.art-9cb5792a8fb34c848d7960af3933422c2022-12-22T01:04:55ZengBMCBMC Cancer1471-24072020-04-0120111010.1186/s12885-020-06802-8Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphismGiselle M. Faria0Igor D. P. Soares1Marcela D’Alincourt Salazar2Marcia R. Amorim3Bruno L. Pessoa4Clovis O. da Fonseca5Thereza Quirico-Santos6Instituto de Biologia, Universidade Federal FluminenseInstituto de Biologia, Universidade Federal FluminenseDepartment of Hematology and HCT, City of Hope Comprehensive Cancer CenterInstituto de Biologia, Universidade Federal FluminensePrograma de Pós-graduação em Neurologia, Faculdade de Medicina, Universidade Federal FluminenseDepartamento de Medicina Especializada, Unidade de Pesquisa Clínica (UPC-HUAP), Universidade Federal FluminenseInstituto de Biologia, Universidade Federal FluminenseAbstract Background Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment. Methods gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event. Results Most rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = − 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = − 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = − 0,450; p = 0.04) or CT (median = 137.80%; rho = − 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length. Conclusion rGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism. Trial registration CONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.http://link.springer.com/article/10.1186/s12885-020-06802-8Perillyl alcoholGlioblastomaMethylationPolymorphismMTHFREpigenetics |
| spellingShingle | Giselle M. Faria Igor D. P. Soares Marcela D’Alincourt Salazar Marcia R. Amorim Bruno L. Pessoa Clovis O. da Fonseca Thereza Quirico-Santos Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism BMC Cancer Perillyl alcohol Glioblastoma Methylation Polymorphism MTHFR Epigenetics |
| title | Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism |
| title_full | Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism |
| title_fullStr | Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism |
| title_full_unstemmed | Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism |
| title_short | Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism |
| title_sort | intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for mthfr rs1801133 polymorphism |
| topic | Perillyl alcohol Glioblastoma Methylation Polymorphism MTHFR Epigenetics |
| url | http://link.springer.com/article/10.1186/s12885-020-06802-8 |
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