Title: Investigating methylation to explain gene expression patterns between Glioblastoma and Alzheimer's Disease
Studies show inverse correlation between Alzheimer’s Disease(AD) and Glioblastoma(GBM), both diseases of the brain. AD and GBM are both associated with epigenetic factors. Can epigenetics explain this correlation? Can cancer or AD drugs, that treat via methylation or related signaling pathways, cause higher risk of other disease
Epigenetics is the study of mechanisms that controls gene expression in potentially heritable way without changes in primary DNA sequence. DNA methylation is one mechanism and is affected by CpG (CG dinucleotide) density. AD is neurodegenerative disorder associated with extracellular plaques of beta-amyloid and intracellular neurofibrillary tangles(NFT) caused by tau protiens. Late Onset AD (> 95% of AD) is highly associated with epigenetic factors. GBM is cancer of glial cells in CNS. Glial cells support neurons with energy and nutrients and maintain blood-brain barrier. Epigenetics (methylation) can cause cancer, especially GBM. Gene expression studies have shown inverse correlation between AD and GBM.
Methylation of CpG causes some genes correlated to both AD and GBM to be inversely expressed.
Inputs to this investigation are the results of past studies done on AD, GBM, Epigenetics (CpG, SNPs, DMRs). These results are published in journals (Nature, JAMA) or reports available from GDAC Broad Institute for GBM. AD inputs are the following which are significantly associated with AD: genes, DMR (differentially methylated regions), SNPs (single nucleotide polymorphisms), and CpG. DMRs, SNPs and CpGs have corresponding mapping to the genes based on location or proximity to genes. GBM inputs are genes related to clinical features and CpG methylation data (and corresponding mapped genes). AD/GBM genes, that are inversely expressed, are used as input for testing methylation significance in AD and GBM. AD genes, which are also found to be significant in GBM CpG data, are retained for methylation tests. Similarly GBM genes, which are found to be significant in AD DMR data, are retained for methylation tests. These and AD/GBM genes, are tested to see if GBM and AD methylation is significant (p-value < 5E-04).
Based on methylation tests, AD and GBM genes are divided in four categories based on methylation significance (AD and GBM, AD only, GBM only, none).
Four genes (MGMT, PPT2, SMC1B, MTCH2) show significant methylation in GBM and AD DMR with CpG features (island, shore and promoter). These genes are inversely expressed in AD and GBM. Of these, methylation of the promoter region of MGMT has shown direct correlation with GBM. MGMT, which repairs DNA damage is also shown to be correlated with AD in cerebrospinal fluid.
The genes SMC1B and PPT2 need further study to identify the role in AD/GBM. MTCH2 gene has been studied for breast cancer and needs additional study for GBM. TMZ (Temozolomide) is a GBM/cancer drug that targets DNA methylation in MGMT gene. It needs further study if AD risk in increased in patients treated by TMZ.