Identifying genes and pathways as an underlying cause of inverse comorbidity between cancer and Alzheimer’s disease

Abstract

Epidemiological studies and clinical evidence suggest an inverse comorbidity between cancer and Alzheimer’s Disease (AD). Several epidemiological studies and biological evidence suggested liver cancer (HCC) and Oesophageal cancer (EC) as most related to AD. Gene expression studies conducted on microarray platforms have also reported genes and biological pathways as inversely regulated between both diseases. However, to best of our knowledge no study has reported molecular level association between AD and EC. Therefore, this study conducts meta-differential expression analysis to get DEGs and pathways inversely regulated between cancer (Oesophageal cancer, Liver cancer) and Alzheimer disease. Two RNA-seq datasets from AD patients and controls from similar brain regions and four datasets from two different cancer types were subjected to differential expression analysis. Meta-analysis was performed using p-value combination method implicated in metaRNASeq. Intersection for inverse genes in each pair was calculated and significance of overlap was tested through Fisher exact test. Inversely regulated genes were then subjected to pathway analysis. Both cancer types (EC, LC) showed a significant overlap in gene expression deregulation in the opposite direction from AD. Functional enrichment comparison revealed several biological pathways which were affected jointly in both diseases, including PI3K/AKT/MTOR, GABAergic, Central Carbon Metabolism in Cancer and Metabolic pathways. Sixteen pathways were found to be deregulated in opposite direction. These results reinforce the previously proposed gene candidates and pathways like PI3K/AKT/MTOR and GABAergic synapse as contributing factor towards true inverse association between cancers and AD. It also reveals new potential candidates and pathways that can be involved.