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Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses.

ABSTRACT: There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions. We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways. Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.

SUBMITTER: Ibanez K

PROVIDER: S-EPMC3930576 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses.

Ibáñez Kristina K Boullosa César C Tabarés-Seisdedos Rafael R Baudot Anaïs A Valencia Alfonso A

PLoS genetics 20140220 2

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions. We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer typ ...[more]

PMID: 24586201

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Project description:BackgroundEchinoderms are emerging as important models in regenerative biology. Significant amount of data are available on cellular mechanisms of post-traumatic repair in these animals, whereas studies of gene expression are rare. In this study, we employ high-throughput sequencing to analyze the transcriptome of the normal and regenerating radial nerve cord (a homolog of the chordate neural tube), in the sea cucumber Holothuria glaberrima.ResultsOur de novo assembly yielded 70,173 contigs, of which 24,324 showed significant similarity to known protein-coding sequences. Expression profiling revealed large-scale changes in gene expression (4,023 and 3,257 up-regulated and down-regulated transcripts, respectively) associated with regeneration. Functional analysis of sets of differentially expressed genes suggested that among the most extensively over-represented pathways were those involved in the extracellular matrix (ECM) remodeling and ECM-cell interactions, indicating a key role of the ECM in regeneration. We also searched the sea cucumber transcriptome for homologs of factors known to be involved in acquisition and/or control of pluripotency. We identified eleven genes that were expressed both in the normal and regenerating tissues. Of these, only Myc was present at significantly higher levels in regeneration, whereas the expression of Bmi-1 was significantly reduced. We also sought to get insight into which transcription factors may operate at the top of the regulatory hierarchy to control gene expression in regeneration. Our analysis yielded eleven putative transcription factors, which constitute good candidates for further functional studies. The identified candidate transcription factors included not only known regeneration-related genes, but also factors not previously implicated as regulators of post-traumatic tissue regrowth. Functional annotation also suggested that one of the possible adaptations contributing to fast and efficient neural regeneration in echinoderms may be related to suppression of excitotoxicity.ConclusionsOur transcriptomic analysis corroborates existing data on cellular mechanisms implicated in regeneration in sea cucumbers. More importantly, however, it also illuminates new aspects of echinoderm regeneration, which have been scarcely studied or overlooked altogether. The most significant outcome of the present work is that it lays out a roadmap for future studies of regulatory mechanisms by providing a list of key candidate genes for functional analysis.

Project description:BackgroundThe objective of this study will be to synthesize the epidemiological evidence and evaluate the validity of the associations between central nervous system disorders and the risk of developing or dying from cancer.Methods/designWe will perform an umbrella review of systematic reviews and conduct updated meta-analyses of observational studies (cohort and case-control) investigating the association between central nervous system disorders and the risk of developing or dying from any cancer or specific types of cancer. Searches involving PubMed/MEDLINE, EMBASE, SCOPUS and Web of Science will be used to identify systematic reviews and meta-analyses of observational studies. In addition, online databases will be checked for observational studies published outside the time frames of previous reviews. Eligible central nervous system disorders will be Alzheimer's disease, anorexia nervosa, amyotrophic lateral sclerosis, autism spectrum disorders, bipolar disorder, depression, Down's syndrome, epilepsy, Huntington's disease, multiple sclerosis, Parkinson's disease and schizophrenia. The primary outcomes will be cancer incidence and cancer mortality in association with a central nervous system disorder. Secondary outcome measures will be site-specific cancer incidence and mortality, respectively. Two reviewers will independently screen references identified by the literature search, as well as potentially relevant full-text articles. Data will be abstracted, and study quality/risk of bias will be appraised by two reviewers independently. Conflicts at all levels of screening and abstraction will be resolved through discussion. Random-effects meta-analyses of primary observational studies will be conducted where appropriate. Parameters for exploring statistical heterogeneity are pre-specified. The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) criteria and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used for determining the quality of evidence for cancer outcomes.DiscussionOur study will establish the extent of the epidemiological evidence underlying the associations between central nervous system disorders and cancer and will provide a rigorous and updated synthesis of a range of important site-specific cancer outcomes.Systematic review registrationPROSPERO CRD42016052762.

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Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses.

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Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses.

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