Epidemiological and molecular associations between central nervous system disorders and cancer

The study of comorbidity is becoming a key topic in biomedical research, which is especially relevant in the context of population ageing. Comorbidity has profound implications for individuals, practitioners, and health care systems. As a consequence, increasing efforts are being made by the scientific community to characterize better how disorders relate to each other and to identify the factors producing these associations. Cancer and central nervous system (CNS) disorders are among the top leading causes of death and disease burden worldwide. In recent decades direct and inverse patterns of association between CNS disorders and cancer have been reported. However, observational studies have often found contrasting results. Consequently, evidence synthesis methods such as systematic reviews and meta-analysis have emerged as a critical tool to synthesize and evaluate the quality of the evidence regarding a specific research question. In addition, in the course of the Omics era, an unprecedented amount of information regarding the molecular bases of individual disorders has been produced, opening the door to the study of comorbidity from a molecular perspective through the identification of joint alterations in variants, genes, and biological processes. In the present thesis, we aimed to characterize the epidemiological and molecular associations between CNS disorders and cancer and to identify the potential role of their indicated medications. To this end, we first determined if CNS disorder patients presented an altered risk of subsequent cancer incidence and mortality by conducting systematic reviews and meta-analyses of observational studies. Second, we investigated if CNS disorders and cancers presented joint patterns of transcriptomic dysregulation using differential gene expression meta-analysis and weighed co-expression network analysis methods. Third, interactome-based methods and genetic correlations were employed to study the involvement of disease-associated genes and shared genetic variability. Finally, the impact of the medications indicated for the treatment of both sets of disorders in the reported comorbidities was assessed by the analysis of a large repository including information of cell lines treated with the indicated drugs. Our results suggest that patients suffering from neurodegenerative disorders are at a reduced risk of subsequent cancer incidence and mortality compared to controls. Autism spectrum disorder, bipolar disorder, and schizophrenia (SCZ) patients are at an increased risk of cancer mortality but not cancer incidence, whereas major depression patients presented an increased risk of cancer incidence and mortality. Several associations between CNS disorders and site-specific cancers were also identified. Significant direct and inverse patterns of transcriptomic dysregulation between CNS disorders and cancers were observed in our transcriptomic analyses, as well as the presence of joint alterations in several biological processes (i.e., cell cycle, apoptosis, immune system, and oxidative phosphorylation). Significant genetic correlations were also identified between CNS disorders and cancers, including those observed between Parkinson’s disease and melanoma and SCZ and breast cancer. Finally, several drugs indicated for the treatment of CNS disorders, such as antipsychotics, antidepressants, and acetyl-cholinesterase inhibitors were found to produce transcriptomic alterations that mimicked or reversed those found in some cancer types, indicating their potential role in the CNS and cancer comorbidity

A trans‐omics comparison reveals common gene expression strategies in four model organisms and exposes similarities and differences between them

The ultimate goal of gene expression regulation is on the protein level. However, because the amounts of mRNAs and proteins are controlled by their synthesis and degradation rates, the cellular amount of a given protein can be attained by following different strategies. By studying omics data for six expression variables (mRNA and protein amounts, plus their synthesis and decay rates), we previously demonstrated the existence of common expression strategies (CESs) for functionally related genes in the yeast Saccharomyces cerevisiae. Here we extend that study to two other eukaryotes: the yeast Schizosaccharomyces pombe and cultured human HeLa cells. We also use genomic data from the model prokaryote Escherichia coli as an external reference. We show that six-variable profiles (6VPs) can be constructed for every gene and that these 6VPs are similar for genes with similar functions in all the studied organisms. The differences in 6VPs between organisms can be used to establish their phylogenetic relationships. The analysis of the correlations among the six variables supports the hypothesis that most gene expression control occurs in actively growing organisms at the transcription rate level, and that translation plays a minor role. We propose that living organisms use CESs for the genes acting on the same physi-ological pathways, especially for those belonging to stable macromolecular complexes, but CESs have been modeled by evolution to adapt to the specific life circumstances of each organism

Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins

Recent discoveries highlight the importance of stochastic epigenetic changes, as indexed by epigenetic outlier DNA methylation signatures, as a valuable tool to understand aberrant cell function and subsequent human pathology. There is evidence of such changes in different complex disorders as diverse as cancer, obesity and, to a lesser extent, depression. The current study was aimed at identifying outlying DNA methylation signatures of depressive psychopathology. Here, genome-wide DNA methylation levels were measured (by means of Illumina Infinium HumanMethylation450 Beadchip) in peripheral blood of thirty-four monozygotic twins informative for depressive psychopathology (lifetime DSM-IV diagnoses). This dataset was explored to identify outlying epigenetic signatures of depression, operationalized as extreme hyper- or hypo-methylation in affected co-twins from discordant pairs that is not observed across the rest of the study sample. After adjusting for blood cell count, there were thirteen CpG sites across which depressed co-twins from the discordant pairs exhibited outlying DNA methylation signatures. None of them exhibited a methylation outlier profile in the concordant and healthy pairs, and some of these loci spanned genes previously associated with neuropsychiatric phenotypes, such as GHSR and KCNQ1. This exploratory study provides preliminary proof-of-concept validation that epigenetic outlier profiles derived from genome-wide DNA methylation data may be related to depression risk

Cancer and central nervous system disorders: protocol for an umbrella review of systematic reviews and updated meta-analyses of observational studies

BACKGROUND: The 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/DESIGN: We 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. DISCUSSION: Our 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 REGISTRATION: PROSPERO CRD42016052762

Transcriptomic and genetic associations between Alzheimer’s disease, Parkinson’s disease, and cancer

Alzheimer’s (AD) and Parkinson’s diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.The research was supported by grant number PROMETEOII/2015/021 from Generalitat Valenciana and the national grant PI17/00719 from ISCIII-FEDER.Peer Reviewed"Article signat per 11 autors/es: Jaume Forés-Martos, Cesar Boullosa, David Rodrigo-Domínguez, Jon Sánchez-Valle, Beatriz Suay-García, Joan Climent, Antonio Falcó, Alfonso Valencia, Joan Anton Puig-Butillé, Susana Puig and Rafael Tabarés-Seisdedos"Postprint (published version

Myopericarditis Associated with the Novavax COVID-19 Vaccine (NVX-CoV2373): A Retrospective Analysis of Individual Case Safety Reports from VigiBase

Abstract Background Myocarditis and pericarditis have been associated most notably with mRNA vaccines, but the association with a recently authorized adjuvated vaccine (NVX-CoV2373) is controversial. Objective The aim was to analyze the cases of myocarditis and pericarditis in association with NVX-CoV2373 reported to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase), applying disproportionality analyses. Patients and methods The main characteristics of the ICSRs reporting myopericarditis with NVX-CoV2373 have been summarized. Reporting odds ratios (RORs) as a measure of disproportionality for reported myopericarditis (November 1967–August 2022) have been calculated for NVX-CoV2373; mRNA and adenoviral vector-based vaccines were also included as a reference. Results In total, 61 ICSRs included NVX-CoV2373. Most of the reports originated in Australia (50; 82.0%); 24 (39.3%) were considered serious. None of them were fatal. The median age of individuals was 35.5 years old, and most were males (38; 62.3%). Chest pain was the most common co-reported event 43 (70.5%). The median induction period was 3 days after immunization. Increased disproportionality for myopericarditis was found for NVX-CoV2373 (ROR 14.47, 95% confidence interval [CI] 11.22–18.67) and mRNA vaccines: BNT162b2 (ROR 17.15, 95% CI 16.88–17.42) and mRNA-1273 (ROR 6.92, 95% CI 6.77–7.08). Higher values were found in males. The adenoviral vector-based vaccine Ad26.COV2.S showed slightly increased disproportionality (ROR 1.83, 95% CI 1.70–1.98), whereas no increased disproportionality was found for ChAdOx1. Conclusions NVX-CoV2373 vaccine showed a similar increased disproportionality as mRNA vaccines. More evidence from controlled studies is necessary; however, a precautionary approach is warranted. Healthcare professionals should be aware of the potential occurrence of myopericarditis with this new vaccine

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

Background Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Methods Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them. Results Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. Conclusions Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer

Protocol paper

Protocol paper (postprint

Risk of mortality among persons with autism spectrum disorder or attention deficit hyperactivity disorder and their first-degree relatives: a systematic review and meta-analysis of observational studies

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are childhood onset neurodevelopmental disorders that may persist into adulthood. ASD and ADHD tend to run in families and may have a significant negative impact on the health and longevity of those with the disorder and their relatives. The aim of this study is to analyze the risk of mortality among persons with ASD or ADHD and their first-degree relatives. The primary outcome is all-cause mortality. The secondary outcome is cause-specific mortality