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Abstract
BackgroundEpidemiological 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.MethodsHere, 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.ResultsFour 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.ConclusionsComparisons 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.
Highlights
Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD)
ASD differential gene-expression meta-analysis and gene set enrichment analysis (GSEA) A total of 13,699 genes were tested for differential expression, yielding 1055 differentially expressed genes (DEGs) in ASD patients relative to controls below an false discovery rate (FDR) threshold of 0.05
The results suggest that treatment with mTOR inhibitors, such as everolimus, sirolimus, and temsirolimus, produce differential expression profiles that mimic the differential expression profile found in ASD while reversing the differential expression profiles found in most cancer types, excluding brain, kidney, thyroid, and pancreatic cancer, the four same direction deregulated cancers (SDDC)
Summary
Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). Several studies have failed to find specific associations between ASD and cancer [16,17,18], others, including a large population cohort study in Taiwan [11] suggested a higher-than-expected occurrence of overall cancer in ASD patients These authors found a standardized incidence ratio of 1.94 (95% CI 1.18–2.99), with further increased incidence for brain and genitourinary cancers. Several studies have found a striking implication of the classically cancer related PTEN pathway in ASD [22, 25,26,27] These findings provide persuasive evidence of a molecular link between ASD and cancer, possibly opening the door to new treatments for both conditions. Chemotherapeutic agents that inhibit PTEN signaling or related pathways, such as PI3K-AKT, mTOR and NF-1 (e.g., rapamycin and everolimus), are potential candidates for treating several manifestations of autism [28]
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