Dataset Information

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

ABSTRACT: Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0 x 10(-8)). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism.

SUBMITTER: Darbro BW

PROVIDER: S-EPMC4774916 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

Darbro Benjamin W BW Singh Rohini R Zimmerman M Bridget MB Mahajan Vinit B VB Bassuk Alexander G AG

PloS one 20160302 3

Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whet ...[more]

PMID: 26934580

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Project description:BackgroundReleasing considerable numbers of radiation-sterilized males is a promising strategy to suppress mosquito vectors. However, releases may also include small percentages of biting females, which translate to non-negligible numbers when releases are large. Currently, the effects of irradiation on host-seeking and host-biting behaviors have not been exhaustively investigated. Information is also lacking regarding the effects of sterilizing treatment on the endosymbiotic bacterium Wolbachia, which is known to affect the vector competence of infected mosquitos.MethodsTo ascertain the effects of irradiation on females, the pupae of two Aedes albopictus strains, differing in their natural or artificial Wolbachia infection type, and Aedes aegypti-which is not infected by Wolbachia-were treated with various doses of X-rays and monitored for key fitness parameters and biting behavior over a period of 2 weeks. The effect of radiation on Wolbachia was investigated by quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) analysis.ResultsPartial Aedes albopictus female sterility was achieved at 28 Gy, but the number of weekly bites more than doubled compared to that of the controls. Radiation doses of 35 and 45 Gy completely inhibited progeny production but did not significantly affect the survival or flight ability of Ae. albopictus females and caused a tripling of the number of bites per female per week (compared to untreated controls). These results were also confirmed in Ae. aegypti after treatment at 50 Gy. Wolbachia density decreased significantly in 45-Gy-irradiated females, with the greatest decreases in the early irradiation group (26 ± 2-h-old pupae). Wolbachia density also decreased as adults aged. This trend was confirmed in ovaries but not in extra-ovarian tissues. FISH analysis showed a strongly reduced Wolbachia-specific fluorescence in the ovaries of 13 ± 1-day-old females.ConclusionsThese results suggest that, under sterile insect technique (SIT) programs, the vector capacity of a target population could increase with the frequency of the irradiated females co-released with the sterile males due to an increased biting rate. In the context of successful suppression, the related safety issues are expected to be generally negligible, but they should be conservatively evaluated when large-scale programs relying on imperfect sexing and high overflooding release ratios are run for long periods in areas endemic for arboviral diseases. Also, the effects of irradiation on the vector competence deserve further investigation.

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Dataset Information

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

Publications

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

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