title: 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.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Iowa, Iowa City, Iowa, United States of America.|Interdisciplinary Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America.|Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.|The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Iowa, Iowa City, Iowa, United States of America.|Department of Pediatrics, Division of Pediatric Hematology/Oncology/BMT, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Rohini
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa, United States of America.
authors.forename: M Bridget
authors.initials: MB
authors.lastname: Zimmerman
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States of America.|Department of Biology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America.|Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.|Department of Pediatrics, Division of Neurology, University of Iowa, Iowa City, Iowa, United States of America.|Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa, United States of America.|Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, United States of America.|University of Iowa eHealth and eNovation Center, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000150:complications* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D009857:Oncogenes; D015995:Prevalence; D055815:Young Adult