TIGS 1255 No. of Pages 8 Forum Table 1 summarizes the characteristics of unclear whether this is related to its signal- Autism and Cancer risk genes for ASD that are also risk genes ing function or a consequence of a second for cancers, extending the original finding independent PTEN activity, but this dual Share Risk Genes, that the PI3K-Akt-mTOR signaling axis function may provide the rationale for the (involving PTEN, FMR1, NF1, TSC1, and dominant role of PTEN in cancer and Pathways, and Drug TSC2) was associated with inherited risk autism. Other genes encoding common Targets for both cancer and ASD [6–9]. Recent tumor signaling pathways include MET8[1_TD$IF],[2_TD$IF] genome-wide exome-sequencing studies PTK7, and HRAS, while p53, AKT, mTOR, Jacqueline N. Crawley,1,2,* of de novo variants in ASD and cancer WNT, NOTCH, and MAPK are compo- Wolf-Dietrich Heyer,3,4 and have begun to uncover considerable addi- nents of signaling pathways regulating Janine M. LaSalle1,4,5 tional overlap. What is surprising about the the nuclear factors described above. genes in Table 1 is not necessarily the Autism is a neurodevelopmental number of risk genes found in both autism Autism is comorbid with several mono- and cancer, but the shared functions of genic neurodevelopmental disorders, disorder, diagnosed behaviorally genes in chromatin remodeling and including Fragile X (FMR1), Rett syndrome by social and communication genome maintenance, transcription fac- (MECP2), Phelan-McDermid (SHANK3), fi de cits, repetitive behaviors, tors, and signal transduction pathways 15q duplication syndrome (UBE3A), and restricted interests. Recent leading to nuclear changes [7,8]. Chroma- neurofibromatosis (NF1), tuberous sclero- genome-wide exome sequencing tin remodeling factors important in altering sis (TSC1 and TSC2), and Cornelia de has revealed extensive overlap in nucleosome accessibility for transcription Lange syndrome (NIPBL and SMC1A) risk genes for autism and for can- and genome maintenance mechanisms (Table 1). Neurofibromatosis and tuberous cer. Understanding the genetic include CHD8, CHD7, CHD2, ARID1B, sclerosis are directly associated with commonalities of autism(s) and and ATRX. ATRX may exert a more spe- tumors, but such tumors are benign and cancer(s), with a focus on mecha- cific function in telomere maintenance, rarely associated, if at all, with malignan- nistic pathways, could lead to analogous to other Swi2/Snf2 family fac- cies. However, mutations in NF1, TSC1, repurposed therapeutics. tors, such as ERCC6, RAD54, HTLF, or TSC2 enhance the risk for developing SHPRH,orRAD16, which function in ded- cancer [6]. Notably, NF1, TSC1, and icated DNA repair pathways. Proteins TSC2 function like PTEN in the AKT path- Autism is a neurodevelopmental disor- involved in histone methyltransferase way of mTOR control. Mutations in tran- der, diagnosed by behavioral symptoms reactions important in setting the histone scriptional factor genes also mediate including impaired social interactions and code include ASHL1, EHMT1, EHMT2, downstream signaling pathways that communication, repetitive behaviors, and KMT2C, KMT2D, and SUV420H1. include key proteins implicated in cell pro- restricted interests [1]. Extraordinarily PHF2, KDM5B, and KDM6B are histone liferation or differentiation pathways impli- high heritability for autism spectrum dis- demethylases, and MACROD2 encodes a cated in cancer and autism, such as order (ASD) has been detected in twin nuclear factor regulated by a metabolite of mTOR, RAS GTPases, MAP kinases, studies, with a range of 50–90% concor- histone deacetylation. Ubiquitin modifica- AKT, EIF4E, WNT, ERK, PI3K, and dance between monozygotic twins, tions to histones and other proteins are CHD8. A risk gene originally identified in compared with 0–30% between dizy- implicated by the risk genes CUL3, individuals with cancer may present as a gotic twins and siblings, and approxi- HERC2, MIB1, TBL1XR1, TRIP12, de novo mutation in a small number of mately 1% prevalence in the general UBE3A, and WAC. Transcription factors individuals with ASD, or may be implicated population, along with a high male:female genetically implicated in both autism and in ASD through interactome analysis of ratio [2]. International consortia searching cancer include ADNP, PAX5, FOXP1, interrelated genes and interacting pro- for the genetic causes of ASD quickly TCF7L2, and TBLXR1. Interestingly, these teins, such as within a signaling pathway recognized that autism is not a mono- nuclear factors are downstream of several (Table 1). genic disorder. Hundreds of de novo key signal transduction pathways also and familial risk genes, copy number var- genetically implicated in ASD and cancer, What does tumor cell proliferation have in iants, and epigenetic modifiers have been including PTEN [7].PTENfunctions in the common with brain development and identified through linkage analysis, AKT signaling pathway, where its phospha- neuronal synapse formation? Similar to genome wide-association studies, and tase activity is needed for AKT downregu- cancers, ‘autisms’ are best conceptual- exon and whole-genome sequencing of lation. Nuclear PTEN also regulates ized in the plural. ASD encompasses a individuals with ASD over the past 2 years recombinational DNA repair, a key genome broad range of putative causes, symptom [2–5]. maintenance pathway (see below). It is presentations, and outcomes, including Trends in Genetics, Month Year, Vol. xx, No. yy 1 2 TIGS 1255 No. of Pages 8 Trends in Genetics, Month Year, Vol. xx, No. yy Table 1. Characteristics of Risk Genes Implicated in Both Autism and Cancer[3_TD$IF] a Gene Symbol Gene Name[5_TD$IF] Human Protein Function Interacting Autism-Related Neu- Cancer Susceptibility Refs (PMID) Chromosome Proteins rodevelopmental or Pathway Location Syndrome ADNP Activity-dependent 20q13.13 Potential transcription factor. May SMARCA4, Helsmoortel-Van[6_TD$IF] der p53, WNT 25891009 neuroprotector mediate some neuroprotective SMARCC2, Aa syndrome homeobox peptide VIP-associated effects ARID1A ANK2 Ankyrin 2, Neuronal 4q25 Attaches integral membrane DMD, DCTN4, Long Proteoglycans 25863124 proteins to cytoskeletal elements ACTF1 (Electrocardiographic) and regulates cell motility, QT Syndrome 4 activation, proliferation, and contact ARID1B AT Rich Interacting 6q25.3 Subunit of SWI/SNF chromatin ARID1A, Coffin[7_TD$IF]–Siris syndrome ESR1, WNT; prostate 25891009 Domain 1B (SWI1- remodeling complex SMARCA2, cancer like), BRG1-Binding RELB, SMAD9, protein ASF1A ASH1L Lysine 1q22 Histone methyltransferase SMAD7, Autism, susceptibility Lysine degradation 26402605 N-Methyltransferase specifically methylating Lys-36 of HIST1H3A 2H histone H3 (H3K36me) ATRX RAD54, Alpha Xq21.1 SWI/SNF ATP-dependent DNA CBX5, DAXX, Alpha-thalassemia/ Breast cancer, 24779060 Thalassemia/Mental motor protein that acts in HDAC1, mental retardation telomeres Retardation heterochromatin and at[8_TD$IF] telomeres SMC1A, SMC3 syndrome Syndrome X-linked CHD2 Chromodomain 15q26.1 SWI/SNF ATP-dependent DNA SUMO1, PARK7 Epileptic Chromatin regulation 25891009 Helicase DNA motor protein that acts as a encephalopathy, Binding Protein 2, chromatin remodeling factor and childhood-onset ATP-dependent transcriptional regulator, and also helicase in DNA repair CHD7 Chromodomain 8q12.2 SWI/SNF ATP-dependent DNA CHD8, PBRM1, CHARGE syndrome WNT signaling, 24768552 Helicase DNA motor protein that acts as a SMARCC1, chromatin regulation Binding Protein 7, chromatin remodeling factor and SMARCC2, ATP-dependent transcriptional regulator SMARCE1 helicase CHD8 Chromodomain 14q11.2 SWI/SNF ATP-dependent DNA RBBP5, WDR5, Autism, susceptibility WNT signaling, 25891009 Helicase DNA motor protein that acts as a CTNNB1, USF1, chromatin regulation Binding Protein 8, chromatin remodeling factor and CTCF HELSNF1, AUTS18 transcriptional regulator CUL3 Cullin 3 2q36.2 Core component of multiple cullin- KLHL3, NEDD8, Autism, susceptibility WNT signaling, 25363768 RING-based BCR (BTB-CUL3- KEAP1, RBX1, chromatin regulation RBX1) E3 ubiquitin–protein ligase CASP8 complex DNMT3A DNA (5-cytosine)- 2p23.3 Required for genome-wide de DNMT3L, Autism, susceptibility Chromatin regulation 26402605 methyltransferase novo methylation; essential for DNMT3B, 3A establishment of DNA methylation UHRF1 patterns during development Table 1. (continued) TIGS 1255 No. of Pages 8 Gene Symbol Gene Name[5_TD$IF] Human Protein Function Interacting Autism-Related Neu- Cancer Susceptibility Refs (PMID) Chromosome Proteins rodevelopmental or Pathway Location Syndrome DYRK1A Dual-specificity 21q22.13 Serine/threonine kinase implicated HIPK2, SFN, Down syndrome, NOTCH signaling, 17583556 tyrosine in cell survival, proliferation, and YWHAB, mental retardation, translation regulation phosphorylation- differentiation YWHAE, DCAF autosomal dominant 7 regulated kinase 1A EHMT1 Euchromatic 9q34.3 Histone methyltransferase of MDM2, p53, Kleefstra syndrome Cellular senescence, 24779060 Histone-Lysine H3K9me and H3K9me2 in SUV39H1, NOTCH, lysine N- euchromatin HIST1H3A, degradation Methyltransferase, CTBP1, KMT1D, CLP SUV39H1 ERBB2IP ERBB2 Interacting 5q12.3 Acts as adapter for ERBB2 ERBB2, SMAD2, Autism, susceptibility TGFb signaling, cervical 26402605 protein receptor, inhibits NOD2- SMAD3, NRG2, and colon cancer dependent NF-k-B signaling and PKP4 proinflammatory cytokine secretion ERCC6 Cockayne's 10q11.23 SWI/SNF ATP-dependent DNA Cockayne's High confidence ASD Transcription-coupled 24768552 Syndrome B motor protein that acts in Syndrome-A/ candidate