title: Deep Genetic Connection Between Cancer and Developmental Disorders.
abstract: Cancer and developmental disorders (DDs) share dysregulated cellular processes such as proliferation and differentiation. There are well-known genes implicated in both in cancer and DDs. In this study, we aim to quantify this genetic connection using publicly available data. We found that among DD patients, germline damaging de novo variants are more enriched in cancer driver genes than non-drivers. We estimate that cancer driver genes comprise about a third of DD risk genes. Additionally, de novo likely-gene-disrupting variants are more enriched in tumor suppressors, and about 40% of implicated de novo damaging missense variants are located in cancer somatic mutation hotspots, indicating that many genes have a similar mode of action in cancer and DDs. Our results suggest that we can view tumors as natural laboratories for assessing the deleterious effects of mutations that are applicable to germline variants and identification of causal genes and variants in DDs.
authors.affiliation: Department of Applied Physics and Applied Mathematics, Columbia University, New York, New York.|Department of Systems Biology, Columbia University Medical Center, New York, New York.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Qi
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California.|Biostatistics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Dong
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California.|Biostatistics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, New York. ys2411@cumc.columbia.edu.|Department of Biomedical Informatics, Columbia University Medical Center, New York, New York. ys2411@cumc.columbia.edu.|JP Sulzberger Columbia Genome Center, Columbia University Medical Center, New York, New York. ys2411@cumc.columbia.edu.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
mesh_terms: D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000235:genetics*
keywords: de novo mutations; developmental disorders; somatic mutation hotspots; tumor suppressors