@article{8643232ee0b9488d94ff574b529bd584,
title = "Framework for microRNA variant annotation and prioritization using human population and disease datasets",
abstract = "MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE, which combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes). The pattern of miRNA variation closely resembles protein-coding exonic regions, with no difference between intragenic and intergenic miRNAs (P = 0.56), and high confidence miRNAs demonstrate higher sequence constraint (P < 0.001). Conservation analysis across 100 vertebrates identified 765 highly conserved miRNAs that also have limited genetic variation in gnomAD. We applied ADmiRE to the TCGA PanCancerAtlas WES dataset containing over 10,000 individuals across 33 adult cancers and annotated 1,267 germline (rare in gnomAD) and 1,492 somatic miRNA variants. Several miRNA families with deregulated gene expression in cancer have low levels of both somatic and germline variants, e.g., let-7 and miR-10. In addition to known somatic miR-142 mutations in hematologic cancers, we describe novel somatic miR-21 mutations in esophageal cancers impacting downstream miRNA targets. Through the development of ADmiRE, we present a framework for annotation and prioritization of miRNA variation in disease datasets.",
keywords = "cancer, conservation, genomics, microRNA, variant annotation",
author = "Ninad Oak and Rajarshi Ghosh and Huang, {Kuan lin} and Wheeler, {David A.} and Li Ding and Plon, {Sharon E.}",
note = "Funding Information: information This work was supported by the Cancer Prevention and Research Institute of Texas [RP10189]; National Cancer Institute [R01-CA138836]; and the National Human Genome Research Institute [5U01HG007436-03, U41HG009649-01] to SEP.The authors would like to thank the Genome Aggregation Database (gnomAD) team and the groups that provided exome and genome variant data toward this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. The authors would also like to thank Dr. Stephen Montgomery, Stanford University and Charles Lin, Baylor College of Medicine for their comments on the manuscript. Funding Information: 1Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 2Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 3Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 4Department of Medicine, Washington University in St. Louis, MO 63108 5McDonnel Genome Institute, Washington University in St. Louis, MO 63108 6Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030 7Department of Genetics, Washington University in St. Louis, MO 63108 8Siteman Cancer Center, Washington University in St. Louis, MO 63108 Correspondence Sharon E. Plon, MD PhD, Feigin Tower, Suite 1200, 1102 Bates Street, Houston, TX 77030. Email: splon@bcm.edu Funding information This work was supported by the Cancer Prevention and Research Institute of Texas [RP10189]; National Cancer Institute [R01-CA138836]; and the National Human Genome Research Institute [5U01HG007436-03, U41HG009649-01] to SEP. Communicated by Stephen J. Chanock ∗To whom correspondence should be addressed. Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",
year = "2019",
month = jan,
doi = "10.1002/humu.23668",
language = "English",
volume = "40",
pages = "73--89",
journal = "Human Mutation",
issn = "1059-7794",
number = "1",
}