title: Transcriptome-wide analysis of UTRs in non-small cell lung cancer reveals cancer-related genes with SNV-induced changes on RNA secondary structure and miRNA target sites.
abstract: Traditional mutation assessment methods generally focus on predicting disruptive changes in protein-coding regions rather than non-coding regulatory regions like untranslated regions (UTRs) of mRNAs. The UTRs, however, are known to have many sequence and structural motifs that can regulate translational and transcriptional efficiency and stability of mRNAs through interaction with RNA-binding proteins and other non-coding RNAs like microRNAs (miRNAs). In a recent study, transcriptomes of tumor cells harboring mutant and wild-type KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes in patients with non-small cell lung cancer (NSCLC) have been sequenced to identify single nucleotide variations (SNVs). About 40% of the total SNVs (73,717) identified were mapped to UTRs, but omitted in the previous analysis. To meet this obvious demand for analysis of the UTRs, we designed a comprehensive pipeline to predict the effect of SNVs on two major regulatory elements, secondary structure and miRNA target sites. Out of 29,290 SNVs in 6462 genes, we predict 472 SNVs (in 408 genes) affecting local RNA secondary structure, 490 SNVs (in 447 genes) affecting miRNA target sites and 48 that do both. Together these disruptive SNVs were present in 803 different genes, out of which 188 (23.4%) were previously known to be cancer-associated. Notably, this ratio is significantly higher (one-sided Fisher's exact test p-value = 0.032) than the ratio (20.8%) of known cancer-associated genes (n = 1347) in our initial data set (n = 6462). Network analysis shows that the genes harboring disruptive SNVs were involved in molecular mechanisms of cancer, and the signaling pathways of LPS-stimulated MAPK, IL-6, iNOS, EIF2 and mTOR. In conclusion, we have found hundreds of SNVs which are highly disruptive with respect to changes in the secondary structure and miRNA target sites within UTRs. These changes hold the potential to alter the expression of known cancer genes or genes linked to cancer-associated pathways.
authors.affiliation: Center for non-coding RNA in Technology and Health, Section for Animal Genetics, Bioinformatics and Breeding, IKVH, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sabarinathan
authors.affiliation: Center for non-coding RNA in Technology and Health, Section for Animal Genetics, Bioinformatics and Breeding, IKVH, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Wenzel
authors.affiliation: Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Novotny
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Tang
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, United States of America.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.affiliation: Center for non-coding RNA in Technology and Health, Section for Animal Genetics, Bioinformatics and Breeding, IKVH, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gorodkin
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D012334:RNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D012984:Software; D020506:Untranslated Regions / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020506:Untranslated Regions