title: Extensive sequence variation in the 3' untranslated region of the KRAS gene in lung and ovarian cancer cases.
abstract: While cancer is a serious health issue, there are very few genetic biomarkers that predict predisposition, prognosis, diagnosis, and treatment response. Recently, sequence variations that disrupt microRNA (miRNA)-mediated regulation of genes have been shown to be associated with many human diseases, including cancer. In an early example, a variant at one particular single nucleotide polymorphism (SNP) in a let-7 miRNA complementary site in the 3' untranslated region (3' UTR) of the KRAS gene was associated with risk and outcome of various cancers. The KRAS oncogene is an important regulator of cellular proliferation, and is frequently mutated in cancers. To discover additional sequence variants in the 3' UTR of KRAS with the potential as genetic biomarkers, we resequenced the complete region of the 3' UTR of KRAS in multiple non-small cell lung cancer and epithelial ovarian cancer cases either by Sanger sequencing or capture enrichment followed by high-throughput sequencing. Here we report a comprehensive list of sequence variations identified in cases, with some potentially dysregulating expression of KRAS by altering putative miRNA complementary sites. Notably, rs712, rs9266, and one novel variant may have a functional role in regulation of KRAS by disrupting complementary sites of various miRNAs, including let-7 and miR-181.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology; Yale University; New Haven, CT USA.
authors.forename: Minlee
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology; Yale University; New Haven, CT USA; Program in Computational Biology and Bioinformatics; Yale University School of Medicine; New Haven, CT USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology; Yale University; New Haven, CT USA.
authors.forename: Lena J
authors.initials: LJ
authors.lastname: Chin
authors.affiliation: Department of Therapeutic Radiology; Yale University School of Medicine; New Haven, CT USA.
authors.forename: Trupti
authors.initials: T
authors.lastname: Paranjape
authors.affiliation: Department of Genetics; Yale University School of Medicine; New Haven, CT USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Speed
authors.affiliation: Department of Genetics; Yale University School of Medicine; New Haven, CT USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.affiliation: Program in Computational Biology and Bioinformatics; Yale University School of Medicine; New Haven, CT USA; Department of Genetics; Yale University School of Medicine; New Haven, CT USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Therapeutic Radiology; Yale University School of Medicine; New Haven, CT USA.
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology; Yale University; New Haven, CT USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
mesh_terms: D020413:3' Untranslated Regions; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C117307:KRAS protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: 3′ UTR; EOC; KRAS; NSCLC; SNP; epithelial ovarian cancer; let-7; microRNA; non-small cell lung cancer; sequence variant