title: Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer.
abstract: Ovarian cancer is a major cause of cancer deaths, yet there have been few known genetic risk factors identified, the best known of which are disruptions in protein coding sequences (BRCA1 and 2). Recent findings indicate that there are powerful genetic markers of cancer risk outside of these regions, in the noncoding mRNA control regions. To identify additional cancer-associated, functional non-protein-coding sequence germline variants associated with ovarian cancer risk, we captured DNA regions corresponding to all validated human microRNAs and the 3' untranslated regions (UTRs) of ~6000 cancer-associated genes from 31 ovarian cancer patients. Multiple single-nucleotide polymorphisms in the 3'UTR of the vascular endothelial growth factor receptor/FLT1, E2F2 and PCM1 oncogenes were highly enriched in ovarian cancer patients compared with the 1000 Genome Project. Sequenom validation in a case-control study (267 cases and 89 controls) confirmed a novel variant in the PCM1 3'UTR is significantly associated with ovarian cancer (P=0.0086). This work identifies a potential new ovarian cancer locus and further confirms that cancer resequencing efforts should not ignore the study of noncoding regions of cancer patients.
authors.affiliation: 1] Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA [2] Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Paranjape
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Stahlhut
authors.affiliation: Discipline of Surgery, National University of Ireland Galway and Galway University, Hospitals, Galway, Ireland.
authors.forename: T
authors.initials: T
authors.lastname: McVeigh
authors.affiliation: Yale University School of Medicine, New Haven, CT, USA.
authors.forename: F
authors.initials: F
authors.lastname: Keane
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nallur
authors.affiliation: Discipline of Surgery, National University of Ireland Galway and Galway University, Hospitals, Galway, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Miller
authors.affiliation: Discipline of Surgery, National University of Ireland Galway and Galway University, Hospitals, Galway, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Kerin
authors.affiliation: Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.affiliation: 1] Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, CT, USA [3] Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Weidhaas
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Slack
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004247:DNA / Q000235:genetics; D050703:E2F2 Transcription Factor / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D001324:Autoantigens; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D005819:Genetic Markers; D035683:MicroRNAs; C086074:PCM1 protein, human; D004247:DNA; C501162:FLT1 protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1