title: A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer.
abstract: The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants.
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Richards
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Permuth-Wey
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Reid
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: School of Medicine, Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D016147:Genes, Tumor Suppressor; D055106:Genome-Wide Association Study; D005838:Genotype; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C484298:HOXA11 protein, human; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding
keywords: HOX cluster; genetic susceptibility; long non-coding RNAs; ovarian cancer; single nucleotide polymorphisms