Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully char-acterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3 0 untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene–environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio ¼ 1.12, P ¼ 10 (cid:2) 8 ) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion ( P ¼ 10 (cid:2) 10 ). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

[1]  Brooke L. Fridley,et al.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer , 2013, Nature Genetics.

[2]  Michelle K. Lupton,et al.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. , 2012, Human molecular genetics.

[3]  N. Eriksson,et al.  Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases , 2012, PLoS genetics.

[4]  Nicholas R. Lemoine,et al.  SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update) , 2012, Nucleic Acids Res..

[5]  W. Chung,et al.  Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[6]  J. Marchini,et al.  Genotype Imputation with Thousands of Genomes , 2011, G3: Genes | Genomes | Genetics.

[7]  R. Vierkant,et al.  MicroRNA Processing and Binding Site Polymorphisms Are Not Replicated in the Ovarian Cancer Association Consortium , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[8]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[9]  C. Carlson,et al.  Principles for the post-GWAS functional characterization of cancer risk loci , 2011, Nature Genetics.

[10]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[11]  T. Noda,et al.  Rubicon and PLEKHM1 Negatively Regulate the Endocytic/Autophagic Pathway via a Novel Rab7-binding Domain , 2010, Molecular biology of the cell.

[12]  Dong Liang,et al.  Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. , 2010, Cancer research.

[13]  Mingming Jia,et al.  COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer , 2010, Nucleic Acids Res..

[14]  A. Whittemore,et al.  A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 , 2010, Nature Genetics.

[15]  A. Whittemore,et al.  Common variants at 19p13 are associated with susceptibility to ovarian cancer , 2010, Nature Genetics.

[16]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[17]  C. Harris,et al.  Genetic variation in microRNA networks: the implications for cancer research , 2010, Nature Reviews Cancer.

[18]  P. Morin,et al.  MicroRNAs in ovarian carcinomas. , 2010, Endocrine-related cancer.

[19]  Eden R Martin,et al.  Genome‐Wide Association Study Confirms SNPs in SNCA and the MAPT Region as Common Risk Factors for Parkinson Disease , 2010, Annals of human genetics.

[20]  W. Wong,et al.  A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. , 2009, Cancer cell.

[21]  A. Whittemore,et al.  A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 , 2009, Nature Genetics.

[22]  Brian D Athey,et al.  New class of microRNA targets containing simultaneous 5'-UTR and 3'-UTR interaction sites. , 2009, Genome research.

[23]  J. Chang-Claude,et al.  Role of genetic polymorphisms and ovarian cancer susceptibility , 2009, Molecular oncology.

[24]  Muin J. Khoury,et al.  Gene Prospector: An evidence gateway for evaluating potential susceptibility genes and interacting risk factors for human diseases , 2008, BMC Bioinformatics.

[25]  Praveen Sethupathy,et al.  MicroRNA target site polymorphisms and human disease. , 2008, Trends in genetics : TIG.

[26]  R. Tothill,et al.  Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome , 2008, Clinical Cancer Research.

[27]  John L Hopper,et al.  Multiple loci with different cancer specificities within the 8q24 gene desert. , 2008, Journal of the National Cancer Institute.

[28]  H. Shill,et al.  Haplotypes and gene expression implicate the MAPT region for Parkinson disease , 2008, Neurology.

[29]  Tian-Li Wang,et al.  MicroRNA Expression and Identification of Putative miRNA Targets in Ovarian Cancer , 2008, PloS one.

[30]  Anil K Sood,et al.  Early events in the pathogenesis of epithelial ovarian cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  E. Halperin,et al.  Estimating Local Ancestry in Admixed Populations , 2022 .

[32]  Huan Yang,et al.  MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. , 2008, Cancer research.

[33]  A. Dimmler,et al.  The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. , 2008, Cancer research.

[34]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[35]  J. Steitz,et al.  Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR , 2007, Proceedings of the National Academy of Sciences.

[36]  Héctor Peinado,et al.  Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? , 2007, Nature Reviews Cancer.

[37]  R. Pfundt,et al.  A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism , 2006, Nature Genetics.

[38]  G. Binetti,et al.  The H2 MAPT haplotype is associated with familial frontotemporal dementia , 2006, Neurobiology of Disease.

[39]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[40]  H. Stefánsson,et al.  A common inversion under selection in Europeans , 2005, Nature Genetics.

[41]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[42]  M. Katoh,et al.  Identification and characterization of ARHGAP27 gene in silico. , 2004, International journal of molecular medicine.

[43]  T. Tamaya,et al.  Clinical Implications of Expression of ETS-1 Related to Angiogenesis in Metastatic Lesions of Ovarian Cancers , 2004, Oncology.

[44]  M. Mattei,et al.  Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1 , 1992, Molecular and cellular biology.

[45]  B. Karlan,et al.  Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. , 2010, Gynecologic oncology.

[46]  C. Croce,et al.  MicroRNA signatures in human ovarian cancer. , 2007, Cancer research.