title: A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.
abstract: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10(-9); OR, 2.43; 95% confidence interval, 1.83-3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene.
  
  
  CONCLUSIONS
  Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland. mirabellol@mail.nih.gov.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
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authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
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authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
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mesh_terms: D000483:Alleles; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002899:Chromosomes, Human, Pair 9; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D016254:Mutagenesis, Insertional; D051839:NFI Transcription Factors / Q000235:genetics*; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D004251:DNA Transposable Elements; D051839:NFI Transcription Factors; C110754:NFIB protein, human