A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma
| Autor: | Robert N. Hoover, Joy Gary, Paul S. Meltzer, Neyssa Marina, Lisa Mirabello, Irene L. Andrulis, Natalie K. Wolf, Silvia Regina Caminada de Toledo, David Thomas, Mandy L. Ballinger, Sholom Wacholder, Piero Picci, Nathan Pankratz, Meredith Yeager, Sharon A. Savage, Margaret A. Tucker, Stephen J. Chanock, Ana Patiño-García, Massimo Serra, Jay S. Wunder, Richard Gorlick, David A. Largaespada, Lee J. Helman, Nalan Gokgoz, Chand Khanna, Joseph F. Fraumeni, Donald A. Barkauskas, Julie M. Gastier-Foster, Katia Scotlandi, Maria Fernanda Amary, Claudia Maria Hattinger, Branden S. Moriarity, Logan G. Spector, Belynda Hicks, Madison T. Weg, Fernando Lecanda, Kelsie L. Becklin, Roelof Koster, Orestis A. Panagiotou, Neil E. Caporaso, George Maxwell Otto, Mitchell J. Machiela, Aurelie Vogt, Joseph Boland, Luis Sierrasesúmaga, Laurie Burdett, Adrienne M. Flanagan, Roberto Tirabosco, Zhaoming Wang, Dina Halai, Antonio Sergio Petrilli, Sean Davis |
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| Rok vydání: | 2015 |
| Předmět: |
musculoskeletal diseases
Genotype Genetic Linkage Quantitative Trait Loci Bone Neoplasms Genome-wide association study Biology Malignancy Polymorphism Single Nucleotide Article Linkage Disequilibrium Germline Metastasis Mice Cell Movement Cell Line Tumor medicine Animals Humans Genetic Predisposition to Disease Neoplasm Metastasis Allele neoplasms Alleles Genetic Association Studies Cell Proliferation Osteosarcoma Genetic Variation medicine.disease Gene Expression Regulation Neoplastic Disease Models Animal Mutagenesis Insertional NFI Transcription Factors Oncology NFIB DNA Transposable Elements Cancer research Chromosomes Human Pair 9 Genome-Wide Association Study Genetic screen |
| Zdroj: | Cancer Discovery. 5:920-931 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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. Significance: 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. Cancer Discov; 5(9); 920–31. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 893 |
| Databáze: | OpenAIRE |
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