| Literature DB >> 26084801 |
Lisa Mirabello1, Roelof Koster2, Branden S Moriarity3, Logan G Spector4, Paul S Meltzer5, Joy Gary6, Mitchell J Machiela2, Nathan Pankratz7, Orestis A Panagiotou2, David Largaespada3, Zhaoming Wang8, Julie M Gastier-Foster9, Richard Gorlick10, Chand Khanna5, Silvia Regina Caminada de Toledo11, Antonio S Petrilli11, Ana Patiño-Garcia12, Luis Sierrasesúmaga12, Fernando Lecanda12, Irene L Andrulis13, Jay S Wunder13, Nalan Gokgoz13, Massimo Serra14, Claudia Hattinger14, Piero Picci14, Katia Scotlandi14, Adrienne M Flanagan15, Roberto Tirabosco16, Maria Fernanda Amary16, Dina Halai16, Mandy L Ballinger17, David M Thomas18, Sean Davis5, Donald A Barkauskas19, Neyssa Marina20, Lee Helman5, George M Otto21, Kelsie L Becklin22, Natalie K Wolf22, Madison T Weg21, Margaret Tucker2, Sholom Wacholder2, Joseph F Fraumeni2, Neil E Caporaso2, Joseph F Boland8, Belynda D Hicks8, Aurelie Vogt8, Laurie Burdett8, Meredith Yeager8, Robert N Hoover2, Stephen J Chanock2, Sharon A Savage2.
Abstract
UNLABELLED: 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. ©2015 American Association for Cancer Research.Entities:
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Year: 2015 PMID： 26084801 PMCID： PMC4560660 DOI： 10.1158/2159-8290.CD-15-0125
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397