A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma

Lisa Mirabello, Roelof Koster, Branden S. Moriarity, Logan G. Spector, Paul S. Meltzer, Joy Gary, Mitchell J. Machiela, Nathan Pankratz, Orestis A. Panagiotou, David Largaespada, Zhaoming Wang, Julie M. Gastier-Foster, Richard Gorlick, Chand Khanna, Silvia Regina Caminada de Toledo, Antonio S. Petrilli, Ana Patiño-Garcia, Luis Sierrasesúmaga, Fernando Lecanda, Irene L. AndrulisJay S. Wunder, Nalan Gokgoz, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, Adrienne M. Flanagan, Roberto Tirabosco, Maria Fernanda Amary, Dina Halai, Mandy L. Ballinger, David M. Thomas, Sean Davis, Donald A. Barkauskas, Neyssa Marina, Lee Helman, George M. Otto, Kelsie L. Becklin, Natalie K. Wolf, Madison T. Weg, Margaret Tucker, Sholom Wacholder, Joseph F. Fraumeni, Neil E. Caporaso, Joseph F. Boland, Belynda D. Hicks, Aurelie Vogt, Laurie Burdett, Meredith Yeager, Robert N. Hoover, Stephen J. Chanock, Sharon A. Savage

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)920-931
Number of pages12
JournalCancer discovery
Issue number9
StatePublished - Sep 1 2015

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© 2015 by the authors; licensee MDPI, Basel, Switzerland.


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