A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.

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.

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

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