TY - JOUR
T1 - A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma
AU - Mirabello, Lisa
AU - Koster, Roelof
AU - Moriarity, Branden S.
AU - Spector, Logan G.
AU - Meltzer, Paul S.
AU - Gary, Joy
AU - Machiela, Mitchell J.
AU - Pankratz, Nathan
AU - Panagiotou, Orestis A.
AU - Largaespada, David
AU - Wang, Zhaoming
AU - Gastier-Foster, Julie M.
AU - Gorlick, Richard
AU - Khanna, Chand
AU - de Toledo, Silvia Regina Caminada
AU - Petrilli, Antonio S.
AU - Patiño-Garcia, Ana
AU - Sierrasesúmaga, Luis
AU - Lecanda, Fernando
AU - Andrulis, Irene L.
AU - Wunder, Jay S.
AU - Gokgoz, Nalan
AU - Serra, Massimo
AU - Hattinger, Claudia
AU - Picci, Piero
AU - Scotlandi, Katia
AU - Flanagan, Adrienne M.
AU - Tirabosco, Roberto
AU - Amary, Maria Fernanda
AU - Halai, Dina
AU - Ballinger, Mandy L.
AU - Thomas, David M.
AU - Davis, Sean
AU - Barkauskas, Donald A.
AU - Marina, Neyssa
AU - Helman, Lee
AU - Otto, George M.
AU - Becklin, Kelsie L.
AU - Wolf, Natalie K.
AU - Weg, Madison T.
AU - Tucker, Margaret
AU - Wacholder, Sholom
AU - Fraumeni, Joseph F.
AU - Caporaso, Neil E.
AU - Boland, Joseph F.
AU - Hicks, Belynda D.
AU - Vogt, Aurelie
AU - Burdett, Laurie
AU - Yeager, Meredith
AU - Hoover, Robert N.
AU - Chanock, Stephen J.
AU - Savage, Sharon A.
N1 - Publisher Copyright:
© 2015 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-15-0125
DO - 10.1158/2159-8290.CD-15-0125
M3 - Article
C2 - 26084801
AN - SCOPUS:84941765323
SN - 2159-8274
VL - 5
SP - 920
EP - 931
JO - Cancer discovery
JF - Cancer discovery
IS - 9
ER -