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

作者：Mirabello Lisa^*; Koster Roelof; Moriarity Branden S; Spector Logan G; Meltzer Paul S; Gary Joy; Machiela Mitchell J; Pankratz Nathan; Panagiotou Orestis A; Largaespada David; Wang Zhaoming; Gastier Foster Julie M; Gorlick Richard; Khanna Chand; de Toledo Silvia Regina Caminada; Petrilli Antonio S; Patino Garcia Ana; Sierrasesumaga Luis; Lecanda Fernando; Andrulis Irene L; Wunder Jay S; Gokgoz Nalan; Serra Massimo; Hattinger Claudia; Picci Piero; Scotlandi Katia

来源：Cancer Discovery, 2015, 5(9): 920-931.

DOI：10.1158/2159-8290.CD-15-0125

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 x 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.

• 出版日期2015-9
• 单位NIH; 河北医科大学