A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma
Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage 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 a 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=1.2x10-9, OR 2.43, 95% CI 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. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had 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.
|ISBN||2159-8290 (Electronic) 2159-8274 (Linking)|
|Authors||Mirabello, L.; Koster, R.; Moriarity, B. S.; Spector, L. G.; Meltzer, P. S.; Gary, J.; Machiela, M. J.; Pankratz, N.; Panagiotou, O. A.; Largaespada, D.; Wang, Z.; Gastier-Foster, J. M.; Gorlick, R.; Khanna, C.; Caminada de Toledo, S. R.; Petrilli, A. S.; Patino-Garcia, A.; Sierrasesumaga, L.; Lecanda, F.; Andrulis, I. L.; Wunder, J. S.; Gokgoz, N.; Serra, M.; Hattinger, C.; Picci, P.; Scotlandi, K.; Flanagan, A. M.; Tirabosco, R.; Fernanda Amary, M.; Halai, D.; Ballinger, M. L.; Thomas, D. M.;|
|Publisher Name||Cancer Discovery|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26084801|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13041|