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

About this Publication
Title
A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.
Pubmed ID
26084801 (View this publication on the PubMed website)
Publication
Cancer Discov. 2015 Sep; Volume 5 (Issue 9): Pages 920-31
Authors
Mirabello L, Koster R, Moriarity BS, Spector LG, Meltzer PS, Gary J, Machiela MJ, Pankratz N, Panagiotou OA, Largaespada D, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, de Toledo SR, Petrilli AS, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Andrulis IL, ...show more Wunder JS, Gokgoz N, Serra M, Hattinger C, Picci P, Scotlandi K, Flanagan AM, Tirabosco R, Amary MF, Halai D, Ballinger ML, Thomas DM, Davis S, Barkauskas DA, Marina N, Helman L, Otto GM, Becklin KL, Wolf NK, Weg MT, Tucker M, Wacholder S, Fraumeni JF, Caporaso NE, Boland JF, Hicks BD, Vogt A, Burdett L, Yeager M, Hoover RN, Chanock SJ, Savage SA
Affiliations
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland. mirabellol@mail.nih.gov.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
  • Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
  • Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
  • Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  • Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, Maryland; College of Veterinary Medicine, Michigan State University, East Lansing, Michigan.
  • Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
  • Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • Nationwide Children's Hospital, and The Ohio State University Department of Pathology and Pediatrics, Columbus, Ohio.
  • Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, New York.
...show more
  • Pediatric Oncology Institute, GRAACC/UNIFESP, São Paulo SP, Brazil.
  • Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain.
  • University of Toronto, Litwin Centre for Cancer Genetics, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
  • University College London Cancer Institute, London, United Kingdom. Royal National Orthopaedic Hospital National Health Service Trust, Stanmore, Middlesex, United Kingdom.
  • Royal National Orthopaedic Hospital National Health Service Trust, Stanmore, Middlesex, United Kingdom.
  • Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
  • The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.
  • Stanford University and Lucile Packard Children's Hospital, Palo Alto, California.
  • Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
  • Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota.
Abstract

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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