A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma

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

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)920-931
Number of pages12
JournalCancer Discovery
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2015

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Osteosarcoma
Genome
Neoplasm Metastasis
Cause of Death
Genome-Wide Association Study
Cell Movement
Single Nucleotide Polymorphism
Meta-Analysis
Alleles
Cell Proliferation
Confidence Intervals
Pediatrics
Bone and Bones

ASJC Scopus subject areas

  • Oncology

Cite this

Mirabello, L., Koster, R., Moriarity, B. S., Spector, L. G., Meltzer, P. S., Gary, J., ... Savage, S. A. (2015). A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma. Cancer Discovery, 5(9), 920-931. https://doi.org/10.1158/2159-8290.CD-15-0125

A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma. / 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.; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan; Serra, Massimo; Hattinger, Claudia; Picci, Piero; Scotlandi, Katia; Flanagan, Adrienne M.; Tirabosco, Roberto; Amary, Maria Fernanda; Halai, Dina; Ballinger, Mandy L.; Thomas, David M.; Davis, Sean; Barkauskas, Donald A.; Marina, Neyssa; Helman, Lee; Otto, George M.; Becklin, Kelsie L.; Wolf, Natalie K.; Weg, Madison T.; Tucker, Margaret; Wacholder, Sholom; Fraumeni, Joseph F.; Caporaso, Neil E.; Boland, Joseph F.; Hicks, Belynda D.; Vogt, Aurelie; Burdett, Laurie; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Savage, Sharon A.

In: Cancer Discovery, Vol. 5, No. 9, 01.09.2015, p. 920-931.

Research output: Contribution to journalArticle

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, SRC, Petrilli, AS, Patiño-Garcia, A, Sierrasesúmaga, L, Lecanda, F, Andrulis, IL, 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 2015, 'A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma', Cancer Discovery, vol. 5, no. 9, pp. 920-931. https://doi.org/10.1158/2159-8290.CD-15-0125
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. ; Patiño-Garcia, Ana ; Sierrasesúmaga, Luis ; Lecanda, Fernando ; Andrulis, Irene L. ; Wunder, Jay S. ; Gokgoz, Nalan ; Serra, Massimo ; Hattinger, Claudia ; Picci, Piero ; Scotlandi, Katia ; Flanagan, Adrienne M. ; Tirabosco, Roberto ; Amary, Maria Fernanda ; Halai, Dina ; Ballinger, Mandy L. ; Thomas, David M. ; Davis, Sean ; Barkauskas, Donald A. ; Marina, Neyssa ; Helman, Lee ; Otto, George M. ; Becklin, Kelsie L. ; Wolf, Natalie K. ; Weg, Madison T. ; Tucker, Margaret ; Wacholder, Sholom ; Fraumeni, Joseph F. ; Caporaso, Neil E. ; Boland, Joseph F. ; Hicks, Belynda D. ; Vogt, Aurelie ; Burdett, Laurie ; Yeager, Meredith ; Hoover, Robert N. ; Chanock, Stephen J. ; Savage, Sharon A. / A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma. In: Cancer Discovery. 2015 ; Vol. 5, No. 9. pp. 920-931.
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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.",
author = "Lisa Mirabello and Roelof Koster and Moriarity, {Branden S.} and Spector, {Logan G.} and Meltzer, {Paul S.} and Joy Gary and Machiela, {Mitchell J.} and Nathan Pankratz and Panagiotou, {Orestis A.} and David Largaespada and Zhaoming Wang and Gastier-Foster, {Julie M.} and Richard Gorlick and Chand Khanna and {de Toledo}, {Silvia Regina Caminada} and Petrilli, {Antonio S.} and Ana Pati{\~n}o-Garcia and Luis Sierrases{\'u}maga and Fernando Lecanda and Andrulis, {Irene L.} and Wunder, {Jay S.} and Nalan Gokgoz and Massimo Serra and Claudia Hattinger and Piero Picci and Katia Scotlandi and Flanagan, {Adrienne M.} and Roberto Tirabosco and Amary, {Maria Fernanda} and Dina Halai and Ballinger, {Mandy L.} and Thomas, {David M.} and Sean Davis and Barkauskas, {Donald A.} and Neyssa Marina and Lee Helman and Otto, {George M.} and Becklin, {Kelsie L.} and Wolf, {Natalie K.} and Weg, {Madison T.} and Margaret Tucker and Sholom Wacholder and Fraumeni, {Joseph F.} and Caporaso, {Neil E.} and Boland, {Joseph F.} and Hicks, {Belynda D.} and Aurelie Vogt and Laurie Burdett and Meredith Yeager and Hoover, {Robert N.} and Chanock, {Stephen J.} and Savage, {Sharon A.}",
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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.

PY - 2015/9/1

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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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