Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

Austin L. Brown; Adam J. De Smith; Vincent U. Gant; Wenjian Yang; Michael E. Scheurer; Kyle M. Walsh; Jonathan M. Chernus; Noah A. Kallsen; Shanna A. Peyton; Gareth E. Davies; Erik A. Ehli; Naomi Winick; Nyla A. Heerema; Andrew J. Carroll; Michael J. Borowitz; Brent L. Wood; William L. Carroll; Elizabeth A. Raetz; Eleanor Feingold; Meenakshi Devidas; Lisa F. Barcellos; Helen M. Hansen; Libby Morimoto; Alice Y. Kang; Ivan Smirnov; Jasmine Healy; Caroline Laverdie`re; Daniel Sinnett; Jeffrey W. Taub; Jillian M. Birch; Pamela Thompson; Logan G. Spector; Maria S. Pombo-De-Oliveira; Andrew T. DeWan; Charles G. Mullighan; Stephen P. Hunger; Ching Hon Pui; Mignon L. Loh; Michael E. Zwick; Catherine Metayer; Xiaomei Ma; Beth A. Mueller; Stephanie L. Sherman; Joseph L. Wiemels; Mary V. Relling; Jun J. Yang; Philip J. Lupo; Karen R. Rabin

doi:10.1182/blood.2018890764

Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

Austin L. Brown, Adam J. De Smith, Vincent U. Gant, Wenjian Yang, Michael E. Scheurer, Kyle M. Walsh, Jonathan M. Chernus, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Naomi Winick, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Eleanor Feingold, Meenakshi DevidasLisa F. Barcellos, Helen M. Hansen, Libby Morimoto, Alice Y. Kang, Ivan Smirnov, Jasmine Healy, Caroline Laverdie`re, Daniel Sinnett, Jeffrey W. Taub, Jillian M. Birch, Pamela Thompson, Logan G. Spector, Maria S. Pombo-De-Oliveira, Andrew T. DeWan, Charles G. Mullighan, Stephen P. Hunger, Ching Hon Pui, Mignon L. Loh, Michael E. Zwick, Catherine Metayer, Xiaomei Ma, Beth A. Mueller, Stephanie L. Sherman, Joseph L. Wiemels, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin

School of Medicine

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; P_meta 5 5.32 × 10^-15), rs3731249 in CDKN2A (OR, 3.63; P_meta 5 3.91 × 10^-10), rs7090445 in ARID5B (OR, 1.60; P_meta 58.44 × 10^-9), and rs3781093 in GATA3 (OR, 1.73; P_meta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; P_meta 54.1 × 10^-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Original language	English (US)
Pages (from-to)	1227-1237
Number of pages	11
Journal	Blood
Volume	134
Issue number	15
DOIs	https://doi.org/10.1182/blood.2018890764
State	Published - Oct 10 2019

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2018890764

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Brown, A. L., De Smith, A. J., Gant, V. U., Yang, W., Scheurer, M. E., Walsh, K. M., Chernus, J. M., Kallsen, N. A., Peyton, S. A., Davies, G. E., Ehli, E. A., Winick, N., Heerema, N. A., Carroll, A. J., Borowitz, M. J., Wood, B. L., Carroll, W. L., Raetz, E. A., Feingold, E., ... Rabin, K. R. (2019). Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome. Blood, 134(15), 1227-1237. https://doi.org/10.1182/blood.2018890764

Brown, AL, De Smith, AJ, Gant, VU, Yang, W, Scheurer, ME, Walsh, KM, Chernus, JM, Kallsen, NA, Peyton, SA, Davies, GE, Ehli, EA, Winick, N, Heerema, NA, Carroll, AJ, Borowitz, MJ, Wood, BL, Carroll, WL, Raetz, EA, Feingold, E, Devidas, M, Barcellos, LF, Hansen, HM, Morimoto, L, Kang, AY, Smirnov, I, Healy, J, Laverdie`re, C, Sinnett, D, Taub, JW, Birch, JM, Thompson, P, Spector, LG, Pombo-De-Oliveira, MS, DeWan, AT, Mullighan, CG, Hunger, SP, Pui, CH, Loh, ML, Zwick, ME, Metayer, C, Ma, X, Mueller, BA, Sherman, SL, Wiemels, JL, Relling, MV, Yang, JJ, Lupo, PJ & Rabin, KR 2019, 'Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome', Blood, vol. 134, no. 15, pp. 1227-1237. https://doi.org/10.1182/blood.2018890764

@article{ec49d53ef25b42a8826d6bbe9144f5a9,

title = "Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome",

abstract = "Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta 5 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta 5 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta 58.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta 54.1 × 10-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.",

author = "Brown, {Austin L.} and {De Smith}, {Adam J.} and Gant, {Vincent U.} and Wenjian Yang and Scheurer, {Michael E.} and Walsh, {Kyle M.} and Chernus, {Jonathan M.} and Kallsen, {Noah A.} and Peyton, {Shanna A.} and Davies, {Gareth E.} and Ehli, {Erik A.} and Naomi Winick and Heerema, {Nyla A.} and Carroll, {Andrew J.} and Borowitz, {Michael J.} and Wood, {Brent L.} and Carroll, {William L.} and Raetz, {Elizabeth A.} and Eleanor Feingold and Meenakshi Devidas and Barcellos, {Lisa F.} and Hansen, {Helen M.} and Libby Morimoto and Kang, {Alice Y.} and Ivan Smirnov and Jasmine Healy and Caroline Laverdie`re and Daniel Sinnett and Taub, {Jeffrey W.} and Birch, {Jillian M.} and Pamela Thompson and Spector, {Logan G.} and Pombo-De-Oliveira, {Maria S.} and DeWan, {Andrew T.} and Mullighan, {Charles G.} and Hunger, {Stephen P.} and Pui, {Ching Hon} and Loh, {Mignon L.} and Zwick, {Michael E.} and Catherine Metayer and Xiaomei Ma and Mueller, {Beth A.} and Sherman, {Stephanie L.} and Wiemels, {Joseph L.} and Relling, {Mary V.} and Yang, {Jun J.} and Lupo, {Philip J.} and Rabin, {Karen R.}",

year = "2019",

month = oct,

day = "10",

doi = "10.1182/blood.2018890764",

language = "English (US)",

volume = "134",

pages = "1227--1237",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "15",

}

TY - JOUR

T1 - Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

AU - Brown, Austin L.

AU - De Smith, Adam J.

AU - Gant, Vincent U.

AU - Yang, Wenjian

AU - Scheurer, Michael E.

AU - Walsh, Kyle M.

AU - Chernus, Jonathan M.

AU - Kallsen, Noah A.

AU - Peyton, Shanna A.

AU - Davies, Gareth E.

AU - Ehli, Erik A.

AU - Winick, Naomi

AU - Heerema, Nyla A.

AU - Carroll, Andrew J.

AU - Borowitz, Michael J.

AU - Wood, Brent L.

AU - Carroll, William L.

AU - Raetz, Elizabeth A.

AU - Feingold, Eleanor

AU - Devidas, Meenakshi

AU - Barcellos, Lisa F.

AU - Hansen, Helen M.

AU - Morimoto, Libby

AU - Kang, Alice Y.

AU - Smirnov, Ivan

AU - Healy, Jasmine

AU - Laverdie`re, Caroline

AU - Sinnett, Daniel

AU - Taub, Jeffrey W.

AU - Birch, Jillian M.

AU - Thompson, Pamela

AU - Spector, Logan G.

AU - Pombo-De-Oliveira, Maria S.

AU - DeWan, Andrew T.

AU - Mullighan, Charles G.

AU - Hunger, Stephen P.

AU - Pui, Ching Hon

AU - Loh, Mignon L.

AU - Zwick, Michael E.

AU - Metayer, Catherine

AU - Ma, Xiaomei

AU - Mueller, Beth A.

AU - Sherman, Stephanie L.

AU - Wiemels, Joseph L.

AU - Relling, Mary V.

AU - Yang, Jun J.

AU - Lupo, Philip J.

AU - Rabin, Karen R.

PY - 2019/10/10

Y1 - 2019/10/10

N2 - Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta 5 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta 5 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta 58.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta 54.1 × 10-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

AB - Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta 5 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta 5 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta 58.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta 54.1 × 10-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

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U2 - 10.1182/blood.2018890764

DO - 10.1182/blood.2018890764

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AN - SCOPUS:85074443103

SN - 0006-4971

VL - 134

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EP - 1237

JO - Blood

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Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

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