Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome

被引：45

作者：

Brown, Austin L. ^{[1
]}

de Smith, Adam J. ^{[2
,3
]}

Gant, Vincent U. ^{[1
]}

Yang, Wenjian ^{[4
]}

Scheurer, Michael E. ^{[1
]}

Walsh, Kyle M. ^{[5
]}

Chernus, Jonathan M. ^{[6
]}

Kallsen, Noah A. ^{[7
]}

Peyton, Shanna A. ^{[7
]}

Davies, Gareth E. ^{[7
]}

Ehli, Erik A. ^{[7
]}

Winick, Naomi ^{[8
]}

Heerema, Nyla A. ^{[9
]}

Carroll, Andrew J. ^{[10
]}

Borowitz, Michael J. ^{[11
,12
]}

Wood, Brent L. ^{[13
,14
]}

Carroll, William L. ^{[15
]}

Raetz, Elizabeth A. ^{[15
]}

Feingold, Eleanor ^{[6
]}

Devidas, Meenakshi ^{[16
]}

Barcellos, Lisa F. ^{[17
]}

Hansen, Helen M. ^{[18
]}

Morimoto, Libby ^{[17
]}

Kang, Alice Y. ^{[17
]}

Smirnov, Ivan ^{[18
]}

Healy, Jasmine ^{[19
]}

Laverdiere, Caroline ^{[19
]}

Sinnett, Daniel ^{[19
]}

Taub, Jeffrey W. ^{[20
]}

Birch, Jillian M. ^{[21
]}

Thompson, Pamela ^{[21
]}

Spector, Logan G. ^{[22
]}

Pombo-de-Oliveira, Maria S. ^{[23
]}

DeWan, Andrew T. ^{[24
]}

Mullighan, Charles G. ^{[25
]}

Hunger, Stephen P. ^{[26
,27
]}

Pui, Ching-Hon ^{[28
]}

Loh, Mignon L. ^{[29
]}

Zwick, Michael E. ^{[30
]}

Metayer, Catherine ^{[17
]}

Ma, Xiaomei ^{[24
]}

Mueller, Beth A. ^{[31
]}

Sherman, Stephanie L. ^{[30
]}

Wiemels, Joseph L. ^{[2
,3
]}

Relling, Mary V. ^{[4
]}

Yang, Jun J. ^{[4
]}

Lupo, Philip J. ^{[1
]}

Rabin, Karen R. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Pediat, Sect Hematol Oncol, Houston, TX 77030 USA

[2] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

[3] Univ Southern Calif, Ctr Genet Epidemiol, Los Angeles, CA USA

[4] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA

[5] Duke Univ, Div Neuroepidemiol, Dept Neurosurg, Durham, NC USA

[6] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[7] Avera Inst Human Genet, Sioux Falls, SD USA

[8] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

[9] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA

[10] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[11] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA

[12] Johns Hopkins Univ Hosp, Dept Oncol, Baltimore, MD 21287 USA

[13] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA

[14] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA

[15] NYU, Dept Pediat, Perlmutter Canc Ctr, New York, NY 10016 USA

[16] Univ Florida, Coll Med Publ Hlth & Hlth Profess, Dept Biostat, Gainesville, FL USA

[17] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA

[18] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[19] St Justine Univ, Hlth Ctr, Div Hematol Oncol, Montreal, PQ, Canada

[20] Wayne State Univ, Dept Oncol, Div Hematol Oncol, Detroit, MI USA

[21] Univ Manchester, Dept Paediat & Adolescent Oncol, Manchester, Lancs, England

[22] Univ Minnesota, Dept Pediat, Div Epidemiol & Clin Res, Minneapolis, MN 55455 USA

[23] Inst Nacl Canc, Pediat Hematol Oncol Program, Rio De Janeiro, Brazil

[24] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA

[25] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[26] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[27] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[28] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[29] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA USA

[30] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA

[31] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA

来源：

BLOOD | 2019年 / 134卷 / 15期

基金：

美国国家卫生研究院;

关键词：

BIRTH-DEFECTS; RISK; PREVALENCE; CHILDREN; JAK2; ASSOCIATION; VARIANTS; CRLF2; LYMPHOCYTE; MUTATIONS;

D O I：

10.1182/blood.2018890764

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in similar to 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 = 5.32 x 10(-15)), rs3731249 in CDKN2A (OR, 3.63; P-meta = 3.91 x 10(-10)), rs7090445 in ARID5B (OR, 1.60; P-meta 58.44 x 10(-9)), and rs3781093 in GATA3 (OR, 1.73; P-meta = 2.89 x 10(-8)). 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 = 4.1 x 10(-4)). This association was maintained 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.

引用

页码：1227 / 1237

页数：11

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