Grant Number:	5R01CA249867-03 Interpret this number
Primary Investigator:	Rabin, Karen
Organization:	Baylor College Of Medicine
Project Title:	Molecular Epidemiology of Acute Lymphoblastic Leukemia in Children with Down Syndrome
Fiscal Year:	2024

Modified Project Summary/Abstract Section Down syndrome (DS) is one of the strongest risk factors for acute lymphoblastic leukemia (ALL), conferring a 20-fold increased risk compared to children without DS. Survival for children with DS-ALL remains 10-20% lower than that of non-DS-ALL patients, due to both relapse and toxicity. Children with DS also have an increased risk of several birth defects and chronic health conditions. Although these increased risks have been known for decades, the basis for the increased risk of leukemia remains unclear, and there is a particular paucity of studies exploring the interplay between other DS phenotypic features and ALL susceptibility. While increased dosage of chromosome 21 genes is likely contributory to ALL risk, trisomy 21 alone is not sufficient, as the lifetime risk of ALL in children with DS is under 2%. We hypothesize that additional genetic modifiers and other DS-related phenotypes in combination with trisomy 21 influence susceptibility to ALL. We have made several important observations to date. 1) In the first genome-wide association study of DS-ALL, we observed that loci in ALL susceptibility genes (e.g., CDKN2A, IKZF1) have stronger effects on ALL risk in children with DS compared to those without. 2) We have preliminary evidence that children with DS-ALL have a greater burden of structural birth defects than children with DS without ALL, perhaps suggesting an ALL- predisposition phenotype with additional syndromic features. These observations suggest unique patterns of ALL susceptibility in the background of trisomy 21. However, we have not yet systematically evaluated: 1) the role of structural, rare, and chromosome 21 variants, 2) the association between inherited genetic variation and somatic genomic abnormalities, or 3) the role of other DS-related phenotypes on leukemia susceptibility and outcomes. Through the NIH INCLUDE and Kids First mechanisms, we and collaborators have initiated large- scale genomic sequencing of 2,500 children with DS (~400 with ALL). Capitalizing on this unprecedented genomic profiling and unique DS cohort, the objectives of the current study are to determine the molecular underpinnings of ALL in children with DS; and to determine whether DS-related phenotypes are associated with risk of ALL and/or with outcomes (toxicities, relapse, and survival). To achieve these objectives, the aims of this study are to 1) perform a comprehensive analysis of heritable variation associated with risk of ALL in children with DS, with a focus on structural, rare, and chromosome 21 variants; and 2) conduct deep phenotyping of children with DS-ALL to identify the impact of DS-related phenotypes on leukemia susceptibility and outcomes. This project will address fundamental questions of why children with DS have an increased risk of ALL, how their leukemia differs from that of children without DS, and how other DS-related phenotypes may influence ALL susceptibility, survival, and toxicities. Findings from this study may lead to improved genetic testing and counseling strategies for children with DS. Insights into genes driving DS-ALL may guide development of targeted therapies.




Genome-wide association studies of Down syndrome associated congenital heart defects.
Authors: Feldman E.R. , Li Y. , Cutler D.J. , Rosser T.C. , Wechsler S.B. , Sanclemente L. , Rachubinski A.L. , Elliott N. , Vyas P. , Roberts I. , et al. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2024-09-06 00:00:00.0; , .
EPub date: 2024-09-06 00:00:00.0.
PMID: 39281767
Related Citations

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.
Authors: Rabin K.R. , Devidas M. , Chen Z. , Ji L. , Kairalla J. , Hitzler J.K. , Yang J.J. , Carroll A.J. , Heerema N.A. , Borowitz M.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2024-01-10 00:00:00.0; 42(2), p. 218-227.
EPub date: 2023-10-27 00:00:00.0.
PMID: 37890117
Related Citations

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.
Authors: Lupo P.J. , Chambers T.M. , Mueller B.A. , Clavel J. , Dockerty J.D. , Doody D.R. , Erdmann F. , Ezzat S. , Filippini T. , Hansen J. , et al. .
Source: International Journal Of Cancer, 2023-09-11 00:00:00.0; , .
EPub date: 2023-09-11 00:00:00.0.
PMID: 37694915
Related Citations

Children's Oncology Group's 2023 blueprint for research: Epidemiology.
Authors: Lupo P.J. , Marcotte E.L. , Scheurer M.E. , Poynter J.N. , Spector L.G. , COG Epidemiology Committee .
Source: Pediatric Blood & Cancer, 2023-07-14 00:00:00.0; , p. e30566.
EPub date: 2023-07-14 00:00:00.0.
PMID: 37449937
Related Citations

Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia.
Authors: Li Z. , Chang T.C. , Junco J.J. , Devidas M. , Li Y. , Yang W. , Huang X. , Hedges D.J. , Cheng Z. , Shago M. , et al. .
Source: Blood, 2023-07-13 00:00:00.0; 142(2), p. 172-184.
PMID: 37001051
Related Citations

Epigenome-wide association study of acute lymphoblastic leukemia in children with Down syndrome.
Authors: Li S. , Sok P. , Xu K. , Muskens I.S. , Elliott N. , Myint S.S. , Pandey P. , Hansen H.M. , Morimoto L.M. , Kang A.Y. , et al. .
Source: Blood Advances, 2022-07-26 00:00:00.0; 6(14), p. 4132-4136.
PMID: 35588500
Related Citations

CRLF2 overexpression results in reduced B-cell differentiation and upregulated E2F signaling in the Dp16 mouse model of Down syndrome.
Authors: Junco J.J. , Zorman B. , Gant V.U. , Muñoz J. , Lacorazza H.D. , Sumazin P. , Rabin K.R. .
Source: Experimental Hematology, 2022-03-17 00:00:00.0; , .
EPub date: 2022-03-17 00:00:00.0.
PMID: 35306048
Related Citations

Prevalence of critical congenital heart defects and select co-occurring congenital anomalies, 2014-2018: A U.S. population-based study.
Authors: Stallings E.B. , Isenburg J.L. , Aggarwal D. , Lupo P.J. , Oster M.E. , Shephard H. , Liberman R.F. , Kirby R.S. , Nestoridi E. , Hansen B. , et al. .
Source: Birth Defects Research, 2022-01-19 00:00:00.0; , .
EPub date: 2022-01-19 00:00:00.0.
PMID: 35048540
Related Citations

Co-occurrence of congenital anomalies by maternal race/ethnicity among infants and fetuses with Down syndrome, 2013-2017: A U.S. population-based analysis.
Authors: Stallings E.B. , Isenburg J.L. , Heinke D. , Sherman S.L. , Kirby R.S. , Lupo P.J. , National Birth Defects Prevention Network .
Source: Birth Defects Research, 2021-12-23 00:00:00.0; , .
EPub date: 2021-12-23 00:00:00.0.
PMID: 34951159
Related Citations

An Mb1-Cre-driven oncogenic Kras mutation results in a mouse model of T-acute lymphoblastic leukemia/lymphoma with short latency and high penetrance.
Authors: Junco J.J. , Chen T. , Rashid R. , Terrell M. , Gant V.U. , Miller M. , Rau R. , Lacorazza H.D. , Rabin K.R. .
Source: Leukemia, 2021 Jun; 35(6), p. 1777-1781.
EPub date: 2020-09-11 00:00:00.0.
PMID: 32918044
Related Citations

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.
Authors: Muskens I.S. , Li S. , Jackson T. , Elliot N. , Hansen H.M. , Myint S.S. , Pandey P. , Schraw J.M. , Roy R. , Anguiano J. , et al. .
Source: Nature Communications, 2021-02-05 00:00:00.0; 12(1), p. 821.
EPub date: 2021-02-05 00:00:00.0.
PMID: 33547282
Related Citations

Prevalence of structural birth defects among infants with down syndrome, 2013-2017: A US population-based study.
Authors: Heinke D. , Isenburg J.L. , Stallings E.B. , Short T.D. , Le M. , Fisher S. , Shan X. , Kirby R.S. , Nguyen H.H. , Nestoridi E. , et al. .
Source: Birth Defects Research, 2020-12-21 00:00:00.0; , .
EPub date: 2020-12-21 00:00:00.0.
PMID: 33348463
Related Citations

The relationship between chronic health conditions and cognitive deficits in children, adolescents, and young adults with down syndrome: A systematic review.
Authors: Gandy K.C. , Castillo H.A. , Ouellette L. , Castillo J. , Lupo P.J. , Jacola L.M. , Rabin K.R. , Raghubar K.P. , Gramatges M.M. .
Source: Plos One, 2020; 15(9), p. e0239040.
EPub date: 2020-09-11 00:00:00.0.
PMID: 32915911
Related Citations