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Suspicions regarding the genetic inheritance of acute lymphoblastic leukemia in patients with down syndrome.

ABSTRACT: Children with Down syndrome (DS) are at markedly increased risk for acute lymphoblastic leukaemia (ALL). DS is caused by trisomy of chromosome 21 affecting approximately 1 in 732 newborns in the USA. ALL is the most common cancer in children and constitutes approximately 25% of cancer diagnoses among children under the age of 15. Different protocols for treatment and management of paediatric ALL are available; however, DS children with ALL (DS-ALL) have increased risk of therapy-related toxicity compared to those without DS. Herein, we summarize the available literature on inherited predisposition for ALL, and possibilities for molecular therapy and treatment for DS-ALL patients.

SUBMITTER: Behluli E

PROVIDER: S-EPMC10032328 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Suspicions regarding the genetic inheritance of acute lymphoblastic leukemia in patients with down syndrome.

Behluli Emir E Nuhii Nexhibe N Liehr Thomas T Temaj Gazmend G

Journal of mother and child 20220301 1

Children with Down syndrome (DS) are at markedly increased risk for acute lymphoblastic leukaemia (ALL). DS is caused by trisomy of chromosome 21 affecting approximately 1 in 732 newborns in the USA. ALL is the most common cancer in children and constitutes approximately 25% of cancer diagnoses among children under the age of 15. Different protocols for treatment and management of paediatric ALL are available; however, DS children with ALL (DS-ALL) have increased risk of therapy-related toxicity ...[more]

PMID: 35853737

Similar Datasets

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Project description: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 = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 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; Pmeta = 4.1 × 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.

| S-EPMC6788009 | biostudies-literature

Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia.

Project description:Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared with 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. A total of 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutations or insertions/deletions, compared with 4.1% in other subtypes. CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, recombination-activating gene-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared with 7.7% in non-DS-ALL. Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival, even after adjusting for known clinical risk factors. These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

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Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome.

Project description:Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.

| S-EPMC6778645 | biostudies-literature

Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries.

Project description:BackgroundChildren with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL.MethodsTo address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period.ResultsAll 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P?=?0.026 and P?=?0.003, respectively) worse for DS-ALL patients with white blood cell counts ?50 × 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P?=?0.029). The platelet counts were lower in the DS-ALL group (P?=?0.005). Abnormal karyotypes were more common in non-DS-ALL (P?<?0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P?<?0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P?<?0.001).ConclusionsThe present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.

| S-EPMC4022076 | biostudies-literature

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2011-07-12 | GSE21094 | GEO

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