Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome

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

doi:10.1182/blood.2018890764

Cited by 43 publications

(46 citation statements)

References 57 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally, in a recent GWAS of DS-ALL, low-frequency CDKN2A missense variant rs3731249 (Genome Aggregation Database [gnomAD] risk allele frequency 5 0.02), a known risk locus for non-DS ALL, 24 demonstrated a significantly higher risk allele frequency in DS-ALL (;8%) than non-DS ALL patients (;4%). 5 WES enabled assessment of this coding variant, revealing a high risk allele frequency (9.6%) in our independent set of 73 DS-ALL patients (supplemental Table 1). Among 46 patients with available CRLF2-rearrangement data, 19 (41.3%) were CRLF2-fusion positive, reflecting the higher proportion of CRLF2 rearrangement known to occur in DS-ALL than in non-DS ALL.…”

Section: Resultsmentioning

confidence: 97%

“…DS-ALL patient genotypes for the low-frequency CDKN2A missense variant rs3731249, which was filtered out in the analysis of rare variants, were assessed separately to confirm the recently reported high frequency of the ALL-associated risk allele in DS-ALL patients. 5 For all 73 patients, rs3731249 had total read depth .20, genotype quality .20, and average genotype quality .35. Alternate allelic ratio for heterozygous carriers of the rs3731249 risk allele ranged from 0.46 to 0.62.…”

Section: Assessment Of Cdkn2a Missense Variant Rs3731249mentioning

confidence: 99%

“…A recent genome-wide association study (GWAS) of DS-ALL confirmed that loci associated with ALL in non-DS children also contribute to risk of ALL in children with DS. 5 Furthermore, several common alleles conferred an increased ALL risk in children with DS relative to non-DS children, including an almost fourfold risk of DS-ALL for the CDKN2A missense variant rs3731249. However, the role of rare, highpenetrance germline variants in predisposition genes in DS-ALL etiology has yet to be examined.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we performed germline whole-exome sequencing (WES) to assess the frequency of rare and likely pathogenic germline variants in 73 DS-ALL patients in the International Study of Down Syndrome Acute Leukemia. 5…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Assessment Of Cdkn2a Missense Variant Rs3731249mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Neonatal DBS were obtained from MNB as part of a genome-wide association study of childhood leukemia risk in children with Down syndrome [18], which permits all original 425 genotyped samples from children born between 1992 and 2008 to be evaluated. Birth records at the Michigan Department of Health and Human Services were linked to the records in the Michigan Cancer Surveillance Program to identify individuals with Down syndrome with and without acute lymphoblastic leukemia in the Michigan Cancer Surveillance program.…”

Section: Methodsmentioning

confidence: 99%

Utilization of archived neonatal dried blood spots for genome-wide genotyping

et al. 2020

Self Cite

View full text Add to dashboard Cite

Introduction Heel pricks are performed on newborns for diagnostic screenings of various pre-symptomatic metabolic and genetic diseases. Excess blood is spotted on Guthrie cards and archived by many states in biobanks for follow-up diagnoses and public health research. However, storage environment may vary across biobanks and across time within biobanks. With increased applications of DNA extracted from spots for genetic studies, identifying factors associated with genotyping success is critical to maximize DNA quality for future studies. Method We evaluated 399 blood spots, which were part of a genome-wide association study of childhood leukemia risk in children with Down syndrome, archived at the Michigan Neonatal Biobank between 1992 and 2008. High quality DNA was defined as having post-quality control call rate � 99.0% based on the Illumina GenomeStudio 2.0 GenCall algorithm after processing the samples on the Illumina Infinium Global Screening Array. Bivariate analyses and multivariable logistic regression models were applied to evaluate effects of storage environment and storage duration on DNA genotyping quality. Results Both storage environment and duration were associated with sample genotyping call rates (p-values < 0.001). Sample call rates were associated with storage duration independent of storage environment (p-trend = 0.006 for DBS archived in an uncontrolled environment and p-trend = 0.002 in a controlled environment). However, 95% of the total sample had high genotyping quality with a call rate � 95.0%, a standard threshold for acceptable sample quality in many genetic studies. Conclusion Blood spot DNA quality was lower in samples archived in uncontrolled storage environments and for samples archived for longer durations. Still, regardless of storage environment or

show abstract

Management of Down Syndrome–Associated Leukemias

et al. 2023

Self Cite

View full text Add to dashboard Cite

ImportanceDown syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.ObservationsA recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS.Conclusions and RelevanceOptimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.

show abstract

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome

Abstract: The authors report the interaction between Down syndrome, a major genetic leukemia predisposition condition, and inherited genetic alleles associated with increased susceptibility to childhood acute lymphoblastic leukemia.

Cited by 43 publications

References 57 publications

Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

Utilization of archived neonatal dried blood spots for genome-wide genotyping

Management of Down Syndrome–Associated Leukemias

Contact Info

Product

Resources

About