Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6

Järviaho, Tekla; Bang, Benedicte; Zachariadis, Vasilios; Taylan, Fulya; Moilanen, Jukka S.; Möttönen, Merja; Smith, C. I. Edvard; Harila‐Saari, Arja; Niinimäki, Riitta; Nordgren, Ann

doi:10.1182/bloodadvances.2018028795

Cited by 12 publications

(10 citation statements)

References 63 publications

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“…[13][14][15] Additional studies have recently identified familial leukemia cases with inherited structural alterations in the ETV6 gene, further highlighting the role of this gene in ALL predisposition. 16,17 To explore the contribution of germline variation in ETV6 more broadly in childhood ALL, we subsequently sequenced 4405 childhood B-ALL cases and identified potential leukemia-related variants in ;1% of patients. 18 Of these, nearly half were located in the essential DNA-binding domain, including 9 variants predicted to be most deleterious by the combined annotationdependent depletion scores.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia

Nishii¹,

Baskin-Doerfler

Yang³

et al. 2021

Blood

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There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with WT ETV6 with potentially dominate negative effects. Whole transcriptome and whole genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both AML and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by ATAC-seq profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia

Nishii¹,

Baskin-Doerfler

Yang³

et al. 2021

Blood

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“…CNV analysis revealed that a significant proportion of PID-related genes were altered across the four pediatric cancer cohorts examined. Deep deletion of ETV6 , a transcription-regulating gene, has been previously implicated in leukemias and may play a role in oncogenesis, treatment response, and outcome in pediatric ALL patients [ 44 , 45 , 46 , 47 ]. Furthermore, the analysis identified CNVs in the ribosomal protein (RP) gene family, specifically RPS15 , with relation to deep deletion in pediatric ALL and AML.…”

Section: Discussionmentioning

confidence: 99%

Identification of Altered Primary Immunodeficiency-Associated Genes and Their Implications in Pediatric Cancers

Standing

Tran

Murguía-Favela

et al. 2022

Cancers

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Background: Cancer is the leading cause of disease-related mortality in children and malignancies are more frequently observed in individuals with primary immunodeficiencies (PIDs). This study aimed to identify and highlight the molecular mechanisms, such as oncogenesis and immune evasion, by which PID-related genes may lead to the development of pediatric cancers. Method: We implemented a novel bioinformatics framework using patient data from the TARGET database and performed a comparative transcriptome analysis of PID-related genes in pediatric cancers between normal and cancer tissues, gene ontology enrichment, and protein–protein interaction analyses, and determined the prognostic impacts of commonly mutated and differentially expressed PID-related genes. Results: From the Fulgent Genetics Comprehensive Primary Immunodeficiency panel of 472 PID-related genes, 89 genes were significantly differentially expressed between normal and cancer tissues, and 20 genes were mutated in two or more patients. Enrichment analysis highlighted many immune system processes as well as additional pathways in the mutated PID-related genes related to oncogenesis. Survival outcomes for patients with altered PID-related genes were significantly different for 75 of the 89 DEGs, often resulting in a poorer prognosis. Conclusions: Overall, multiple PID-related genes demonstrated the connection between PIDs and cancer development and should be studied further, with hopes of identifying new therapeutic targets.

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“…Moreover, a focal germline ETV6 splice site deletion resulting in exon skipping and protein truncation has been reported in a highly penetrant family (Rampersaud et al 2019). Another report identified a constitutional translocation disrupting ETV6 (Jarviaho et al 2019). These studies indicate that careful analysis of germline structural variants is required to describe the full repertoire of deleterious germline alterations in ALL.…”

Section: Inherited Variants In Allmentioning

confidence: 98%

The Biology of B-Progenitor Acute Lymphoblastic Leukemia

Roberts

Mullighan

2019

Cold Spring Harb Perspect Med

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Genomic analyses have revolutionized our understanding of the biology of B-progenitor acute lymphoblastic leukemia (ALL). Studies of thousands of cases across the age spectrum have revised the taxonomy of BALL by identifying multiple new subgroups with diverse sequence and structural initiating events that vary substantially by age at diagnosis and prognostic significance. There is a growing appreciation of the role of inherited genetic variation in predisposition to ALL and drug responsiveness and of the nature of genetic variegation and clonal evolution that may be targeted for improved diagnostic, risk stratification, disease monitoring, and therapeutic intervention. This review provides an overview of the current state of knowledge of the genetic basis of BALL , with an emphasis on recent discoveries that have changed our approach to diagnosis and monitoring.

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Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6

Abstract: Key PointsWe report the first known family with a constitutional translocation disrupting ETV6 predisposing to ALL. Germline monoallelic expression of ETV6 contributes to leukemia predisposition without thrombocytopenia.

Cited by 12 publications

References 63 publications

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia

Identification of Altered Primary Immunodeficiency-Associated Genes and Their Implications in Pediatric Cancers

The Biology of B-Progenitor Acute Lymphoblastic Leukemia

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