<i>TP53, ETV6</i> and <i>RUNX1</i> germline variants in a case series of patients developing secondary neoplasms after treatment for childhood acute lymphoblastic leukemia

Junk, Stefanie V.; Klein, Norman W.; Schreek, Sabine; Zimmermann, Martin; Möricke, Anja; Bleckmann, Kirsten; Alten, Julia; Dağdan, Elif; Cario, Gunnar; Kratz, Christian P.; Schrappe, Martin; Stanulla, Martin

doi:10.3324/haematol.2018.205849

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…A recent germline analysis of SMN cases after pediatric ALL treatment revealed that the relative prevalence of germline pathogenic variants was not high. 30 In our study, mutations in LZTR1 , which have been shown to be associated with B-cell ALL in recent studies, were identified in only one case. 7 For children with ALL, variants of thiopurine-metabolizing genes such as TMPT and NUDT15 might be the most potent and frequent germline determinants of the risk of developing SMNs.…”

Section: Discussionmentioning

confidence: 43%

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

et al. 2021

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The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

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Section: Discussionmentioning

confidence: 43%

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

et al. 2021

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“…Moreover, the enriched KEGG pathway was found to be involved in leukemia (hsa05221 and hsa05220) and cancer‐related pathways (hsa05200, hsa05202, and hsa05230), which was consistent with findings from other previous studies on the pathogenesis of leukemia (McClure et al., 2018; de Noronha, Mitne‐Neto, & Chauffaille, 2017). Seven key genes ( CEBPA , FLT3 , PAX5 , PAX8 , RUNX1 , TP53 , and WT1 ) were obtained from PPIs network, most of which were reported to play a critical role in carcinogenesis and tumor progression (Junk et al., 2019; Rhodes, Vallikkannu, & Jayalakshmi, 2017; Slattery, Herrick, & Mullany, 2017).…”

Section: Discussionmentioning

confidence: 99%

Spectrum of gene mutations identified by targeted next‐generation sequencing in Chinese leukemia patients

Yao

Chen

et al. 2020

Molec Gen & Gen Med

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Background Despite targeted sequencing have identified several mutations for leukemia, there is still a limit of mutation screening for Chinese leukemia. Here, we used targeted next‐generation sequencing for testing the mutation patterns of Chinese leukemia patients. Methods We performed targeted sequencing of 504 tumor‐related genes in 109 leukemia samples to identify single‐nucleotide variants (SNVs) and insertions and deletions (INDELs). Pathogenic variants were assessed based on the American College of Medical Genetics and Genomics (ACMG) guidelines. The functional impact of pathogenic genes was explored through gene ontology (GO), pathway analysis, and protein–protein interaction network in silico. Results We identified a total of 4,655 SNVs and 614 INDELs in 419 genes, in which PDE4DIP, NOTCH2, FANCA, BCR, and ROS1 emerged as the highly mutated genes. Of note, we were the first to demonstrate an association of PDE4DIP mutation and leukemia. Based on ACMG guidelines, 39 pathogenic and likely pathogenic mutations in 27 genes were found. GO annotation showed that the biological process including gland development, leukocyte differentiation, respiratory system development, myeloid leukocyte differentiation, mesenchymal to epithelial transition, and so on were involved. Conclusion Our study provided a map of gene mutations in Chinese patients with leukemia and gave insights into the molecular pathogenesis of leukemia.

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“…[26][27][28][29]31,32 In addition, 38 sporadic cases of ALL (35 confirmed BCP subtype) with rare germline pathogenic variants in ETV6 have been described. 28,54 A majority had a HeH karyotype (80%), older age at diagnosis (13.3 vs 6.8 years without risk variants) and leukocyte counts ,50 3 10 9 /L at diagnosis. 28,33 These findings are consistent with the present study, in which 2 individuals developed HeH BCP-ALL at age 8 and 12 years, respectively, with leukocyte counts at diagnosis far below 50 3 10 9 /L.…”

Section: Discussionmentioning

confidence: 99%

“…Solid tumors have also been reported in families carrying pathogenic germline variants in ETV6. 27,29,32,54 In addition, secondary malignancies, both hematological and solid, have been reported in childhood ALL cases with germline variants in ETV6. 31,54 Even so, there is not yet compelling evidence regarding ETV6 germline predisposition to solid tumors, 59 but further investigation is needed.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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TP53, ETV6 and RUNX1 germline variants in a case series of patients developing secondary neoplasms after treatment for childhood acute lymphoblastic leukemia

Cited by 6 publications

References 16 publications

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

Spectrum of gene mutations identified by targeted next‐generation sequencing in Chinese leukemia patients

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

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