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Genetics of Childhood Acute Lymphoblastic Leukemia

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 12387

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Dr. Luca Lo Nigro

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Center of Pediatric Hematology-Oncology, Azienda Policlinico–San Marco, 95123 Catania, Italy
Interests: acute lymphoblastic leukemia; acute myeloid leukemia; biomarkers; new targets of disease; novel immunotherapy; leukemia stem cell
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Dear Colleagues,

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Despite the high cure rate, we need to better characterize the biological subgroup in order to design the most active and least toxic treatment.

As a consequence of the breakthroughs in genotyping and next-generation sequencing technologies, researchers have been able to identify novel and recurrent ALL cancer genetic abnormalities, to improve treatment strategies and have a better understanding of the disease and its heterogeneity. For this latter purpose, research is currently expanding on leukemic predisposition genes.

In this Special Issue of Genes, we extend an invitation for reviews on the genetic basis childhood acute lymphoblastic leukemia; as well as original research articles that focus on the discovery of genetic variations or mutations that could be used to distinguish clinically-relevant disease or predict therapeutic efficacies and outcomes or indicate a genetic predisposition for a disease.

Dr. Luca Lo Nigro
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

acute lymphoblastic leukemia
ALL
children
genetic abnormalities
prognostic markers

Published Papers (3 papers)

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17 pages, 901 KiB

Open AccessArticle

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

by Nikola Kotur, Jelena Lazic, Bojan Ristivojevic, Biljana Stankovic, Vladimir Gasic, Lidija Dokmanovic, Nada Krstovski, Goran Milosevic, Dragana Janic, Branka Zukic and Sonja Pavlovic

Genes 2020, 11(4), 468; https://doi.org/10.3390/genes11040468 - 24 Apr 2020

Cited by 18 | Viewed by 4425

Abstract

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients. Full article

(This article belongs to the Special Issue Genetics of Childhood Acute Lymphoblastic Leukemia)

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18 pages, 1953 KiB

Open AccessArticle

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia

by Diego Alberto Bárcenas-López, Juan Carlos Núñez-Enríquez, Alfredo Hidalgo-Miranda, Fredy Omar Beltrán-Anaya, Didier Ismael May-Hau, Elva Jiménez-Hernández, Vilma Carolina Bekker-Méndez, Janet Flores-Lujano, Aurora Medina-Sansón, Edna Liliana Tamez-Gómez, Víctor Hugo López-García, José Ramón Lara-Ramos, Nora Nancy Núñez-Villegas, José Gabriel Peñaloza-González, Luz Victoria Flores-Villegas, Raquel Amador-Sánchez, Rosa Martha Espinosa-Elizondo, Jorge Alfonso Martín-Trejo, Martha Margarita Velázquez-Aviña, Laura Elizabeth Merino-Pasaye, María Luisa Pérez-Saldívar, David Aldebarán Duarte-Rodríguez, José Refugio Torres-Nava, Beatriz Cortés-Herrera, Karina Anastacia Solís-Labastida, Ana Itamar González-Ávila, Jessica Denisse Santillán-Juárez, Alejandra Jimena García-Velázquez, Haydee Rosas-Vargas, Minerva Mata-Rocha, Omar Alejandro Sepúlveda-Robles, Juan Manuel Mejía-Aranguré and Silvia Jiménez-Morales Show full author list Hide full author list

Genes 2020, 11(3), 302; https://doi.org/10.3390/genes11030302 - 13 Mar 2020

Cited by 18 | Viewed by 4015

Abstract

Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46–11.86) and HR: 1.99 (95% CI: 0.66–6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14–8.05) and HR: 6.87 (95% CI: 1.50–31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA–mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl–tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL. Full article

(This article belongs to the Special Issue Genetics of Childhood Acute Lymphoblastic Leukemia)

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20 pages, 2995 KiB

Open AccessArticle

Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS)

by Veronica Tisato, Paola Muggeo, Tracy Lupiano, Giovanna Longo, Maria Luisa Serino, Massimo Grassi, Ermanno Arcamone, Paola Secchiero, Giorgio Zauli, Nicola Santoro and Donato Gemmati

Genes 2019, 10(9), 634; https://doi.org/10.3390/genes10090634 - 22 Aug 2019

Cited by 11 | Viewed by 3541

Abstract

Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1–8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency. Full article

(This article belongs to the Special Issue Genetics of Childhood Acute Lymphoblastic Leukemia)

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