Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia

Abstract Introduction: Thromboembolism (TE) is a major toxicity of acute lymphoblastic leukemia (ALL) treatment and contributes to substantial morbidity and mortality. Several germline DNA variants have been associated with TE in adults without cancer. A meta-analysis of genome-wide association studies on TE by Germain et al. (Am J Hum Genet 2015) identified single nucleotide polymorphisms (SNPs) in 8 genes that contribute to increased risk of TE in adults (ABO,F2, F5,F11, FGG,PROCR,TSPAN15, and SLC44A2). De Haan et al. (Blood 2012) found that SNPs in 5 of these (F5, F2, F11, FGG, and ABO) predicted TE almost as well as a 31 SNP-based risk score. However, the impact of these SNPs in patients with cancer, particularly in children, remains uncertain. Materials and methods: The Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol for children and adults (1-45 years) included a 3-drug induction (vincristine, doxorubicin, glucocorticosteroid) followed by exposure to asparaginase (1,000 IU/m.sq. i.m.) from week 5 until week 33 (details of therapy in Toft, Leukemia 2018). We collected germline DNA and prospectively registered TE events on 1482 children and adults diagnosed with ALL and treated according to the ALL2008 protocol in seven Nordic and Baltic countries (7/2008-7/2016) (Rank, Blood 2018). Inclusion criteria for TE were i) symptomatic venous or arterial TE confirmed by imaging or by autopsy for TE diagnosed post mortem or ii) asymptomatic TE confirmed by imaging due to other non-TE symptoms and treated with systemic anticoagulation. Based on previously published data and a priori power calculations, we selected and genotyped 5 SNPs: F5 rs6025 (risk allele frequency (RAF) 0.05), F11 rs2036914 (RAF 0.52), FGG rs2066865 (RAF 0.22), and ABO SNPs rs8176719 (RAF 0.39) and rs2519093 (RAF 0.24). Three SNPs (F5 and the two ABO SNPs) were found by imputation, which was done on a subset of patients with European ancestry and included in the NOPHO ALL2008 protocol (N = 1229). We constructed genetic risk scores using a combination of the SNPs. Results: During the ALL treatment period 107 of 1482 patients developed TE (2.5-year cumulative incidence 7.3%, 95% confidence interval (CI) 5.9-8.5). In multivariate Cox regression analysis controlling for age, gender, presence of mediastinal mass and enlarged lymph nodes (N = 1192, whereof TE events 84), we found statistically significant associations with TE development for SNPs F5 rs6025 (hazard ratio (HR) 2.96, 95% CI 1.59-5.48), F11 rs2036914 (HR 1.62, 95% CI 1.18-2.24), and FGG rs2066865 (HR 1.40 95% CI 1.01-1.95), whereas there were no significant associations with ABO SNPs rs8176719 (HR 0.98, 95% CI 0.64-1.51) or rs2519093 (HR 1.06, 95% CI 0.65-1.73). An unweighted 3 SNP risk score based on SNPs F5, F11, and FGG was associated with TE development (HR 1.59, 95% CI 1.27-1.98) (Figure 1). Twenty-six of 217 patients with ≥3 risk alleles developed TE (12.0%, 95% CI 8.1-17.2), compared to 62 of 1007 patients with <3 risk alleles (6.2%, 95% CI 4.8-7.9). The association was strongest in the adolescent age group (10-18 years; HR 1.88, 95% CI 1.35-2.63). Thirteen of 43 adolescents with ≥3 risk alleles developed TE (30.2%, 95% CI 17.8-46.3), compared to 20 of 182 adolescents with <3 risk alleles (11.0%, 95% CI 7.0-16.7) (Figure 2). In adults (>18 years) the proportion who developed TE was quite high in both the group with ≥3 risk alleles (23.5%, 95% CI 7.8-50.2) and with <3 risk alleles (17.6% 95%CI 11.1-26.3). In children (1-10 years) the proportion who developed TE was low in both the group with ≥3 risk alleles (5.7%, 95% CI 2.8-10.9) and with <3 risk alleles (3.2%, 95% CI 2.1-4.8). A weighted 3 SNP genetic risk score based on estimated odds ratios from literature for SNPs F5, F11 and FGG was also associated with TE development (HR 2.84, 95% CI 1.85-4.36). Again, the association was strongest in adolescents (HR 4.20, 95% CI 2.22-7.94). Conclusion: Based on the strong association between F5 rs6025, F11 rs2036914, and FGG rs2066865 and TE development, not least for adolescents, future preventive measures for TE should target adolescents with ≥3 risk alleles as well as any adults ≥18 years. Disclosures No relevant conflicts of interest to declare.

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Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival and Drug Toxicity

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-1555 ◽

2009 ◽

Vol 16 (1) ◽

pp. 320-329 ◽

Cited By ~ 70

Author(s):

T. Okazaki ◽

M. Javle ◽

M. Tanaka ◽

J. L. Abbruzzese ◽

D. Li

Keyword(s):

Pancreatic Cancer ◽

Single Nucleotide Polymorphisms ◽

Drug Toxicity ◽

Cancer Survival ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Metabolic Genes

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Involvement of single nucleotide polymorphisms in acute lymphoblastic leukemia susceptibility

Gene Reports ◽

10.1016/j.genrep.2020.100971 ◽

2020 ◽

Vol 21 ◽

pp. 100971

Author(s):

Behnaz Hamzei ◽

Toktam Sheidaeian ◽

Neghar Bahadorzehi ◽

Parvin Sheibani ◽

Marzie Akbari ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Single Nucleotide Polymorphisms ◽

Lymphoblastic Leukemia ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Single Nucleotide Polymorphisms of DNA Synthetic and Repair Enzymes and Risk of Childhood Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v104.11.4447.4447 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4447-4447

Author(s):

Samart Pakakasama ◽

Thanasan Sirirat ◽

Saowanee Kajanachumpol ◽

Ampaiwan Chaunsumrit ◽

Suradej Hongeng

Keyword(s):

Dna Repair ◽

Acute Lymphoblastic Leukemia ◽

Single Nucleotide Polymorphisms ◽

Lymphoblastic Leukemia ◽

Metabolic Enzymes ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Dna Repair Enzymes ◽

Childhood All ◽

Repair Enzymes

Abstract Although the outcome of children with acute lymphoblastic leukemia (ALL) has been improving, the origin of this disease is still unknown. It is likely that individual genetic susceptibility and environmental exposure play a role in carcinogenesis. To maintain normal hematopoiesis, DNA synthesis and repair systems need to be intact. Folate metabolism, producing purines and pyrimidines, is the source of nucleotides while base excision and nucleotide excision repair enzymes, i.e. XRCC1 and XPD, have important roles in protection of DNA damage. Single nucleotide polymorphisms (SNPs) of enzymes involving these processes alter their enzymatic structures and functions. We hypothesized that SNPs of folate metabolic enzymes including methylenetetrahydrofolate reductase (MTHFR 677 C>T; 1298 A>C), methionine synthase (MS 2756 A>G), and tandem repeats of thymidylate synthase (TS 2R or 3R) and of DNA repair enzymes (XRCC1 26304 C>T; 27466 G>A; 28152 G>A and XPD 23591 G>A; 35931 A>C) could effect the risk of ALL in children. We performed genotyping of these SNPs in 108 ALL and 317 normal controls by using PCR RFLP method. Genotype frequencies of folate metabolic enzymes SNPs were not different between cases and controls. However, TS 2R allele showed a trend to decrease risk of ALL (OR=0.66; 95% CI 0.41–1.07). We observed a 4.5 fold reduction in the risk of ALL in individuals with the XRCC1 26304 TT genotype (OR=0.22; 95% CI 0.5–0.96). XRCC1 26304 T allele showed a protective effect to this disease (OR=0.67; 95% CI 0.47–0.97). In contrast, individuals with XRCC1 28152 A allele had an increased risk of ALL (OR=1.67; 95% CI 1.2–2.33) compared to those with G allele. XRCC1 28152 GA and GA+AA genotypes were significantly higher among patients with ALL compared to controls (OR=2.17; 95% CI 1.37–3.45 and OR=2.18; 95%CI 1.38–3.42). No association between genotype or allele frequencies of both XPD SNPs and risk of ALL was shown in this study. In conclusion, our data demonstrated that SNPs of DNA repair enzymes (XRCC1 26304 C>T and 28152 G>A) but not folate-dependent DNA synthetic enzymes may influence risk of childhood ALL.

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Role of rs10406069 in miR-5196 in hyperdiploid childhood acute lymphoblastic leukemia

Epigenomics ◽

10.2217/epi-2020-0152 ◽

2020 ◽

Vol 12 (22) ◽

pp. 1949-1955

Author(s):

Angela Gutierrez-Camino ◽

Chantal Richer ◽

Pascal St-Onge ◽

Elixabet Lopez-Lopez ◽

Ana Carbone Bañeres ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Target Genes ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Mirna Genes ◽

Relevant Role ◽

The Impact

Aim: To determine the role of single nucleotide polymorphisms (SNPs) in noncoding RNAs in childhood acute lymphoblastic leukemia (ALL) subtypes. Materials & methods: We screened all SNPs in 130 pre-miRNA genes to assess their role in the susceptibility of the most common subtypes of ALL: hyperdiploid and ETV6-RUNX1. Results: In two independent cohorts, we found a significant association between rs10406069 in miR-5196 and the risk of developing hyperdiploid ALL. This observation could be explained by the impact of the SNP on miR-5196 expression and in turn, in its target genes. Indeed, rs10406069 was associated with expression changes in SMC1A, a gene involved in sister chromatin cohesion. Conclusion: rs10406069 in miR-5196 may have a relevant role in hyperdiploid ALL risk.

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Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Cancers ◽

10.3390/cancers12051285 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1285 ◽

Cited By ~ 1

Author(s):

Marion K. Mateos ◽

Morten Tulstrup ◽

Michael CJ Quinn ◽

Ruta Tuckuviene ◽

Glenn M. Marshall ◽

...

Keyword(s):

Venous Thromboembolism ◽

Acute Lymphoblastic Leukemia ◽

Single Nucleotide Polymorphisms ◽

Lymphoblastic Leukemia ◽

Meta Analysis ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

All Treatment

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.

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