scholarly journals Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Marion K Mateos ◽  
Glenn M Marshall ◽  
Pasquale M Barbaro ◽  
Michael CJ Quinn ◽  
Carly George ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Aspartate Aminotransferase ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Serum Aspartate Aminotransferase

Symptomatic methotrexate-related central neurotoxicity, ‘MTX neurotoxicity’, is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1251 consecutive Australian children enrolled on BFM or COG-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95/1251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, OR 2.31 (1.28–4.16)) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age a10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1174) (P=0.047). Five-year CNS relapsefree survival was 89.2%±4.6% when intrathecal MTX was ceased compared to 95.4%±0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified SNPs associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P>1E-06). In conclusion, increased serum aspartate aminotransferase and age a10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

2019 ◽  
Vol 111 (12) ◽  
pp. 1350-1357 ◽  
Author(s):  
Maoxiang Qian ◽  
Xujie Zhao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Yoshihiro Gocho ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Luciferase Assay ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

scholarly journals Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (18) ◽  
pp. 2133-2140 ◽  
Author(s):  
Chengcheng Liu ◽  
Wenjian Yang ◽  
Meenakshi Devidas ◽  
Cheng Cheng ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Common Variants ◽  
Genome Wide

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

Genome-wide association study of childhood acute lymphoblastic leukemia in Korea

2010 ◽  
Vol 34 (10) ◽  
pp. 1271-1274 ◽  
Author(s):  
Sohee Han ◽  
Kyoung-Mu Lee ◽  
Sue K. Park ◽  
Jong Eun Lee ◽  
Hyo Seop Ahn ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Genome Wide

scholarly journals Genome-Wide Association Study Identifies Germline Polymorphisms Associated with Relapse of Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 878-878
Author(s):  
Jun J. Yang ◽  
Cheng Cheng ◽  
Devidas Meenakshi ◽  
Xueyuan Cao ◽  
Dario Campana ◽  
...  
Keyword(s):  
Risk Factors ◽  
Treatment Outcome ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Genome Wide Association ◽  
Childhood All ◽  
Genome Wide ◽  
A Genome

Abstract Abstract 878 Introduction: Treatment outcome of childhood acute lymphoblastic leukemia (ALL) has improved dramatically in the last 40 years thanks to risk-directed therapy. However, a substantial proportion of patients still experience relapse, many of whom have no known risk factors. Prior efforts to improve risk stratification have primarily focused on genetic variations of the tumor (e.g., cytogenetic abnormalities) or on assessment of early antileukemic response (e.g., upfront prednisone response, minimal residual disease [MRD] after remission induction). The role of inherited genetic variation on treatment response in children with ALL is poorly characterized. Methods: We performed a genome-wide association study to evaluate the association of genotypes at 444,044 germline SNPs with the risk of relapse in 2,535 children with newly diagnosed ALL enrolled on 5 frontline clinical trials: St. Jude Total Therapy XIIIB, XV, the Children's Oncology Group (COG) P9904, P9905, and P9906 protocols. The associations between SNP genotypes and ALL relapse were evaluated by Gray's test and by Fine and Gray's hazard regression model, adjusting for genetic ancestry and treatment regimens. To identify SNPs reproducibly associated with relapse across treatment regimens, we performed 100 rounds of discovery and replication, each round dividing patients into 2 cohorts at a 1:1 ratio. Each time, we used the discovery cohort to perform a genome-wide screen, and then filtered SNPs based on their association in the replication cohort. Finally, SNPs were prioritized on the basis of the number of times their association with relapse was replicated. Results: A total of 134 SNPs, representing 88 genomic loci, were replicated in at least 10 rounds of discovery-replication tests. Across the genome, the strongest association with relapse risk was observed at 14q22.1 in the PYGL gene (rs7142143). Each copy of the C allele at this PYGL intronic SNP (rs7142143) conferred a 3.6-fold increase in the hazard rate of relapse (P=6.7×10−9) and the association of this SNP with relapse was replicated in 79 of 100 rounds of discovery-replication tests. Of 134 relapse SNPs, 73 were associated with one or more known prognostic clinical features in childhood ALL: 32 SNPs were related to leukocyte count ≥50,000/μl at diagnosis; 19 were enriched in children older than 10 years of age; 16 were associated with hyperdiploid ALL (DNA index ≥ 1.16); and 61 were associated with ALL molecular subtype and/or lineage (MLL rearrangements, ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, or T-cell ALL). Interestingly, 110 of the 134 relapse SNPs (82%) were prognostic even among MRD-negative patients, and 133 (99%) remained significantly associated with relapse after adjusting for all known risk factors, strongly indicating the potential value of germline genetic variations in ALL risk classification. To explore the mechanisms by which SNPs might influence treatment outcome of ALL, we examined the association of the 134 relapse SNPs with four pharmacokinetic and pharmacodynamic endophenotypes in the St. Jude Total XIIIB and XV cohorts: methotrexate plasma clearance, intracellular accumulation of polyglutamated (active) methotrexate, dexamethasone plasma clearance, and asparaginase antibody levels. Fourteen of the 134 relapse SNPs were significantly associated with at least one of the four pharmacologic phenotypes in a manner consistent with a pharmacokinetically intuitive association with relapse (i.e., lower drug exposure translated into a higher risk of relapse). Conclusion: In this genome-wide association study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some also influenced outcome by affecting host disposition of antileukemic drugs. Disclosures: No relevant conflicts of interest to declare.

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