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Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia.

ABSTRACT: Aim: Acute myeloid leukemia (AML) is a heterogeneous disease in pathogenesis and response to therapy. Nucleotide excision repair (NER) pathway has a major role in the elimination of genotoxic effects of chemotherapeutic agents. We aimed to clarify the effects of selected variants of XPD, XPC, ERCC5 and ERCC1 genes on the outcomes of induction therapy. Materials & methods: The prevalence of NER genetic variants was evaluated in 67 subjects with AML and their effects on clinical outcomes were analyzed by ?2 test. Results: The XPD 751 Lys variant was associated with improved response to chemotherapy compared with XPD 751 Gln and Lys/Gln variants (p = 0.023; odds ratio: 4.5; 95% CI: 1.14-17.73). There were no associations between other genotypes and any outcomes. Conclusion: Current findings suggest that XPD Lys751Gln variant could be considered as a prognostic factor in AML.

SUBMITTER: Sharifi Z

PROVIDER: S-EPMC7677594 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia.

Sharifi Zohreh Z Faranoush Mohammad M Mohseni Alireza A Rostami Shahrbano S Ramzi Mani M Sharifi Mohammad J MJ

Personalized medicine 20191024 6

Aim: Acute myeloid leukemia (AML) is a heterogeneous disease in pathogenesis and response to therapy. Nucleotide excision repair (NER) pathway has a major role in the elimination of genotoxic effects of chemotherapeutic agents. We aimed to clarify the effects of selected variants of XPD, XPC, ERCC5 and ERCC1 genes on the outcomes of induction therapy. Materials & methods: The prevalence of NER genetic variants was evaluated in 67 subjects with AML and their effects on ...[more]

PMID: 31647372

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Project description:BackgroundNucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients. We hypothesized that increased expression of NER genes was associated with drug resistance and relapse in ALL.MethodsWe performed secondary data analysis on two sets of pediatric ALL patients that all ultimately relapsed, and who had matched diagnosis-relapse gene expression microarray data (GSE28460 and GSE18497). GSE28460 included 49 precursor-B-ALL patients, and GSE18497 included 27 precursor-B-ALL and 14 T-ALL patients. Microarray data were processed using the Plier 16 algorithm and the 20 canonical NER genes were extracted. Comparisons were made between time of diagnosis and relapse, and between early and late relapsing subgroups. The Chi-square test was used to evaluate whether NER gene expression was altered at the level of the entire pathway and individual gene expression was compared using t-tests.ResultsWe found that gene expression of the NER pathway was significantly increased upon relapse in patients that took 3 years or greater to relapse (late relapsers, P = .007), whereas no such change was evident in patients that relapsed in less than 3 years (early relapsers, P = .180). Moreover, at diagnosis, the NER gene expression of the early relapsing subpopulation was already significantly elevated over that of the late relapsing group (P < .001). This pattern was validated by an 'NER score' established by averaging the relative expression of the 20 canonical NER genes. The NER score at diagnosis was found to be significantly associated with disease-free survival in precursor-B-ALL (P < .001).ConclusionPatients are over two times more likely to undergo early relapse if they have a high NER score at diagnosis, hazard ratio 2.008, 95% CI (1.256-3.211). The NER score may provide a underlying mechanism for "time to remission", a known prognostic factor in ALL, and a rationale for differential treatment.

Project description:ImportanceTests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.ObjectivesTo determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML.Design, setting, and participantsWhole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50.8 years) treated with standard induction chemotherapy at a single site starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.ExposuresWhole-genome or exome sequencing and targeted deep sequencing. Risk of identification based on genetic data.Main outcomes and measuresMutation patterns (including clearance of leukemia-associated variants after chemotherapy) and their association with event-free survival and overall survival.ResultsAnalysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free and overall survival vs the 26 who cleared all mutations. Patients with intermediate cytogenetic risk profiles had similar findings. [table: see text].Conclusions and relevanceThe detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival. These data suggest that this genomic approach may improve risk stratification for patients with AML.

Dataset Information

Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia.

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Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia.

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