Dataset Information

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

ABSTRACT: Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium (HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

SUBMITTER: Gagne V

PROVIDER: S-EPMC7299187 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Gagné Vincent V St-Onge Pascal P Beaulieu Patrick P Laverdière Caroline C Leclerc Jean-Marie JM Tran Thai H TH Sallan Stephen E SE Neuberg Donna D Silverman Lewis B LB Sinnett Daniel D Krajinovic Maja M

Pharmacogenomics 20200506 8

Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods:HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an ass ...[more]

PMID: 32372697

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Project description:The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030.

Dataset Information

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Publications

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

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