Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

Abstract

With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P ‫؍‬ 6.7 ؋ 10 ؊9 ). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present 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 of which also influenced outcome by affecting host disposition of antileukemic drugs.

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

“…37 Furthermore, PDE4B variants were associated with a higher rate of relapse in childhood ALL. 38 Corroborating these observations, genes associated with glucocorticoid resistance in ALL were enriched in DLBCLs that express high levels of PDE4B, 8 whereas PDE4 inhibitors restored glucocorticoid sensitivity and reduced tumor burden in in vivo preclinical models of human lymphoma. 8 In these studies, the effects of PDE4 on glucocorticoid sensitivity were associated with modulation of Figure 1.…”

CDKN2A and CDKN2B Gene Variants in Acute Lymphoblastic Leukemia in Tunisian Population

“…ALL constitutes 25% of cancer that affect people before their twenties; with 2 at 5years peak age. Current therapy allows the cure of approximately 60%-80% nowadays of (young) ALL patients and the five-year survival is estimated at 60% [2][3][4][5]. ALL is characterized by infiltration of monoclonal immature cells medullar and extra medullar areas [6][7][8].…”

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…[86][87][88][89][90] Associations with specific ALL subtypes and relapse have also been identified. [91][92][93][94][95] Several genes such as IKZF1, CEBPE, and GATA3 encode transcription factors that are also targets of somatic genetic alteration in ALL.…”