Host Genetic Variants of ABCB1 and IL15 Influence Treatment Outcome in Paediatric Acute Lymphoblastic Leukaemia

Overview

Journal Br J Cancer

Specialty Oncology

Date 2014 Jan 18

PMID 24434428

Citations 6

Authors

Y Lu

S K Y Kham

H Ariffin

A M I Oei

H P Lin

A M Tan

T C Quah

A E J Yeoh

Affiliations

Soon will be listed here.

Abstract

Background: Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL.

Methods: We investigated the associations between 20 germline variations and various clinical end points in 463 children with ALL.

Results: After adjusting for known prognostic factors, variants in two genes were found to be independently associated with poorer EFS: ABCB1 T/T at either 2677 (rs2032582) or 3435 (rs1045642) position (P=0.003) and IL15 67276493G/G (rs17015014; P=0.022). These variants showed a strong additive effect affecting outcome (P<0.001), whereby patients with both risk genotypes had the worst EFS (P=0.001), even after adjusting for MRD levels at the end of remission induction. The adverse effect of ABCB1 T/T genotypes was most pronounced in patients with favourable cytogenetics (P=0.011) while the IL15 67276493G/G genotype mainly affected patients without common chromosomal abnormalities (P=0.022). In both cytogenetic subgroups, increasing number of such risk genotypes still predicted worsening outcome (P<0.001 and=0.009, respectively).

Conclusion: These results point to the prognostic importance of host genetic variants, although the specific mechanisms remain unclarified. Inclusion of ABCB1 and IL15 variants may help improve risk assignment strategies in paediatric ALL.

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Dawidowska M, Kosmalska M, Sedek L, Szczepankiewicz A, Twardoch M, Sonsala A Sci Rep. 2016; 6:29427.

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References

Kimchi-Sarfaty C, Oh J, Kim I, Sauna Z, Calcagno A, Ambudkar S . A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2006; 315(5811):525-8. DOI: 10.1126/science.1135308. View

Hoffmeyer S, Burk O, von Richter O, Arnold H, Brockmoller J, Johne A . Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000; 97(7):3473-8. PMC: 16264. DOI: 10.1073/pnas.97.7.3473. View

Mega J, Close S, Wiviott S, Shen L, Walker J, Simon T . Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010; 376(9749):1312-9. PMC: 3036672. DOI: 10.1016/S0140-6736(10)61273-1. View

Davies S, Borowitz M, Rosner G, Ritz K, Devidas M, Winick N . Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008; 111(6):2984-90. PMC: 2265447. DOI: 10.1182/blood-2007-09-114082. View

Wolf S, Bachtiar M, Wang J, Sim T, Chong S, Lee C . An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. Pharmacogenomics J. 2011; 11(5):315-25. DOI: 10.1038/tpj.2011.16. View

Efferth T, Sauerbrey A, Steinbach D, Gebhart E, Drexler H, Miyachi H . Analysis of single nucleotide polymorphism C3435T of the multidrug resistance gene MDR1 in acute lymphoblastic leukemia. Int J Oncol. 2003; 23(2):509-17. View

Cunningham L, Aplenc R . Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin Pharmacother. 2007; 8(15):2519-31. DOI: 10.1517/14656566.8.15.2519. View

Leschziner G, Andrew T, Pirmohamed M, Johnson M . ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J. 2006; 7(3):154-79. DOI: 10.1038/sj.tpj.6500413. View

McClure R, Kaur P, Pagel E, Ouillette P, Holtegaard C, Treptow C . Validation of immunoglobulin gene rearrangement detection by PCR using commercially available BIOMED-2 primers. Leukemia. 2005; 20(1):176-9. DOI: 10.1038/sj.leu.2404049. View

10.

Davidsen M, Dalhoff K, Schmiegelow K . Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008; 30(11):831-49. DOI: 10.1097/MPH.0b013e3181868570. View

11.

van der Velden V, de Bie M, van Wering E, van Dongen J . Immunoglobulin light chain gene rearrangements in precursor-B-acute lymphoblastic leukemia: characteristics and applicability for the detection of minimal residual disease. Haematologica. 2006; 91(5):679-82. View

12.

Scrucca L, Santucci A, Aversa F . Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant. 2010; 45(9):1388-95. DOI: 10.1038/bmt.2009.359. View

13.

Xu H, Cheng C, Devidas M, Pei D, Fan Y, Yang W . ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2012; 30(7):751-7. PMC: 3295551. DOI: 10.1200/JCO.2011.38.0345. View

14.

Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, Mirowski M . Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol. 2004; 72(5):314-21. DOI: 10.1111/j.1600-0609.2004.00228.x. View

15.

de Jonge R, Hooijberg J, van Zelst B, Jansen G, Jansen G, van Zantwijk C . Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood. 2005; 106(2):717-20. DOI: 10.1182/blood-2004-12-4941. View

16.

Chang K, Kim J, Yoo N, Kim W, Park J, Choi I . Restoration of P-glycoprotein function is involved in the increase of natural killer activity with exogenous interleukin-15 in human immunodeficiency virus-infected individuals. Yonsei Med J. 2000; 41(5):600-6. DOI: 10.3349/ymj.2000.41.5.600. View

17.

Hodges L, Markova S, Chinn L, Gow J, Kroetz D, Klein T . Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2010; 21(3):152-61. PMC: 3098758. DOI: 10.1097/FPC.0b013e3283385a1c. View

18.

Feng J, Tang Y . Prognostic significance of IKZF1 alteration status in pediatric B-lineage acute lymphoblastic leukemia: a meta-analysis. Leuk Lymphoma. 2012; 54(4):889-91. DOI: 10.3109/10428194.2012.723212. View

19.

Rocha J, Cheng C, Liu W, Kishi S, Das S, Cook E . Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005; 105(12):4752-8. PMC: 1895006. DOI: 10.1182/blood-2004-11-4544. View

20.

Kroetz D, Pauli-Magnus C, Hodges L, Huang C, Kawamoto M, Johns S . Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003; 13(8):481-94. DOI: 10.1097/00008571-200308000-00006. View