Review

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Pharmacogenetic considerations for acute lymphoblastic leukemia therapies 1.

Introduction

2.

Polymorphisms highlighted by candidate gene approaches

3.

Polymorphisms highlighted by genome-wide association study

4.

Genetic predictors of late treatment-related complications in ALL

5.

Conclusion

6.

Expert opinion

Ste´phanie Dulucq, Caroline Laverdie`re, Daniel Sinnett & Maja Krajinovic† †

University of Montreal, University Health Center Sainte Justine, Research Center, Montreal, QC, Canada

Introduction: Advances in our understanding of the pathobiology of childhood acute lymphoblastic leukemia (ALL) have led to risk-targeted treatment regimens and remarkable improvement in survival rates. Still, up to 20% of patients experience treatment failure due to drug resistance. Treatmentrelated toxicities are often life-threatening and are the primary cause of treatment interruption, while ALL survivors may develop complications due to exposure to chemotherapy and/or irradiation during a vulnerable period of development. Different factors may contribute to variable treatment outcomes including patient genetics that has been shown to play important role. Areas covered: This review summarizes candidate gene and genome-wide association studies that identified common polymorphisms underlying variability in treatment responses including a few studies addressing late effects of the treatment. Genetic variants influencing antileukemic drug effects or leukemic cell biology have been identified, including for example variants in folate-dependent enzymes, influx and efflux transporters, metabolizing enzymes, drug receptor or apoptotic proteins. Expert opinion: Many pharmacogenetic studies have been conducted in ALL and a variety of potential markers have been identified. Yet more comprehensive insight into genome variations influencing drug responses is needed. Whole exome/genome sequencing, careful study design, mechanistic explanation of association found and collaborative studies will ultimately lead to personalized treatment and improved therapeutic and health outcomes. Keywords: acute lymphoblastic leukemia, pharmacogenetics, pharmacogenomics, polymorphisms Expert Opin. Drug Metab. Toxicol. (2014) 10(5):699-719

1.

Introduction

A better risk stratification of acute lymphoblastic leukemia (ALL) according to biologic features at diagnosis, evaluation of early response and use of combination drug therapy, allowed great progress in treatment such that ~ 80 -- 85% of childhood patients are cured with current therapy regimen. Therapy resistance in a significant number of children is still a major obstacle to successful treatment. Intensive chemotherapy also has significant short- and long-term side effects [1]. Different factors can contribute to the variability in treatment response including constitutive genetic profile of the patient. Pharmacogenetics identifies genetic polymorphisms that may predict this variability prior to drug administration ultimately leading to individualized treatment tailor to patient genetics [2]. Identification of pharmacogenetic markers was initially addressed through candidate gene approach that analyses variations in genes essential for drug effects (e.g., those which encode for pharmacokinetic and pharmacodynamic determinants of 10.1517/17425255.2014.893294 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

699

S. Dulucq et al.

Article highlights. .

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Therapy resistance in a significant number of acute lymphoblastic leukemia (ALL) patients is still a major obstacle to successful treatment. Intensive chemotherapy also has significant short- and long-term side effects. A number of polymorphisms that influence efficacy of ALL treatment or drug-related complications have been identified through ALL pharmacogenetic studies, which included analysis of single candidate genes, or several genes in the same pathway, and since recently, genome-wide association studies. Genes within action pathways of ALL treatment drugs have been analyzed through candidate gene approach including metabolizing enzymes, transporter, target genes or genes coding for transcription factor and apoptotic proteins. Polymorphisms in thiopurine methyltransferase (TPMT) have become a part of clinical management of ALL patients. Several groups reported association between risk of relapse and the polymorphism in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) or glutathione S-transferase (GST) genes. GWAS interrogated the genetic influence on several phenotypes related to treatment response, including drug disposition, early response, risk of relapse, onset of asparaginase hypersensitivity and osteonecrosis. One of the SNPs detected through GWAS that was well replicated in subsequent studies is a variant in solute carrier organic anion B1 (SLCOB1), a hepatic organic anion transporter polypeptide that plays a role in methotrexate disposition. There is growing interest to identify genetic determinants of late complications of treatment including neurocognitive problems, bone morbidity, metabolic syndrome or cardiac dysfunction. Although many interesting results are obtained, there is yet no clear conclusion which treatment in the context of patient’s genetic background (with the exception of 6-MP and TPMT) will be the most suitable and how to adjust the treatment to improve efficacy and mitigate drug-related toxicity. Promising results obtained thus far will soon be coupled with data obtained through new generation sequencing ultimately leading to personally tailored treatment in ALL.

This box summarizes key points contained in the article.

drug effects). First studies analyzed the impact of one polymorphism, whereas more recent studies analyzed the impact of several polymorphisms of same gene or screened polymorphic content of many relevant genes. Progress in molecular biology, allowed addressing genetics of variable treatment response through whole-genome approaches that can screen all potentially important genes and could identify new resistance mechanisms, as well as new targets of treatment or diagnosis [2,3]. DNA microarray technology led to the development of genome-wide association study (GWAS) allowing the analysis of > 500,000 polymorphisms at the same time that could thus identify additional genes and 700

variations that can affect therapeutic responses. With the recent advent of next-generation sequencing technologies, it will be possible to obtain more in-depth view of genomic variations (both common and rare) leading to the variability in treatment responses [4]. This review summarizes the pharmacogenomic studies of ALL, which highlighted the impact of genetic polymorphisms on treatment responses including short overview of the role of genetic component in late treatment-related side effects in ALL survivors. Therapy of ALL is based on multiple chemotherapeutics, and studies focused on each components of this treatment: ALL has a much higher incidence in children than in adults [5], thus the majority of pharmacogenetic studies have been carried out in childhood patients. This review focuses on pharmacogenetic studies in adult or pediatric ALL, but many data are also available in leukemic cell lines.

Polymorphisms highlighted by candidate gene approaches

2.

Pharmacokinetic determinants Metabolizing enzymes 2.1.1.1 Thiopurine S-methyl transferase 2.1

2.1.1

TPMT gene encodes the thiopurines S-methyl transferase (TPMT) enzyme, which metabolizes thiopurines (including 6-mercaptopurine, [6-MP]) and prevents the accumulation of its main active cytotoxic metabolites, the thioguanine nucleotides (TGN) (Figure 1) [2]. 6-MP is administered as a daily oral dose mainly during consolidation and maintenance therapy. It could be responsible of severe myelosupression whose risk depends on intracellular TGN levels, in inverse proportion to TPMT activity [2]. The most frequent variants given in Table 1 are TPMT*2, TPMT*3A and TPMT*3C [2,6]. Less than 10% of the population is heterozygous for nonfunctional variants, resulting in intermediate enzyme activity, whereas individuals with two nonfunctional alleles (1 in 300) have very low or no enzyme activity [6]. Reduction to 10% of standard 6-MP doses is recommended for individuals that are homozygous for variant TPMT alleles. Heterozygous individuals might also benefit from dose reduction, but controversial advices exist because of the risk of less efficiency due to less exposure to the drug. Recently, the Clinical Pharmacogenetics Implementation Consortium published guidelines and strongly recommends determination of TPMT genotypes before 6-MP administration to adapt initial drug doses, in children and adult patients [7]. TPMT variants, conferring lower activity, were also associated with a lower rate of minimal residual disease (MRD) [8]. By contrast, patients with high TPMT activity are at higher risk of relapse due to low TGN levels [9] and those with high levels of methylated metabolites (6-MMPN) are at higher risk of hepatotoxicity [10]. TPMT genotyping does not permit to identify these patients and complementary clinical laboratory tests such as TPMT activity dosage, TGN or methylated metabolites levels can be helpful [7,11].

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

Methyl-thio-ITP

Hepatotoxicity

TPMT

Thiouric acid

Thio-ITP XO ITPA HPRT

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6-MP TPMT

Methyl-MP

Thio-IMP

6-TGN

TPMT

DNA incorporation

Hematopoietic toxicity de novo purines synthesis inhibition

Methyl-thio-IMP

Figure 1. Metabolism of 6-mercaptopurine. Modified with permission from [14]. 6-MP: 6-Mercaptopurine; HPRT: Hypoxanthine phosphoribosyltransferase; IMP: Inosine monophosphate; ITP: Inosine triphosphate; ITPA: Inosine triphosphatase pyrophosphatase; TGN: Thioguanine nucleotide; TPMT: Thiopurine methyl transferase; XO: Xanthineoxidase.

Inosine triphosphate pyrophosphatase Other polymorphisms of 6-MP pathway may contribute to 6-MP-related toxicity in children [12-14]. For example, inosine triphosphate pyrophosphatase (ITPA) catalyzes the conversion of inosine triphosphate (ITP) into inosine monophosphate, thereby preventing the accumulation of ITP in normal cells. In ITPA-deficient patients treated with thiopurines, accumulation of ITP can occur resulting in drug-related toxicity [15]. Two polymorphisms are associated with ITPA deficiency: c.94C>A (Pro32Thr) in exon 2 and IVS2 + 21A>C near the splice donor site of intron 2 [11]. These polymorphisms correlated with thrombocytopenia [12] and febrile neutropenia [13]. TPMT and ITPA genotypes may interact because they both contribute to the 6-MMPN formation [11,13]. Indeed, the c.94 C>A variation has a significant influence on the risk of febrile neutropenia in pediatric ALL patients only if 6-MP doses are adjusted for TPMT genotype [13,14]. As well, higher levels of 6-MMPN were observed in patients with a nonfunctional ITPA variant and wild-type TPMT [14]. Patients with ITPA 94A allele were also reported to have a lower event-free survival (EFS) [16]. 2.1.1.2

Glutathione S-transferases Glutathione S-transferases (GSTs) are Phase II enzymes involved in detoxification of endogenous reactive species, xenobiotics and drugs, including drugs used in ALL treatment. Several GST subfamilies are described with multiple polymorphisms-modulating enzyme activity. GSTM1 and GSTT1 null genotypes result from homozygous gene deletion leading to the loss of GST activity. These genotypes could represent a therapeutic advantage or may confer higher risk of drug-related toxicity [17]. A lower incidence of relapse was found in pediatric ALL patients with GSTM1/GSTT1 null genotypes [18,19]. Likewise, 2.1.1.3

an improved prednisone response has been associated with homozygous GSTT1 deletion [20]. A higher risk of severe infectious and hepatotoxicity was reported in childhood ALL patients with GSTM1 null genotype [17,21]. NADP(H) quinone oxidoreductase Polymorphisms in NADP(H) Quinone oxidoreductase (NQO1) gene implicated in the two electron reduction of quinone containing-drugs, such as doxorubicin, were also highlighted in some childhood candidate gene studies [22,23]. The variant NQO1 609 C>T (*2), resulting in reduction of enzyme activity, was associated with a shorter survival probability [22] and a slower response to induction chemotherapy [23]. Decreased NQO1 activity may enhance the drug effect and reactive oxygen species (ROS) formation. It is possible that an impaired cell protection from free radicals may lead to the development of recurrent malignancies [23]. 2.1.1.4

2.1.2

Transporters Reduced folate carrier

2.1.2.1

Methotrexate (MTX), a folate antagonist, is a key chemotherapeutic agent not only used in consolidation and maintenance of ALL therapy but also in prevention of CNS relapse. MTX enters the cells via the reduced folate carrier (RFC, solute carrier family 19 member1 SLC19A1), which is also responsible for the cellular uptake of reduced folates. Mostly studied polymorphism is 80G>A substitution that leads to His27Arg replacement and has been demonstrated to increase MTX uptake, particularly in individuals with AA genotype [24]. In childhood ALL patients, the presence of A allele was associated with higher degree of gastrointestinal and bone marrow toxicities [24-26]. Relationship with the risk of relapse is somewhat controversial: some groups reported absence of association [19,27], whereas others found association of either A [26]

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

701

702

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

7270101

1127354

1142345

1800460

*2: c.238G>C Ala80Pro Caucasians: 0.5% Africans: 0.3% Asians: 0% *3A: c.460G>A; c.719A>G Ala 154Thr; Tyr240Cys Caucasians: 4 -- 7% Africans: 0% Southwest Asians: 1 -- 2% *3B c.460G>A Ala154Thr Caucasians: 0 -- 3% Africans: 0 Asians: 0% *3C: c.719A>G Tyr240Cys Caucasians: 1 -- 3% Africans: 3 -- 7% Eastern Asians: 1 -- 3% c.94C>A, Pro32Thrg Caucasians: 7 -- 8% Africans: 3 -- 5% Asians: 11 -- 15% IVS2 + 21A>C Caucasians: 13% Africans: 11% Asians: 0% Null genotype Caucasians: 17 -- 20% Africans: 23% Asians: 35 -- 50% Indian: 15%

Genetic variation frequency of minor allele in different ethnicities

Deletion

Reduced

Reduced

Reduced

Reduced

Reduced

Reduced

Function (variant allele)

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

Alkylating agents, anthracyclines, CS, etoposide

Thiopurines

Thiopurines

Thiopurines

Thiopurines

Thiopurines

Thiopurines

Drug

Lower incidence of relapse, improved prednisone response Neurocognitive problems

Thrombocytopenia (not adjusted for TPMT genotypes)

Febrile neutropenia (adjusted for TPMT genotypes). Lower EFS

Toxicity (myelosupression, secondary malignancies), efficacy (lower MRD)

Toxicity (myelosupression, secondary malignancies), efficacy (lower MRD)

Toxicity (myelosupression, secondary malignancies), efficacy (lower MRD)

Toxicity (myelosupression, secondary malignancies), efficacy (lower MRD)

Association

[18,20,93]

[12,14]

[13,14,16]

[2,6-8]

[2,6-8]

[2,6-8]

[2,6-8]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

GSTT1

ITPA

1800462

TPMT

1800460 -1142345

rsID

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment.

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S. Dulucq et al.

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

717620

868853

MRP2

MRP4

3435C>T Ile1145 = Caucasians: 47 -- 55% Africans: 7 -- 20% Asians: 37 -- 52% -24C>T Caucasians: 18 -- 22% Africans: 3 -- 4% Asians: 18 -- 26% -1393T>C Caucasians: 9% Africans: 37% Asians: 9 -- 19% 934C>A Lys304Asn Caucasians: 2% Africans: 10 -- 19% Asians: 17 -- 29%

Null genotype Caucasians: 50 -- 53% Africans: 21 -- 27% Asians: 42 -- 62% Indian: 28% *2 609 C>T Pro187Ser Caucasians: 8 -- 21% Africans: 17 -- 19% Asians: 39 -- 52% 80G>A His27Arg Caucasians: 45 -- 55% Africans: 30% Asians: 50%

Genetic variation frequency of minor allele in different ethnicities

Increased

Reduced

Reduced

Increased

Reduced

Deletion

Function (variant allele)

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

MTX, 6-MP

MTX, etoposide, vincristine

Glucocorticoids, anthracycline, vincristine, etoposide

MTX

Quinone containing drug: doxorubicin

Alkylating agents, anthracyclines, CS, etoposide

Drug

Lower EFS and higher thrombocytopenia (AC)

Better EFS and lower MTX levels (TC)

Higher MTX levels

Increased gastrointestinal toxicity and myelosuppression Conflicting result on efficacy: increased risk of relapse (GG or AG/AA) Better EFS, lower rate of CNS relapse, increased risk of infection

Shorter survival probability, slower response to induction

Lower incidence of relapse Higher incidence of severe infectious, transaminitis

Association

[39]

[39]

[38]

[31,34]

[24-28]

[22,23]

[17-19,21]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

2274407

1045642

1051266

RFC1

ABCB1

1800566

rsID

NQO1

GSTM1

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

703

704

9895420

1650694

MRP3

DHFR

34743033

1801133

TS

MTHFR

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

c.677C>T Ala220Val Caucasians: 34% Africans: 8% Eastern Asians: 42% 1298 A>C Glu429Ala Caucasians: 29 -- 36% Africans: 12 -- 14% Asians: 15 -- 20%

5¢UTR repetition 28pb 2R-97 3R Caucasians: 50 -- 60% Southwest Eastern: 60% Eastern Asians: 80%

-1610C>G/T Caucasians: 35/11% -317A>G Caucasians: 42% -308 G>A Caucasians: 12% Ins/Del 19bp (intron1 + 57) Caucasians: 50%

-189A>T Caucasians: 15% Africans: 9%

Genetic variation frequency of minor allele in different ethnicities

Reduced

Reduced

Increased

Reduced

Increased

Increased

Increased

Increased

Function (variant allele)

Candidate gene

Candidate gene

MTX

MTX

MTX

MTX

Candidate gene

MTX

MTX

MTX

MTX

Candidate gene

Drug

MTX, etoposide

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

Increased risk of hepatotoxicity Better EFS (AA) Neurocognitive problems (CA/CC)

Thrombocytopenia in homozygous WT Increased risk of relapse CNS relapse (3R3R) osteonecrosis, lower leukocytopenia/ thrombocytopenia and stomatitis (2R2R) Increased risk of relapse Reduced OS (TT) Myelosuppression

Hepatotoxicity

Reduced EFS (HR patients)

Reduced EFS

Higher MTX levels, reduced EFS, higher CNS relapse lower thrombocytopenia (AT/ AA) Reduced EFS

Association

[27,94,95]

[21,44,45, 51-55]

[19,21,23, 27,46-50]

[45]

[44]

[43]

[42]

[42]

[29]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

1801131

70991108

DHFR

1105525

408626

rsID

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

S. Dulucq et al.

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

2279115

11168070, 11959427, 1042711, 1801704

11554772

BCL2

ADRB2

ATF5

870A>G Caucasians: 50% Africans: 20% Asians: 39 -- 54% IVS2 646G>C Caucasians: 36% Africans: 14% -1082A>G Caucasians: 33 -- 53% Africans: 27 -- 40% Asians:2 -- 5% 29201 C>T Ile65 = Caucasians: 30 -- 33% Africans: 18 -- 26% Asians:8 -- 13% -486G>T Caucasians:42 -- 54% Africans: 71 -- 82% Asians: 60 -- 83% -938 C>A Caucasians: 57% Africans: 10% Asians: 43% -468C>G, -376T>C, -47T>C, -20T>C Caucasians: 41% Africans: 17% Asians: 8 -- 12% 5¢UTR 1562C>T Caucasians: 3% Africans: 7%

Genetic variation frequency of minor allele in different ethnicities

Increased

Altered

Increased

Increased

Exonic splicer element, ratio isoform altered

Increased

Alternative splicing

Function (variant allele)

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

Asparaginase

MTX, 6-MP

CS

CS

CS

CS

CS

MTX

Drug

Reduced EFS (E. coli asparaginase)

Worse initial treatment response (GCCC haplotype)

Poor prednisone response (CC)

Reduced OS (TT)

Reduced OS (TT)

Improved response to prednisone (GG)

Reduced EFS (CG/GG)

Reduced EFS and less myelosuppression and hepatotoxicity (AA)

Association

[70]

[69]

[68]

[66,67]

[66]

[62]

[60,61]

[56,57]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

9803935

MCL1

1800896

IL10

724710

41423247

GR

BCL2L11

9344

rsID

CCND1

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

705

706

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

2286128

1799987

4149056

CNTNAP2

CCR5

SLCO1B1

G>A, Ala15Thr Caucasians: 10% Africans: 0% Asians: 9 -- 21% FokI T>C Caucasians: 60% Africans: 80% Asians: 55 -- 67% 870C>T Arg223Gln Caucasians: 45 -- 50% Africans: 19 -- 50% Asians: 11 -- 17% 2744G>A Arg913Gln Caucasians: 12 -- 14% Africans: 0% Asians: 3 -- 12% 7673C>T Xbal Caucasians: 50% Africans: 19% Asians: 3.5 -- 7% 2226C>T Caucasians: 0% Africans: 9% Asians: 3 -- 6% c.246A>G Caucasians: 22% Africans: 54 -- 65% 521T>C, Val174Ala Caucasians: 18% Africans: 1,9% Native Amricans: 24%

Genetic variation frequency of minor allele in different ethnicities

Reduced

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Function (variant allele)

GWAS

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

MTX

CS

CS

CS

CS

CS

CS

Drug

Lower MTX clearance, higher MTX concentrations, increased gastrointestinal toxicity

Higher incidence of MRD negative (AG/GG)

CS-induced hypertension

CS-induced hypertension

CS-induced hypertension

CS-induced hypertension

Osteonecrosis

Osteonecrosis

Association

[27,75-79]

[74]

[73]

[73]

[73]

[73]

[49]

[71]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

693

APOB

1137101

LEPR

11643718

2228570

VDR

SLC12A3

6092

rsID

PAI-1

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

S. Dulucq et al.

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

4958381

12714403 and 10167992

4241316 and 10193882

17007695 and 35964658

6479778

7142143

6683977 524770 641262

GRIA1

ACP1

SH3YL1

IL15

ARID5B

PYGL

PDE4B

T>C Caucasians: 0 -- 1% Africans: 12 -- 15% Asians: 0% G>C C>T A>G Caucasians: 58 -- 60% 35 -- 38% 45 -- 58% Africans: 1% 25 -- 28% 12 -- 14% Asians: 9 -- 20% 44 -- 60% 9 -- 21%

C>T Caucasians: 41 -- 42% Africans: 45% Asians: 3 -- 6% A>G Caucasians: 3% G>A C>T Caucasians: 14 -- 50% Africans: 0 -- 3% Asians: 9 -- 14% T>C and A>T Caucasians: 14 -- 50% Africans: 0 -- 4% Asians: 8 -- 14% T>C A>G Caucasians: 6 9% Africans: 0,4 -- 3% Asians: 37 -- 49% C>T Caucasians: 50% Africans: 34 -- 50%

Genetic variation frequency of minor allele in different ethnicities

Unknown

Unknown

Unknown

Increased

Unknown

Unknown

Unknown

Reduced TPMT activity

Function (variant allele)

GWAS

GWAS

GWAS

GWAS

GWAS

GWAS

GWAS

GWAS

Approach

All MTX++

All

All

All

CS

CS

Asparaginase

6-MP

Drug

Increased risk of relapse Reduced levels of MTX polyglutamates (GC/CC or CT/TT or AG/AA)

Increased risk of relapse, higher incidence of MRD positive at the end of induction (CT/TT) Increased risk of relapse (CT/ CC)

Higher positive MRD at the end of induction (CC)

Osteonecrosis

Highest risk of asparaginase sensitivity (AG/AA) Osteonecrosis

Increased gastrointestinal toxicity (TT)

Association

[88]

[88]

[87]

[83]

[72]

[72]

[82]

[78]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

2413739

rsID

PACSIN2

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

707

708

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

429358

1805087

APOE4

MS

G>A G>A Caucasians: 5 -- 21% 5 -- 13% Africans: 34 -- 46% 36 -- 50% Asians: 10 -- 16% 13% T>C Caucasians: 19 -- 23% Africans: 43% Asians: 0 -- 1% A>G Caucasians: 9% Africans: 6% Asians: 62 -- 72% c.66 +78 C>T Caucasians: 5 -- 6% Africans: 7 -- 10% Asians: 30% 3¢UTR C>T Caucasians: 14 -- 20% Africans: 16 -- 29% Asians: 38 -- 48% T>C Cys112Arg Caucasians: 9% Africans: 2% Asians: 0 -- 1% 2756 A>G Caucasians: 16% Africans: 24 -- 32% Asians: 7 -- 21%

Genetic variation frequency of minor allele in different ethnicities

Reduced

Reduced

Unknown

Increased

Unknown

Unknown

Unknown

Function (variant allele)

Candidate gene

Candidate gene

Candidate gene

Candidate gene

GWAS

GWAS

GWAS

Approach

All

All

Anthracycline

Anthracyclines

MTX 6-MP

All asparaginase

All CS++

Drug

Neurocognitive problems

Neurocognitive problems

Anthracycline-induced left ventricular dysfunction

Cardiac toxicity

Severe hepatoxicity (AA)

Increased risk of relapse Higher asparaginase antibodies (CT/CC)

Increased risk of relapse Higher Dexamethasone clearance (GA/AA)

Association

[93]

[93]

[92]

[91]

[89]

[88]

[88]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

3743527

1966862

ARHGAP24

MRP1

251177

FCHSD

10836235

10264856 4728709

ABCB1

CAT

rsID

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

S. Dulucq et al.

1137070

2070744

MAOA

NOS3

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

9939609

1876828

FTO

CRHR1

1460 C>T Asp470 = Caucasians: 17 -- 27% Africans: 30 -- 40% Asians: 47 -- 69% -786T>C Caucasians: 59% Africans: 0 -- 14% Asians: 0% 894G>T Caucasians: 34 -- 50% Africans: 7 -- 14% Asians: 7 -- 11% G>A Arg192His Caucasians: 1% Africans: 0% Asians: 7 -- 11% T>A Caucasians: 39 -- 46% Africans: 33 -- 52% Asians: 12 -- 17% G>A Caucasians: 21%

Genetic variation frequency of minor allele in different ethnicities

Unknown

Unknown

Reduced

Reduced

Reduced

Unknown

Function (variant allele)

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Candidate gene

Approach

CS

Obesity associated

Pancreatic b-cell function

All

All

Drug

Osteoporosis

Increased body mass index

Glucose tolerance

Neurocognitive problems

Neurocognitive problems

Neurocognitive problems

Association

[100]

[99]

[98]

[97]

[97]

[93]

Ref.

ABCB1: ATP-binding cassette transporter B1; ACP1: Acid phosphatase 1; ADRB2: b-2 Adrenergic receptor; APOB: Apolipoprotein B; APOE4: Apolipoprotein E; ARHGAP24: Rho GTPase activating protein 24; ARID5B: AT-rich interactive domain protein 5B; ASS1: Argininosuccinate synthase1; ATF5: Activating transcription factor 5; BCL2: B-cell CLL/lymphoma2; BCL2L11: Bcl-2 like11; CAT: Catalase; CCND1: Cyclin D1; CCR5: Chemokine receptor 5; CNTNAP2: Contractin-associated protein like2n; CRHR1: Corticotrophin-releasing hormone receptor 1; CS: Corticosteroids; DHFR: Dihydrofolate reductases; EFS: Event-free survival; FCHSD: FCH and double SH3 domain protein 1; FTO: Fat mass and obesity associated gene; GR: Glucocorticoid receptor; GRIA1: Glutamate receptor ionotropic; GSTM1: Glutathione S-transferase; IL: Interleukin; IPTA: Inosine triphosphate pyrophosphatase; LEPR: Leptin receptor; MAOA: Monoamineoxidase; MCL1: Myeloid cell leukemia sequence1; MDR: Multi-drug resistance; MRD: Minimal residual disease; MRP: Multi-drugresistance-associated protein; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; MTX: Methotrexate; NOS3: Nitric acid synthase; NQO1: NADP(H) Quinone oxidoreductase; OS: Overall survival; PACSIN2: Protein kinase C and casein kinase substrate in neuron 2; PAI-1: Serpine peptidase inhibitor or plasminogen activator inhibitor type 1; PAX4: Paired box 4; PDE4B: Phosphodiesterase 4B; PYGL: Glycogen phosphorylase; RFC1: Reduced folate carrier; SCL12A3: Sodium chloride transporter; SH3YL1: SH3 domain containing Ysc 84 like 1; SLCOB1: Solute carrier organic anion transporter; TPMT: Thiopurine S-methyl transferase; TS: Thymidylate synthase; VDR: Vitamin D receptor.

2233580

PAX4

1799983

rsID

Genes

Table 1. Summary of the polymorphisms associated with efficacy and/or toxicity of ALL treatment (continued).

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

709

MRP 4

RFC1 RFC

THF

5,methyl THF

DHFR

MTHFR Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.

MRP 2

Methionine Homocysteine

MRP 3

MRP 1

S. Dulucq et al.

5,10 methyleneTHF

DHF MTX

MTHFD1

10, formyl THF

TS dUMP

dTMP MTX (Glu)n ADN

Purines

Figure 2. Methotrexate and folate cycle. Modified with permission from [41]. DHF: Dihydrofolate; DHFR: Dihydrofolate reductase; dTMP: Deoxythymidine monophosphate; dUMP: Deoxyuridine monophosphate; MRP: Multi-drug-resistance-associated proteins; MTHFD1: Methylenetetrahydrofolate dehydrogenase; MTHFR: Methylenetetrahydrofolate reductase; MTX(Glu)n: Methotrexate polyglutamate; RFC1: Reduced folate carrier; THF: Tetrahydrofolate; TS: Thymidylate synthase.

or G allele [24] or GG genotype [28] suggesting modifying effect of MTX doses, of folate intake and levels, or confounding effect of other polymorphisms. Multi-drug resistance protein and multi-drugresistance-associated proteins

2.1.2.2

Bioavailability of many drugs used in ALL treatment (i.e., MTX, 6-MP, corticosteroids [CS], anthracycline, vincristine, etoposide and cyclophosphamide) depends also on the activity and expression of the ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp) and multi-drug-resistance (MDR)-related proteins (MRP) [29]. These transporters use ATP as an energy source to export drugs and are expressed in the membrane of many tissues as intestine, liver, kidney, blood--brain barrier and hematopoietic cells. P-gp is encoded by the MDR1 gene. A 3435C>T in exon 26 is frequently investigated functional polymorphism, leading to a change in substrate specificity [30]. However, controversial results exist regarding its clinical impact in ALL. Childhood ALL patients with the 3435T allele showed a better EFS and/or a lower rate of CNS relapse [31], whereas others [32,33] reported no impact on prognosis of childhood or adult ALL. Increased risk of infectious complications was also observed in children with 3435T allele [34]. MRPs are encoded by MRP genes and comprise 13 members with 9 major transporters, MRP1 -- MRP9, contributing to drug resistance [35]. MTX, vincristine, 6-MP and doxorubicin used in ALL treatment protocols are all MRP substrates. Several MRPs mediate efflux of each of these drugs [35]. 710

SNPs in MRP1 (2684T>C, 2007C>T, 2012C>T, 2665C>T) do not seem to influence ALL outcome [36]. A C-24T polymorphism, located in the regulatory region of the MRP2 gene, has been associated with lower mRNA levels [37] and higher MTX concentration in childhood ALL requiring more frequent leucovorin rescue [38]. The A-189 allele of the A to T substitution in promoter of MRP3 gene correlated with higher risk of relapse in CNS and lower frequency of thrombocytopenia in childhood ALL [29]. Two polymorphisms in MRP4 gene, -1393T>C located in the promoter region and 934C>A leading to Lys304Asn aminoacid substitution, affected MTX levels and EFS in childhood ALL patients [39]. The C934 allele correlated also with higher frequency of high-grade thrombocytopenia [39]. However, MRP4 results were not confirmed in an adult ALL cohort [40], possibly highlighting differences in pharmacogenetic findings, disease characteristics or treatment protocols between childhood and adult patients. Pharmacodynamic determinants Targets 2.2.1.1 Dihydrofolate reductase 2.2

2.2.1

Dihydrofolate reductase (DHFR) is the main target of MTX, which catalyzes reduction of dihydrofolate into tetrahydrofolate (THF), resulting in depletion of reduced folate (Figure 2) and inhibition of nucleic acid formation [41]. A comprehensive study of the DHFR polymorphisms in the minor promoter found that the reduction in EFS was associated with -317 A>G and -1610C>G/T variants and haplotype

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

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Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

*1 defined by A and C alleles [42]. Additional study of the adjacent major promoter/non-coding transcript region [43] identified three tag polymorphisms (-35C>T, -308 G>A and length polymorphism composed of two sequence motifs) further dividing the haplotype *1 into five subtypes. Lower EFS was associated with the 308A allele and haplotype *1b, particularly in high-risk patients. Haplotype *1b was associated with higher mRNA levels likely explaining the worse prognosis for *1b carriers [43]. Insertion/deletion (indel) of 19pb sequence in the first intron of DHFR gene was also studied by several groups. Deletion allele was associated with an increased risk of hepatotoxicity in adult ALL [44]. Homozygosity for the insertion allele was, in contrast, associated with thrombocytopenia in childhood ALL [45], whereas others did not find such an association [42]. 19bp indel is in LD with the promoter polymorphisms [42], which might explain some differences seen across studies. Thymidylate synthase Thymidylate synthase (TS) is a key enzyme in the nucleotide biosynthetic pathway that catalyzes conversion of deoxyuridylate to deoxythymidylate (Figure 2). Several enzymes of purine and pyrimidine synthesis, including TS, are inhibited by MTX polyglutamates [41]. A repeat polymorphism was identified in the enhancer element of the 5¢UTR region [41]. This polymorphism contains variable numbers of a 28-bp repeat element with most frequent double (2R) and triple repeat (3R) alleles. Patients who are homozygous for the triple repetition (3R3R) have higher TS mRNA levels than 2R2R patients [41]. Higher risk of relapse has been reported not only for childhood ALL 3R3R patients [23,46-48] but also for those with 3R4R genotype [21]. Another study demonstrated that in low-risk group, patients with 3R3R genotype had a predisposition for CNS relapse, whereas in high-risk group, patients with a combined TS 3R3R and GSTM1 non-null genotype had an increased risk of hematologic relapse [19]. By contrast, patients with low-activity genotypes are more sensitive to MTX: higher incidence of osteonecrosis of the hip has been demonstrated in childhood ALL patients with 2R2R genotype [49]; lower incidence of leukocytopenia/ thrombocytopenia and less frequent/less severe stomatitis was observed in children without 2R2R genotype [27,50]. 2.2.1.2

Methylenetetrahydrofolate reductase The N5, N10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of the N5, N10-methylene THF into N5-methyl THF that provides a methyl group for homocysteine methylation (Figure 2) [41]. Increased N5, N10-methylene THF levels can antagonize MTX effect by providing more efficient thymidylate synthesis. Two common polymorphisms in MTHFR gene with functional impact have been described: 677C>T (Ala220Val) and 1298A>C(Glu429Ala) [41]. Decrease enzymatic activity is observed in individuals who are homozygous for minor alleles and to a lesser extent in heterozygous individuals [41]. The presence of 677T was associated with an 2.2.1.3

increased risk of relapse in several cohorts of childhood ALL patients [21,45,51-53] or with reduced overall survival (OS) in both pediatric and adult ALL [44,54,55]. Better EFS in patients with 1298AA as compared with patients carrying the 1298C allele was also reported [27]. Homozygosity for the 677T allele was associated with an increased risk of hepatotoxicity or myelosuppression in adult ALL [55]. Many studies conducted in childhood ALL patients did not find an association of 677T allele with MTX-related toxicity [27,50,52,56]. Two recent studies reported, nevertheless, that children with variant MTHFR genotype developed more frequently myelosuppression [45,51] and had higher creatinine levels [45]. Differences in MTX dose and administration schedule, concurrent medications, folate status, diet and a different mechanism leading to drug-related toxicity may contribute to these differences. Cyclin D1 Cyclin D1 (CCND1) is a key protein that regulates the G1 phase of the cell cycle. CCND1 has an important role in the phosphorylation and the functional inactivation of the retinoblastoma (pRB) which in turn may increase transcription of MTX targets like DHFR and TS [41]. An A to G substitution (870A>G) has been described in the splicing donor site (exon/intron 4) that modulates the mRNA isoform ratio [41]. The 870A allele codes for mRNA with a longer half-life, keeping the pRB phosphorylated for a longer time. Children with genotype 870AA had reduced EFS [57] and less drug-related toxicity [56]. CCND1 can modulate response to several drugs and the observed impact could be due to the response modulation of the other drugs used in ALL treatment [41]. 2.2.1.4

Glucocorticoid receptor (NR3C1) and IL10 Prednisone and dexamethasone are key components of ALL treatment. About 10% of children show glucocorticoid resistance [58] at diagnosis, which can further increase at relapse [58]. CS act through binding to a specific cytoplasmic glucocorticoid receptor (GR or NR3C1). Several studies analyzed the impact of GR gene polymorphism [59-61]. One group reported an association of 646 C>G substitution in intron 2 of GR gene (also known as Bcl I polymorphism) with GR isoform ratio and ALL outcome [60,61]. IL10 is an anti-inflammatory cytokine that modulates the transcriptional activity of the GR. Overproduction of IL10 seems to upregulate the binding capacity for dexamethasone [62]. A polymorphism (-1082 A>G) in the regulatory region of the IL-10 gene leads to an increased expression of IL-10. Pediatric ALL patients who are homozygous for allele G had an improved response to prednisone [62]. 2.2.1.5

Genes of apoptotic pathway and transcription regulators

2.2.2

Induction of Bim (Bcl-2 homology 3, BH3-only molecule), an apoptotic protein of the Bcl-2 family, appears essential for glucocorticoid-mediated apoptosis [63,64] and plays

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

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important role in glucocorticoid resistance in ALL [65]. Study investigating whether polymorphisms of BCL2L11 encoding Bim affect response to treatment in ALL patients found an association with the synonymous SNP 29201 C>T, located in BH3 domain of exon 8. The genotype 29201TT was associated with lower OS in ALL patients and affected generation of g RNA isoforms that lack pro-apoptotic BH3 domain [66]. Likewise, the promoter variation (-486G>T) in anti-apoptotic Mcl1 gene was associated with increased Mcl1 expression and reduced OS in ALL [67]. The effect on OS was further potentiated when unfavorable genotypes of these two genes were combined and was particularly prominent in high-risk patients with more progressive disease that require higher CS doses [66]. Role of apoptosis in CS resistance had also been highlighted in a study that analyzed polymorphisms of anti-apoptotic BCL2 [68]. An SNP in the promoter of BCL2 (BCL2 -938 C>A), associated with higher BCL2 expression, seems to predispose ALL children to be classified in high-risk group (CC genotype), because of a poor prednisone response [68]. Wide genome profiling of treatment-induced changes in expression between childhood ALL patients that relapsed and those who remained in continuous complete remission revealed significant changes in the b-2 adrenergic receptor gene (ADRB2) expression [69]. The ADRB2 has been reported to regulate apoptosis [69]. Subsequent analysis of the ADRB2 promoter polymorphism (-468C>G, -367T>C, -47T>C, -20T>C) and resulting haplotype has shown their relation to early treatment response in ALL [69]. Asparaginase is a standard component of childhood ALL treatment. Asparagine is normally produced by the enzyme asparagine synthetase (ASNS). Malignant lymphoblasts are thought to have low ASNS levels; depletion of asparagine by asparaginase can thus selectively kill leukemia cells by decreasing protein biosynthesis. ASNS expression can be upregulated by the basic region leucine zipper activating transcription factor (ATF) whose expression is triggered by acid amino-acid deprivation [70]. Analysis of genes in asparaginase pathway revealed that T allele of 1562C>T substitution in the 5¢UTR of the ATF5 gene is associated with higher promoter activity and confers higher risk of ALL relapse in patients who received Escherichia coli asparaginase [70]. Other candidate genes Several candidate gene studies have been conducted to identify genetic predictors of CS-associated osteonecrosis in children. Polymorphisms (rs6092 G>A) in SERPINE 1 or PAI-1 (serpin peptidase inhibitor or plasminogen activator inhibitor type 1) [71] and vitamin D receptor genes (VDR FokI polymorphism C>T) [49] have been identified as putatively related to the development of this treatment complication. The association of VDR and PAI-1 polymorphisms was not, however, confirmed in subsequent replication studies [49,72]. Hypertension is another complication of CS treatment. Polymorphisms in several genes, including leptin receptor (LEPR, 2.2.3

712

Gln233Arg), sodium chloride transporter (SLC12A3, 2744G>A, Arg913Gln), apolipoprotein B (APOB, XbaI polymorphism) and contactin-associated protein like2 (CNTNAP2, rs22886128), were identified as a potential modulators of CS-induced hypertension in childhood ALL patients [73]. With regard to the efficacy of treatment, the polymorphism (+246 A>G rs1799987) in the promoter of the chemokine receptor 5 gene was found to influence MRD level. Children carrying the allele G were more likely MRD negative [74].

Polymorphisms highlighted by genomewide association study

3.

3.1

Methotrexate Solute carrier organic anion transporter

3.1.1

The importance of several genes for therapeutic responses in ALL was revealed through GWAS. One of the first GWA study conducted in ALL pharmacogenetics pointed to the role of solute carrier organic anion transporter (SLCOB1), a hepatic organic anion transporter polypeptide (OATP), in MTX disposition [75,76]. A non-synonymous 521T>C polymorphism, resulting in a Val174Ala substitution, has been identified [75,77]. The 521C allele is associated with decreased transporter function in vitro [75]. Patient with this allele had lower MTX clearance and higher MTX plasma concentration [27,75-77]. The same variant was associated with gastrointestinal toxicity in childhood ALL patients [77,78], although not in all studies [27]. Detailed analysis of the polymorphisms across the SLCOB1 gene identified particular haplotypes that are associated with a low and high MTX clearance [76,79]. Interestingly, rare variations obtained by sequencing were also analyzed in the same study [79]. Those predicted to be functionally damaging were more frequent among patients with the lowest MTX clearance. Thiopurines Crossing gene expression profile with genome-wide genotypes at multiloci and TPMT activity in human HapMap cells lines, Stocco et al., identified an SNP (rs2413739 C>T) located in the PACSIN2 gene (protein kinase C and casein kinase substrate in neuron 2). The allele C leads to highest TPMT activity [78]. PACSIN2 plays a role in endocytosis, cell cycle control and autophagy [78]. In childhood ALL patients, this SNP was associated with severe gastrointestinal toxicity (i.e., stomatitis and mucositis), independently from TPMT genotypes [78]. 3.2

L Asparaginase A recent GWAS identified genes of aspartate metabolism as contributors to asparaginase sensitivity in vitro in HapMap cell lines and primary ALL cells [80]. Polymorphisms in several genes have been identified including adenylosuccinate lyase, aspartyl-tRNA synthase and argininosuccinate synthase 1 (ASS1) genes [80]. ASS1 can affect the level of aspartate that serves as a source for de novo asparagine synthesis [80] 3.3

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and has been identified through microarray expression profiling as upregulated in cell lines with resistance to asparaginase [81]. Another GWAS was conducted in order to find SNPs predisposing to asparaginase hypersensitivity [82]. An association with nine SNPs located in GRIA1 (glutamate receptor) gene, in which the rs4958381 has the strongest impact, was found [82]. Children with allele A are more likely than those with genotype GG to develop allergy to asparaginase. GRIA1 encodes a subunit of the AMPA receptor, a tetrameric ligand-gated ion channel that transmits glutamatergic signals in the brain and seems to play a role as neurotransmitter but also as immunomodulator [82].

dexamethasone clearance and SNP (rs251177) in FCHSD gene (FCH and double SH3 domain protein 1) was associated with higher asparaginase antibodies in childhood ALL patients [88]. The SNP rs 1966862 in Rho GTPase activating protein 24 (ARHGAP24) gene has been found to be the most predictive SNP for drug-induced hepatoxicity during maintenance therapy in a childhood Japanese ALL cohort [89]. Further replications of the polymorphisms identified through GWAS are needed. Likewise, the functional impact of majority of SNP identified by this approach (or SNPs in LD) remains to be elucidated.

3.4

Corticosteroids Association of several polymorphisms in genes coding for ACP1 (acid phosphatase 1, rs12714403 G>A and rs10167992 C>T) and SH3YL1 (SH3 domain containing Ysc84-like 1, rs4241316 T>C and rs10193882 A>T) were also identified through GWAS, as independent predictive factors for osteonecrosis in children [72].

4.

All drugs GWAS allowed the discovery of others candidate genes that may play a role in the modulation of MRD status and ALL relapse. For example, a polymorphism in interleukin 15 (IL15) gene was associated with MRD status at the end of remission induction in GWAS [83]. IL15 is a proinflammatory cytokine that promotes T-cell proliferation and upregulates cytokine secretion, cell adhesion and migration [84]. Higher expression of IL15 was found in lymphoblasts of children with CNS relapse or presenting CNS disease [83]. Several SNPs of AT-rich interactive domain protein 5B (ARID5B) gene has been associated with a higher risk of ALL in two GWAS [85,86]. ARID5B is a transcription factor that plays role in embryogenesis and growth regulation. Several polymorphisms that were associated with ALL susceptibility were also associated with poor treatment outcome. For example, children with T allele of rs6479778 C to T substitution had higher risk of relapse; T allele was also associated with a positive MRD at the end of induction therapy [87]. Another GWAS conducted in 2535 childhood ALL patients revealed the strongest association with the risk of relapse and an SNP (rs 7142143) located in the intronic region of glycogen phosphorylase gene. Patients with the allele C had a higher risk of relapse as compared to those with the allele T. This effect remained prognostic after adjusting for all known risk factors [88]. Same GWAS identified several other SNPs associated with the higher risk of relapse: SNPs in phosphodiesterase 4B (PDE4B: rs6683977, rs524770, rs641262) gene were also associated with reduced levels of polyglutamated MTX in ALL blasts; SNPs in the ABCB1 gene (rs10264856, rs4728709) were also associated with

While ALL therapies are highly effective, studies have shown excesses of morbidity in ALL survivors. These morbidities include cardiac toxicity, neurocognitive dysfunction, metabolic syndrome, infertility, bone morbidity and second neoplasms. They are likely related to an exposure to chemotherapy and radiotherapy and may manifest years after the treatment has been completed [90]. Genetic variations can also modulate the onset of these late treatment complications. Cardiac toxicity is an important late effect after anthracycline treatment and is thought to occur by ROS-mediated cardiac damage. Polymorphisms in genes coding for the enzymes that detoxify ROS (superoxide dismutase, catalase [CAT] and GSTs) in relation to cardiac damage in childhood ALL survivors have been analyzed. Significant correlation with CC homozygosity for the polymorphism (rs10836235 [c.66 + 78C>T]) in CAT gene has been found [91]. The MRP1 efflux transporter is expressed in heart and takes part in the detoxification and protection of cells from the toxic effects of anthracycline. The TT genotype of C to T rs3743527 substitution located in 3¢UTR of MRP1 gene was associated with anthracycline-induced left ventricular dysfunction in childhood ALL patients [92]. Neurocognitive problems, generally characterized by reduced attention and processing speed, are long-term drug side effects observed in survivors of childhood ALL [93]. GSTT1 null genotype was associated with problems in attentiveness [93]. SNPs in apolipoprotein E (APOE4) and methionine synthase (MS) have been associated with the onset of neurocognitive impairment [93]; the MS 2756 A>G (rs 1805087) and the APOE4 Cys112Arg (rs 429358) were associated with attention defects and MS 2756 A>G was also associated with a slower response speed [93]. Genotypes related to lower folate levels (and higher homocysteine concentrations) such as those in MTHFR gene were also more likely to correlate with attention-deficit/hyperactivity disorder (ADHD). The 1298A>C variant appeared to be the linked to the inattentive symptoms of ADHD [94] and impaired neurocognitive functioning [95].

3.5

Genetic predictors of late treatmentrelated complications in ALL

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Monoamine oxidase (MAOA) is involved in serotonin and norepinephrine catabolism. A defect in this catabolism could be responsible of an overactivation of the sympathetic nervous system, which leads to anxiety and physiologic stress. This could explain the association observed between the MAOA SNP 1460 C>T (rs1137070) and the onset of neurocognitive problems in childhood ALL survivors [93]. Functional polymorphisms (-786T>C and 894G>T) in NOS3 gene coding for endothelial nitric acid synthase showed significant association with lower level of externalizing problems (i.e., improved affect and emotion control) [96]. Homozygous children for the T 894 allele were also at higher risk for long-term neurocognitive decline [97]. Nitric oxide acts as a molecular second messenger and is a potent vasodilator. It can also catalyze the formation of S-nitroso-homocysteine attenuating homocysteine-related endothelial cytotoxicity. Paired box 4 (PAX4) and transcription factor 7-like 2 are transcription factors that play critical roles in pancreatic b-cell development and/or function. Several variants of these genes have been associated with onset of type 1 and 2 diabetes. Same polymorphisms have been analyzed for relationship with glucose tolerance (IGT) and insulin resistance in childhood ALL survivors. PAX4 Arg192His mutation (rs2233580) was significantly associated with IGT after adjustment for age [98]. The fat mass and obesity-associated gene (FTO) has been recently found to contribute to the risk of obesity. Polymorphism of rs9939609 T>A (allele A) was associated with an increased body mass index in children aged ‡ 7 years. Significant negative association (protective effect) between the T allele and prevalence of overweight status was found in subset of childhood ALL survivors treated with cranial radiation therapy [99]. Some patients may suffer from CS-related toxicity. In about 20% of children treated for ALL, a decrease in bone mineral density is reported, resulting in osteoporosis. The association of genetic variation (rs1876828 G>A) in corticotropin-releasing hormone receptor 1 (CRHR1) gene has been also associated in a sex-specific manner with increased risk of bone density deficit [100]. Finally, TPMT variants seem to be associated with a higher risk to develop secondary acute myeloid leukemia following ALL treatment or secondary brain tumors in children receiving at the same time thiopurine and radiation therapy [6]. 5.

Conclusion

In the last 10 years, many pharmacogenetic studies has been conducted in ALL and variety of potential markers have been identified. Developments in molecular biology and bioinformatics changed genomic landscape and provided knowledge of how genetic factors influence treatment responses. Further research is needed to identify predictors of treatment failure and drug-side effects since only few pharmacogenetic markers, such as those in TPMT genes has been used thus far to adjust drug dose in ALL patients. 714

6.

Expert opinion

The difficulty to identify best predictors of treatment response in ALL is in part caused by specificity of ALL treatment protocols that combine several drugs. Each drug is essential for treatment efficacy, but can also contribute to treatment resistance and treatment-related toxicity. The effect of each drug is modulated by many genes, and many genetic factors thus can affect disease progression and responses to treatment. Many genes remain to be studied. For example, microRNA and gene implicated in methylation of genes represent new potential candidates [101,102]. Down-regulation of mir355 was associated with outcome in ALL [103] or specific profiles of miRNA regulation were related to drug resistance patterns [101]. Drugs used in ALL treatment often share similar side effects and exhibit the phenomenon of cross-resistance. For example, a genome-wide expression analysis identified a set of differentially expressed genes exhibiting cross-resistance to prednisolone, vincristine, asparaginase and daunorubicin. These genes are involved in number of pathways including transcription, transport and cell cycle maintenance, underlying complexity of mechanisms leading to resistance in ALL [104]. Discordant phenotypes may further complicate identification of pharmacogenetic biomarkers. For example, overexpression of ribosomal protein genes was associated to an asparaginase resistance phenotype but was, in contrast, associated with higher sensitivity to vincristine [104]. Drug action pathways are not always fully understood and selection of candidates is not necessarily obvious through rational approaches. In that regard, GWAS offers more large view combining impact of many SNPs and genes implicated in different pathways. Success of GWAS is, however, largely influence by the sample size. It is worth also noting that rare or low-frequency variants are not tagged by the GWAS platform explaining why none of the variants identified thus far fully account for all the episodes of a specific adverse drug reaction [105]. It has been recently proposed that contribution of rare variants to complex disease, in conjunction with, or above common variants is an important component of missing heritability [106]. Rare variants are more likely than common ones to be functional and tend to have a stronger effect. It was recently suggested that variants influencing therapeutic efficacy are more likely to include rare disease- and treatment-modifying mutations [107]. In years to come, the data generated by whole exome/genome sequencing will give more comprehensive view on how common and rare variant influence therapeutic responses. Discrepancies have been seen across studies published so far in ALL pharmacogenetics that could be explained by different treatment protocol used, environmental and dietary factors but also by different population background as illustrated in a recent study [108]. Severity of the disease and drug dose used is important confounding component of pharmacogenetic studies. ALL is heterogeneous disease that harbors different

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Pharmacogenetic considerations for acute lymphoblastic leukemia therapies

resistance mechanisms and the effect of polymorphism(s) may differ depending on disease subtypes or risk groups. Moreover, in addition to the germ-line genome of the patient, the somatic genome of the tumor can alter the toxicity or efficacy of cancer chemotherapy. Indeed several somatic alterations (not addressed in this review) have been identified and have defined novel subtypes of ALL associated with poor prognosis and increased risk of relapse [109]. Many more pharmacogenetic/genomic studies are still needed to identify new markers and validate obtained results through replication studies and studies of associated functional effects. Genetic markers identified thus far are not likely of equal importance. Many work remains prior to implementation in patient care, in order to define their relative contribution, predictive power, how they are dependent on each other, or how they can be modulated by disease and treatment characteristics. In that regard, replication studies and collaborative efforts are essential to estimate whether any these biomarkers can eventually enter prospective studies Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Ste´phanie Dulucq1, Caroline Laverdie`re2, Daniel Sinnett2 & Maja Krajinovic†2,3 † Author for correspondence 1 University Health Center Bordeaux, Heamatology Laboratory, Bordeaux, France 2 University of Montreal, University Health Center Sainte Justine, Research Center, Department of Pediatrics, Montreal, QC, Canada 3 University of Montreal, Department of Pharmacology, Montreal, QC, Canada E-mail: [email protected]

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Pharmacogenetic considerations for acute lymphoblastic leukemia therapies.

Advances in our understanding of the pathobiology of childhood acute lymphoblastic leukemia (ALL) have led to risk-targeted treatment regimens and rem...
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