Med Oncol (2017)34:179 DOI 10.1007/s12032-017-1038-7

REVIEW ARTICLE

Genetic susceptibility in childhood acute lymphoblastic leukemia Angela Gutierrez-Camino1

· Idoia Martin-Guerrero1 · Africa García-Orad1,2

Received: 11 July 2017 / Accepted: 5 September 2017 © Springer Science+Business Media, LLC 2017

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future. Keywords Childhood · Acute lymphoblastic leukemia · Susceptibility · SNP

Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy in developed countries [1, 2]. However, the causes of the disease are poorly understood. It is known that chromosomal abnormalities such as translocations or aneuploidies, characteristics of the most ALL cases, occur in utero [3]. Nevertheless, these events are insufficient to cause ALL by themselves. For instance, this is the case for TEL–AML1, the most common translocation for ALL. Studies using cord bloods from normal born children indicate that these translocations may occur at a rate of 1% or more in the normal population [4, 5]. This result suggests that a significant proportion of the population carries preleukemic clones, and the vast majority of these clones are self-limiting and do not result in disease. Therefore, a secondary event is essential for the development of ALL in those patients in which preleukemic clones persist [5, 6]. The specific causes for both initiating and secondary events are unknown, but like cancer in general probably arise from interaction between environmental exposures and genetic (inherited) susceptibility. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL, specifically in B-cell precursor ALL (BALL), which is the major subtype. We will also point to new findings that could be interesting for consideration in the near future.

& Africa Garcı´a-Orad [email protected] 1

2

Department of Genetics, Physic Anthropology and Animal Physiology, Faculty of Medicine and Nursery, University of the Basque Country, UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain BioCruces Health Research Institute, Barakaldo, Spain

Genetic factors The genetic component of ALL is supported by the high risk of ALL associated with Bloom’s syndrome, Li-Fraumeni, neurofibromatosis, ataxia telangiectasia and

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constitutional trisomy 21 [7], most of them caused by rare mutations of high penetrance in genes like TP53, NBN or ATM, that predispose to cancer risk. In addition, studies of familial ALL have also identified more rare germline mutations of high penetrance in genes such as PAX5, SH2B3 or ETV6 [8–10]. However, the vast majority of childhood ALL occurrences are not explained by these predisposing genetic abnormalities; instead, ALL susceptibility is likely influenced by the co-inheritance of multiple low-penetrant variants associated with a modestly increased risk of ALL [11]. The commonest method for identifying common lowrisk variants is through association studies based on comparing the frequency of polymorphic genotypes, usually single-nucleotide polymorphisms (SNPs), in cases versus controls [12]. The majority of the studies performed in ALL followed a candidate gene approach and identified some noteworthy potential candidates implicated in, for example, folate metabolism or the immune response. However, most of these studies were statistically underpowered or not reproducible [13]. By contrast, genomewide association studies (GWAS), that allow the screening of genetic variation across the entire genome, have provided unambiguous evidence that inherited genetic variation contributes to childhood ALL predisposition.

Genome-wide association studies (GWAS) This approach does not depend upon prior knowledge of function or presumptive involvement of any gene in disease causation. Moreover, it minimizes the probability of failing to identify important common variants in hitherto unstudied loci because, by using high-throughput genotyping technologies, up to a few million genetic markers are tested per patient [14]. In ALL, there are up to seven GWAS-related studies that have identified seven regions (eight loci) associated with ALL risk with p values much more significant than the values obtained in the candidate gene approach. The AT-rich interactive domain 5B (ARID5B) gene at 10q21.2 was one of the first regions identified by the two first pair of GWAS carried out by Trevin˜o et al. and Papaemmanuil et al. [11, 15]. ARID5B is a member of the ARID family of transcription factors with an important role in embryogenesis and growth regulation. The specific role of ARID5B in childhood ALL remains unknown, but accumulating evidence appears to indicate that ARID5B has a role in ALL development. For instance, Arid5b knockout mice exhibit abnormalities in B-lymphocyte development [16, 17], and ARID5B mRNA expression is upregulated in hematologic malignancies such as acute promyelocytic leukemia [18] and acute megakaryoblastic leukemia [19].

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A total of five SNPs in ARID5B were associated with childhood B-ALL in both GWAS (Table 1). The highest association signal was found for rs7089424 in the GWAS performed by Papaemmanuil et al., and it was in high linkage disequilibrium (LD) with rs10821936, reported by Trevin˜o et al. Remarkably, all the significant SNPs in ARID5B were located in intron 3 or exhibit high LD with intron 3. However, up to date, it is unknown how this region increases the susceptibility to ALL. The association of these SNPs with ALL risk was a novel finding and was confirmed in all subsequent studies and different ethnic groups [20–32], which supports the hypothesis that ARID5B is clearly involved in a general mechanism that contributes to the etiology of childhood ALL. The region 7p12.2 including Ikaros family zinc finger protein 1 (IKZF1) gene was the second locus simultaneously identified in the GWAS performed by Trevin˜o et al. and Papaemmanuil et al. [11, 15]. IKZF1 gene encodes the early lymphoid transcription factor Ikaros, which is a DNA-binding zinc finger transcription factor involved in the development of all lymphoid lineages [33]. Germline mutant mice expressing only non-DNA-binding dominantnegative leukemogenic Ikaros isoforms develop an aggressive form of lymphoblastic leukemia [34]. Moreover, chromosomal deletions involving IKZF1 are common (30%) in high-risk/poor-prognosis B-cell precursor ALL and are highly prevalent (95%) in ALL with BCR-ABL1 fusions [35, 36]. In IKZF1, a total of four SNPs were associated with childhood B-ALL in both GWAS (Table 1). The highest association signal was found for rs4132601 in the GWAS performed by Papaemmanuil et al. which was in high LD with rs11978267, reported by Trevin˜o et al. A relatively large number of studies evaluated the association between IKZF1 rs4132601 polymorphism and ALL risk, but the results were inconsistent due to limited sample sizes and different study populations [37]. In order to clarify the possible association between rs4132601 and risk of ALL, two meta-analyses were carried out, both confirming the existence of association [33, 37]. In the last year, new studies showing controversial results have been performed [30, 31, 38], so it could be interesting to include these data in a new metaanalysis. The SNP rs4132601 maps in the 3´untranslate region (UTR) of IKZF1, where another significant SNP, rs6944602, was also localized, suggesting an important role of this region in the increased risk of ALL. In fact, Papaemmanuil et al. [11] found that IKZF1 mRNA expression was significantly associated with rs4132601 genotype in a dose-dependent fashion, with lower expression being associated with risk alleles. However, up to date, this SNP has an unknown function. The third locus identified was CEBPE (CCAAT/enhancer-binding protein epsilon), reported by

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Table 1 Significant SNPs reported by GWAS and subsequent studies Gene

SNP

p

Study

ARID5B

rs7073837

p = 1.03 9 10−15

rs10740055

p = 1.61 9 10−14

Papaemmanuil et al. [11], Trevin˜o et al. [15], Migliorini et al. [57], Xu et al. [56], Orsi et al. [41]

rs7089424

p = 1.41 9 10−19

rs10821936

p = 1.40 9 10−15

rs10994982

p = 5.7 9 10−9

rs6964823

p = 1.8 9 10−13

rs4132601

p = 9.3 9 10−20

rs6944602

p = 1.5 9 10−15

rs11978267

p = 8.8 9 10−11

rs2239633

p = 5,6 9 10−8

rs10143875 rs4982731

p = 1 9 10−3 p = 1 9 10−12

rs2239635

p = 5,1 9 10−11

rs3731217

p = 1.13 9 10−8

IKZF1

CEBPE

CDKN2A/B

PIP4K2A

−3

rs2811709

p = 1 9 10

rs17756311

p = 1 9 10−5

rs3731249

p = 9.4 9 10−23

rs662463

p = 1.87 9 10−10

rs7901152

p = 1.89 9 10−8

Papaemmanuil et al. [11], Trevin˜o et al. [15], Migliorini et al. [57], Xu et al. [56], Orsi et al. [41]

Papaemmanuil et al. [11], Migliorini et al. [57], Xu et al. [56], Orsi et al. [41], Wiemels et al. [44]

Sherborne et al. [47], Orsi et al. [41], Xu et al. [51], Walsh et al. [52], Vijayakrishnan et al. [22], Hungate et al. [42]

Migliorini et al. [57], Xu et al. [56]

−9

rs11013046

p = 2.92 9 10

rs7088318

p = 1.13 9 10−11

rs7075634

p = 2.06 9 10−10

rs10828317

p = 2.3 9 10−9

LHPP

rs35837782

p = 1.38 9 10−11

Vijayakrishnan et al. [63]

ELK3

rs4762284

p = 8.41 9 10−9

Vijayakrishnan et al. [63]

Papaemmanuil et al. [11] at 14q11.2 in their GWAS. CEBPE is a member of CEBPs family of transcription factors and is involved in terminal differentiation and functional maturation of myeloid cells, especially neutrophils and macrophages [39]. In childhood ALL, intrachromosomal translocations involving IGH and CEBPE have been described, resulting in the upregulation of CEBPE expression [40]. At CEBPE, the highest association signal was found for rs2239633 (Table 1). This finding was replicated in some populations [25, 41, 42], but not in others [21, 22, 29]. A recent meta-analysis evaluating the association between this polymorphism and the risk of ALL concluded that rs2239633 was associated with the disease [39]. Nevertheless, this study did not include two important studies analyzing rs2239633 in ALL [21, 43], and since its publication in 2015, new studies have been published [30, 31]. Remarkably, the SNP rs2239633 maps within a 25.7-kb region of LD that encompasses the gene CEBPE and is located in 5´UTR region of the gene. Two other SNPs associated with ALL risk at p = 10−5 (rs7157021 and

rs10143875) map within this region of LD, providing additional support for 14q11.2 as a susceptibility locus. However, the rs2239633 has an unknown function, suggesting that additional polymorphisms underlie the association peak near CEBPE. Recently, Wiemels et al. [44] performing imputation-based fine mapping and functional validation analyses of this locus identified another polymorphism more significantly associated with B-ALL risk, rs2239635, at the promoter region of CEBPE. In fact, the role of CEBPE in B-ALL has been clarified with the identification of this SNP. The SNP rs2239635 is a ciseQTL (expression quantitative trait locus) for this gene, with an increased gene expression associated with risk allele. Interestingly, rs2239635 is located within an Ikaros transcription factor binding site, and the risk allele disrupts Ikaros binding near CEBPE [44]. One of the Ikaros functions in the normal lymphoid development is to silence CEBPE. Therefore, incomplete suppression of CEBPE by Ikaros due to rs2239635 may lead to lineage confusion, a common feature of leukemogenesis [45], and, in turn, promote B-ALL. In addition, Wiemels et al. in their study

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tested the interaction between rs2239635 and rs4132601, the SNP in IKZF1 aforementioned, and found that the combined effect of rs2239635 and rs4132601 risk alleles was greater than it would be expected if they operated independently, in contrast of the independent effect of each locus which had been suggested before [46]. The fourth region associated with B-ALL risk was at 9p21.3 [47]. This region comprises CDKN2A and CDKN2B genes and a long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS). CDKN2A codifies for INK4-class cyclin-dependent kinase (CDK) inhibitors p16INK4A and p14ARF [48]. These proteins are tumor suppressors that block cell cycle division during the G1/S phase and inhibit MDM2, respectively. The second gene CDKN2B encodes for the tumor suppressor p15INK4B, which is also a cyclin kinase inhibitor. Finally, ANRIL has widespread influences on gene expression, impacting the cell cycle by regulating the expression of tumor suppressors p14ARF, p15INK4B and p16INK4A [49]. The locus 9p21.3 is particularly remarkable due to independent signals recently discovered at this region in association with B-ALL susceptibility (Table 1). The first variant identified was rs3731217 [47], located in intron 1 of CDKN2A. This association was identified in children from the UK and replicated in several populations such as Germany, Canada [47] and France [41], but not in others like Poland [26], Hispanic [50] or Thai population [22]. In 2015, three independent studies pointed to rs3731249 in exon 2 of CDKN2A as the causal variant that conferred up to threefold increased risk of B-ALL in children of European ancestry and Hispanic children [51–53], also validated in a Spanish cohort [54]. Genotype correlation between rs3731249 and rs3731217 showed to be exceedingly low (r2 \ 0.01 in Europeans), and multivariate analyses including both SNPs indicated an independent contribution to ALL risk [51]. Finally, in 2016, Hungate et al. [42] pointed to rs662463 in ANRIL as an independent locus associated with B-ALL susceptibility in European and African-Americans. Therefore, although there is an obvious involvement of CDKN2A/B locus in B-ALL susceptibility, the variants annotated by the different studies are independent. This may be due to the fact that these SNPs could alter the locus function through diverse mechanisms in each population. In fact, it has been suggested that the alleles of the variant rs3731217 create two overlapping cis-acting intronic splice enhancer motifs (CCCAGG and CAGTAC) that might regulate alternative splicing of CDKN2A [42]. The SNP rs3731249 is a missense SNP in CDKN2A which produces a change in the amino acid sequence (alanine to threonine), resulting in reduced tumor suppressor function of p16INK4A [51]. Intriguingly, this SNP is also located in the 3´UTR region of p14ARF creating a microRNA (miRNA) binding

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site [55] that could cause the downregulation of the locus. Finally, rs662463 regulates CDKN2B expression by disrupting a transcription factor binding site for CEBPB (CCAAT/enhancer-binding protein b), a TF important for haematopoietic differentiation, in individuals of European ancestry [42]. All these data confirmed the implication of CDKN2A/B locus in the development of B-ALL since all these SNPs could act through different mechanisms that might alter the cluster [54]. The fifth region identified in 2013 by two independent studies [56, 57] was at 10p12.2, where PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase type 2 alpha) gene is located. PIP4K2A belongs to class II of PIP kinases, which also includes PIP4K2B and PIP4K2C [58]. PIP4K2A catalyzes the phosphorylation of phosphatidylinositol-5phosphate to form phosphatidylinositol-5,4-bisphosphate (PIP2), a precursor of the important second messenger molecule, PIP3 (phosphatidylinositol-3,4,5-trisphosphate) [56]. Through this mechanism, PIP4K2A is involved in secretion, cell proliferation, differentiation and motility [57]. Interestingly, it has been reported that PIP4K2A is highly expressed in peripheral blood cells and is upregulated during hematopoietic cell differentiation [58]. Moreover, suppression of PIP4K2A expression can prevent tumor cell growth and induce apoptosis in cell line and mouse models, indicating that causal variants on PIP4K2A could impact leukemogenesis through regulating its expression level [59]. In PIP4K2A, a total of five SNPs were reported to be associated with B-ALL risk in high LD (Table 1). The most significant SNP reported by Xu et al. [56] at this locus was rs7088318, an intronic variant with unknown function. The most significant SNP identified by Migliorini et al. was rs10828317, responsible for the N215S polymorphism in exon 7 of the gene, although it is predicted to be benign. These results were replicated in a Chinese population [60], but other two studies found no association with B-ALL risk [61, 62]; although in one of the studies, when analyses were limited to hyperdiploid B-ALL, the association approached significance [61]. Finally, Vijayakrishnan et al. [63] conducted a metaanalysis of two GWAS with imputation using 1000 Genomes and UK10K Project data as reference (a total of 1658 cases and 7224 controls) and identified new risk loci for B-ALL at 10q26.13 (rs35837782) and 12q23.1 (rs4762284), both with generic effects on the development of ALL (Table 1). Up to date, there are no studies that have validated this recent association signal. At 10q26.13, rs35837782 is located in intron 6 of the gene encoding phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP), whose function in B-cell development or B-cell malignancy needs to be established. The SNP rs4762284 at 12q23.1 maps to intron 1 of the gene encoding the ETS-domain protein (ELK3), and risk allele

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was associated with reduced expression of this gene in blood. ELK3 is highly expressed primarily at the early stages of B-lymphocyte development; therefore, reduced expression of ELK3 could cause B-cell developmental arrest, a hallmark of ALL [63].

Future directions First of all, it should be recognized that the biologically different subtypes of ALL suggest different etiologies [2, 13]. Therefore, risk variants are likely to have differential effects on ALL risk depending on cell lineage and phenotype. This is the case of ARID5B and PIP4K2A variants, which are highly associated with the risk of developing hyperdiploid ALL [15, 56]. In this line, Ellinghaus and colleagues performed a GWAS in patients with ALL characterized by translocation TEL–AML1 (ETV6-RUNX1), one of the most common subtypes. They found rs17505102 in TP63, rs1945213 in OR8U8, rs920590 in INTS10 and rs3942852 in PTPRJ specifically associated with this subtype of ALL [43]. In another study, Perez-Andreu et al. found rs3824662 in GATA3 associated with the risk of Ph-like ALL [64]. Therefore, subtype analysis of ALL could help to elucidate these different etiologies. Secondly, it has been estimated that the heritability of ALL attributable to all common variation is approximately 12% [63]. This estimate does not include the potential impact of gene–gene interactions or dominance effects, or gene–environment interactions impacting on ALL risk, factors that need to be considered. For instance, Wiemels et al. [44] recently showed that the combined effect of rs2239635 (CEBPE) and rs4132601 (IKZF1) risk alleles was greater than would be expected if they operated independently, although it had been suggested that each locus had an independent role in B-ALL development [46]. Regarding gene–environment interactions, the incidence of the disease has increased close to 1% per year in the past two decades, indicating that causal factors for the disease are likely to have become more prevalent in the population in the past decades [5]. Since genetic factors do not change on this time scale, it is probable that environmental factors play a significant role in the etiology of childhood ALL [65]. Therefore, incorporating epistatic gene–gene interaction or non-genetic risk factors into the studies could help to elucidate the etiology of ALL. On the other hand, the currently identified risk SNPs in ARID5B, IKZF1, CEBPE, CDKN2A/B (two loci), PIP4K2A, LHPP and ELK3 only account for 19% of the additive heritable risk [63], although the power of these studies to identify common alleles conferring relative risks of 1.5 or greater is high. Genotyping platforms used in

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GWAS predominantly focus on relatively common genomic variants, and only approximately 10% of SNPs with minor allele frequencies (MAF) of 5–10% are tagged in these GWAS. This limits the power to detect this class of susceptibility alleles [63]. Rare germline variants may confer more profound effects on risk and, then, have greater significance for individuals [14]. Recovery of untyped genotypes through imputation provides a mechanism of exploiting GWAS data sets to identify new risk alleles, and it enables fine mapping and refinement of association signals. This is the case of SNP rs3731249 in exon 2 of CDKN2A, which thanks to fine mapping and imputation was identified [51–53]. Moreover, the molecular mechanisms by which some of these variants are linked to ALL risk are unknown. Most of these variants lack of a clear function, like SNPs in ARID5B or PIP4K2A; instead, they could be in linkage with other variants biologically active, such as the SNP rs2239635 in the promoter region of CEBPE. As a result, findings from GWAS usually require extensive subsequent studies to discover the causal genetic variants underlying the GWAS signal [66]. Additionally, functional studies to understand the mechanism of involvement are also needed. For instance, rs4132601 in IKZF1 is associated with changes in gene expression but it is not known yet how this deregulation is produced. Finally, these GWAS also revealed that many loci that are associated with ALL susceptibility lie in noncoding regions of the genome. Noncoding elements, such as noncoding RNAs (ncRNAs), are increasingly believed to have relevant roles in cancer development [67]. NcRNAs are a diverse family of RNA transcripts that can be divided into several categories, such as small nucleolar RNAs (snoRNAs), small nuclear (snRNAs), miRNAs and long ncRNAs (lncRNAs; which are [200 nucleotides) [68]. All these RNAs act through different mechanisms to modulate gene expression, and many are known to have an important role in cancer biology, in particular miRNAs and lncRNAs. SNPs in these noncoding RNA molecules could affect their expression or function, affecting, in turn, the regulation of their target genes. Numerous SNPs in miRNAs have been described in association with cancer risk [69, 70]. In ALL, few studies analyzing the involvement of SNPs in miRNAs have been performed, and interestingly, all of them found significant findings [71–74]. Regarding lncRNAs, one of the locus described in the previous GWAS mentioned before, CDKN2A/B, contains the long noncoding RNA ANRIL, which has an important function silencing the cluster, and several SNPs in this lncRNA were associated with B-ALL risk [42, 54]. Other noncoding elements such as promoters, enhancers and splicing regulators are also central elements of the cell regulatory network that are acquiring relevance.

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With the introduction of whole-genome sequencing technologies, the identification of a high number of pathogenic variants located in the noncoding genome is increasing; therefore, a current goal is to elucidate the importance of noncoding variants in cancer, identifying driver mutations and distinguishing them from passenger mutations [67]. In this line, the interpretation of noncoding variants is turning into a realistic aim through major highthroughput studies such as the Encyclopedia of DNA Elements (ENCODE) [75], the “29 Mammals” Project [76], the Health Roadmap Epigenomics project [77] and specifically, the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, a collaboration between The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) which aims to analyze noncoding variants in 2500 tumor and matched normal whole genomes [78]. Therefore, although these GWAS have showed unequivocal evidence for an inherited genetic basis of ALL susceptibility, future studies that include subtype analysis, epistatic gene–gene interaction or non-genetic risk factors, SNPs with lower frequencies, noncoding regions or including functional analyses are likely to lead to further insights into ALL biology. Acknowledgements This study was funded by the Basque Government (IT989-16), UPV/EHU (UFI11/35). AGC was supported by a “Fellowship for Recent Doctors until their Integration in Postdoctoral Programs” by the Investigation Vice-Rector’s office of the UPV/ EHU.

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Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest.

11.

Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. 12.

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