LETTER TO THE EDITOR

The difference between pre-B cell acute lymphoblastic leukemia andBurkitt lymphoma in relation to DNA damage repair genepolymorphisms in childhood

TIRAJE CELKAN1, MEHMET GUVEN2, BAHADIR BATAR2, & SAFA ALHAJ1

1Department of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, _Istanbul University, _Istanbul, Turkey, and2Department of Medical Biology, Cerrahpasa Medical Faculty, _Istanbul University, Turkey

(Received 14 January 2008; accepted 17 April 2008)

The clinical presentation and cytogenetic character-

istics of acute lymphoblastic leukemia (ALL) and

non-Hodgkin lymphoma (NHL) with the same cell

type (B or T) are very similar supporting the concept

that both represent a spectrum of a single disease.

Both diseases have many features in common. They

are morphologically indistinguishable and are con-

sidered as a part of a biological unity. In paediatric

oncology, both pathologies are still considered to

represent two different disease entities and ALL is

diagnosed when bone marrow contains more than

25% lymphoblasts. Previous studies which were

designed to differentiate between these two diseases

by phenotype and expression profile, suggest that

ALL derive from a cell progenitor of the bone

marrow, while blasts of lymphoma are more mature.

The human DNA damage repair system can

recognise and repair damage to maintain genomic

stability. We investigated whether putatively func-

tional single nucleotide polymorphisms in DNA

repair genes influence susceptibility to pre-B ALL

or Burkitt lymphoma. There are several DNA repair

pathways, including direct repair (MGMT), base

excision repair (XRCC1, OGG1, PARP4), nucleotide

excision repair (ERCC1, ERCC2/XPD, ERCC5/

XPG), double strand break repair (BRCA1,

BRCA2, LIG4, WRN, XRCC3, RAG1), and mis-

match repair (MSH2). We studied XRCC1 (X-ray

repair cross-complementing group 1) and XPD

(xeroderma pigmentosum group D) genes located

on the 19th chromosome, which are involved in base

excision repair (BER) and nucleotide excision repair

(NER), respectively. Chromosome 19 is also the

location of genes (LYL1, NOTCH 3, AXL, CEBPA,

BCL3 and BAX) which are associated with leukemia

and lymphoma (especially BCL 3 (B cell leukemia-

lymphoma) gene) [1].

Polymorphisms were studied in 52 children with

pre B cell ALL (mean age+SD; 5.9+4 years) and 33

children with Burkitt lymphoma (BL) (mean

age+SD; 8.2+3.4 years, p5 0.01) in Cerrahpasa

Medical Faculty Pediatric Hematology-Oncology

Unit between 1995 and 2008. The control group

(n¼ 60) was matched for age, sex and ethnicity. The

diagnosis of pre B ALL was done by bone marrow

aspiration and immunophenotyping while BL was

diagnosed by biopsy of the involved site or cyto-

chemical examination of peritoneal or pleural fluid.

Bone marrow was involved in 7 children with BL.

Genomic DNA was extracted from leukocytes

using NucleoSpin DNA purification kit (Macherey-

Nagel GmbH, Duren, Germany) according to the

manufacturer’s instructions. Genotyping of XRCC1

codon 194 Arg to Trp (C4T) and 399 Arg to Gln

(G4A), and XPD codon 312 Asp to Asn (G4A),

and 751 Lys to Gln (A4C) polymorphisms were

performed using polymerase chain reaction-based

restriction fragment length polymorphism (PCR-

RFLP) technique. These methods were previously

described [2,3].

In our study, there was no significant difference in

the genotype distribution between pre B ALL and BL

Correspondence: Tiraje Celkan, Armakent B2/8 Konaklar Mah, Sebboy Sok. 4, Levent- _Istanbul 80620. E-mail: tirajecelkan@yahoo.com

Leukemia & Lymphoma, August 2008; 49(8): 1638–1640

ISSN 1042-8194 print/ISSN 1029-2403 online � 2008 Informa UK Ltd.

DOI: 10.1080/10428190802140063

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patients and controls for XPD codon 312 or codon

751 or XRCC1 codon 399 polymorphisms

(p4 0.05).

However, there was a significant difference

between frequencies for XRCC1-194 Arg/Trp gen-

otype in BL patients and healthy controls (Table I;

3% of BL patients and 10% of controls; p¼ 0.004).

There was a also a significant difference between

frequencies of XRCC1-194 Arg/Trp genotype in BL

and pre B ALL patients (Table I; 3% of BL patients

and 16% of pre B ALL patients). The XRCC1

194Trp allele showed a protective effect against

development of childhood BL, in other words it was

associated with a reduced risk of BL but not

childhood pre B ALL. We also evaluated the BL

group with bone marrow infiltration, but no

significant difference was found in the relation to

polimorphism. c-Myc translocations are thought to

be a by-product of immunoglobulin somatic hyper-

mutation and class switching occurring physiologi-

cally in mature B cells (but not pre-B cells) during

the germinal centre reaction [4]. Ig gene remodel-

ling, V(D)J recombination, isotype switching and

somatic hypermutation generates double-strand

DNA breaks. Differences in XRCC1 function might

influence the rate development of c-Myc transloca-

tions and BL because XRCC1 is involved in base

excision repair and in accordance repair of deami-

nated uracils that are produced during these

immunoglobulin remodelling mechanisms [5].

Shen et al. also showed that XRCC1 Arg194Trp

polymorphism was associated with decreased NHL

risk (Arg/Trp vs. Arg/Arg, OR: 0.72; 95% CI: 0.49–

1.07; Trp/Trp vs. Arg/Arg, OR: 0.45; 95% CI: 0.10–

1.99; p trend: 0.05) in diffuse large B-cell lymphoma

[6]. However, similar studies have reported contra-

dictory findings regarding the association between

DNA polymorphisms and NHL [7–9].

In our study, the association between genetic

polymorphisms in DNA repair genes and risk of BL

or pre B ALL may be a coincidental finding.

However, immunoglobulin formation and class

switching which must be completed before mature

B cell formation may trigger DNA breakage and

individual polymorphisms of DNA repair genes may

result in leukemia or lymphoma development.

References

1. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, et al.

Modulation of nucleotide excision capacity by XPD poly-

morphisms in lung cancer patients. Cancer Res 2001;61:1354–

1357.

2. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA.

XRCC1 polymorphisms: effects on aftatoxin B DNA adducts

and glycophorin A variant frequency. Cancer Res 1999;59:255–

256.

Table I. Distribution of allele and genotype frequencies of XPD and XRCC1 polymorphisms in controls and patients.

Pre B ALL Burkitt lymphoma

OR (95% CI)b pbGenotype Control Patients OR (95% CI)a pa Patients OR (95% CI)a pa

XPD 312

Asp/Asp 21 20 Reference 13 Reference Reference

Asp/Asn 30 24 0.84 (0.34–2.05) 0.83 16 0.86 (0.31–2.39) 0.93 1.02 (0.36–2.92) 0.85

Asn/Asn 9 8 0.93 (0.26–3.34) 0.86 4 Fisher’s exact test 0.45 Fisher’s exact test 0.49

Asp allele frequency 0.60 0.62 Reference 0.64 Reference Reference

Asn allele frequency 0.40 0.38 0.92 (0.50–1.68) 0.88 0.36 0.84 (0.45–1.55) 0.66 0.91 (0.49–1.69) 0.88

XPD 751

Lys/Lys 21 19 Reference 12 Reference Reference

Lys/Gln 29 24 0.99 (0.37–2.26) 0.99 19 1.15 (0.42–3.16) 0.95 1.25 (0.44–3.57) 0.81

Gln/Gln 10 9 0.99 (0.29–3.40) 0.78 2 Fisher’s exact test 0.19 Fisher’s exact test 0.19

Lys allele frequency 0.59 0.60 Reference 0.65 Reference Reference

Gln allele frequency 0.41 0.40 0.95 (0.52–1.75) 1.00 0.35 0.77 (0.42–1.43) 0.46 0.81 (0.42–1.49) 0.56

XRCC1 194

Arg/Arg 48 37 Reference 32 Reference Reference

Arg/Trp 12 13 0.49 (0.18–1.31) 0.18 0 Fisher’s exact test 0.004 Fisher’s exact test 0.0008

Trp/Trp 0 2 Fisher’s exact test 0.20 1 Fisher’s exact test 0.34 Fisher’s exact test 0.56

Arg allele frequency 0.90 0.84 Reference 0.97 Reference Reference

Trp allele frequency 0.10 0.16 1.71 (0.68–4.33) 0.29 0.03 Fisher’s exact test 0.04 Fisher’s exact test 0.001

XRCC1 399

Arg/Arg 20 15 Reference 15 Reference Reference

Arg/Gln 30 32 1.42 (0.57–1.42) 0.54 13 0.58 (0.20–1.62) 0.36 0.40 (0.13–1.18) 0.10

Gln/Gln 10 5 0.66 (0.15–2.77) 0.75 5 0.66 (0.16–2.77) 0.75 1.00 (0.19–5.19) 0.71

Arg allele frequency 0.58 0.60 Reference 0.65 Reference Reference

Gln allele frequency 0.42 0.40 0.92 (0.50–1.68) 0.88 0.35 0.74 (0.40–1.37) 0.38 0.80 (0.44–1.49) 0.56

aPearson chi-square test or Fisher’s exact test (Control þ Patients).b(pre B ALL þ Burkitt lymphoma groups).

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translocations in B cell lymphomas. Oncogene 2001;20:5580–

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5. Akbari M, Otterlei M, Pena-Diaz J, Aas PA, Kavli B, Liabakk

NB, et al. Repair of U/G and U/A in DNA by UNG2-associated

repair complexes takes place predominantly by short-patch

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Acids Res 2004;32:5486–5498.

6. Shen M, Purdue MP, Kricker A, Lan Q, Grulich AE, Vajdic

CM, et al. Polymorphisms in DNA repair genes and risk of

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Haematologica 2007;92:1180– 1185.

7. Shen M, Zheng T, Lan Q, Zhang Y, Zahm SH, Wang SS, et al.

Polymorphisms in DNA repair genes and risk of non-Hodgkin

lymphoma among women in Connecticut. Hum Genet

2006;119:659–668.

8. Hill DA, Wang SS, Cerhan JR, Davis S, Cozen W, Severson

RK, et al. Risk of non-Hodgkin lymphoma (NHL) in relation to

germline variation in DNA repair and related genes. Blood

2006;108:3161–3167.

9. Hughes AM, Armstrong BK, Vajdic CM, Turner J, Grulich A,

Fritschi L, et al. Pigmentary characteristics, sun sensitivity and

non-Hodgkin lymphoma. Int J Cancer 2004;110:429–434.

1640 Letter to the Editor

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