|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-06-1627.
NEOPLASIA
From the Pediatric Clinic II, Juliane Marie Centre,
Department of Clinical Immunology, and Department of Pathology,
Laboratory Centre, The University Hospital, Rigshospitalet, Copenhagen,
Denmark.
Epidemiological data indicate that acute lymphoblastic
leukemia (ALL) could be induced by interactions between the immune system and early childhood infections. Mannose-binding lectin (MBL)
plays a critical role in the immune response in early childhood before
specific immune protection develops. We investigated whether there may
be an association between childhood ALL and low-producing MBL
genotypes. Serum MBL levels depend on normal (A)
or defective (O) alleles, and on normal
(Y) or reduced (X) promoter activities. For
this study, 137 noninfants with ALL and 250 controls were classified
into 3 MBL genotype groups according to their influence on
the serum level of functional MBL: group I, YA/YA and
YA/XA (higher levels); group II, XA/XA and
YA/O (intermediate levels); and group III, MBL
insufficiency with XA/O or O/O
(MBL-deficient) genotypes. Compared with controls, cases
more often had low-level genotypes (I/II/III: 63 [46%]/44
[32%]/30 [22%] vs 145 [58%]/65 [26%]/40 [16%];
P = .02) and MBL deficiency (8.8% vs 2.8%;
P = .009). Thus, the ALL odds ratio for
MBL-deficient versus nondeficient individuals was 3.3 (95% CI, 1.3-8.7), whereas the ALL odds ratio for group I versus group
II/III genotypes was 0.62 (95% CI, 0.41-0.94). MBL group III patients
were significantly younger at diagnosis than patients in group I/II
(median, 3.9 vs 5.2 years; P = .04). The study shows
that the presence of low-level MBL genotypes is associated
with an increased risk of childhood ALL, particularly with early age at onset.
(Blood. 2002;100:3757-3760) Acute lymphoblastic leukemia (ALL) is a group of
closely related yet cytogenetically distinct hematological
malignancies. Approximately 50% of all cases of ALL have either a
high-hyperdiploid genotype (chromosome modal number higher than 51) or
the chromosomal translocation t(12;21)(p13;q22) (TEL/AML1
gene fusion).1,2 Epidemiological data have
indicated that childhood ALL may occur as a consequence of an abnormal
interaction between the immune system and certain unidentified
infections.3-6 Given that the characteristic incidence
peak of ALL emerges by the age of 2 to 3 years, it has been proposed
that this abnormal interaction should take place during early childhood
when the immune system is immature.6,7 Mannose-binding
lectin (MBL) is a serum protein that plays a critical role in
the innate immune response, with a particular role in the vulnerable
period of infancy before adequate specific immune protection is
established.8,9 A single functional gene (mbl2) at chromosome 10 codes for human MBL.10,11 The
normal wild-type MBL allele is designated A,
whereas the 3 common variant alleles that cause low serum MBL levels
are designated O.12 The variant alleles are
relatively common in many ethnic groups including Eskimos (12%) and
whites (20%).13 Serum MBL concentrations are further dependent on polymorphisms in the promoter region of the mbl2 gene.14,15 In particular, a polymorphism
at position Presently, knowledge is lacking with respect to those factors that
influence the development of critical leukemogenic cytogenetic aberrations in lymphoblasts. Because of the importance of MBL for the
infectious pattern during early childhood, we investigated whether the
presence or absence of variant MBL alleles may influence the occurrence
of ALL.
Patients
Cytogenetics
Treatment outcome Using a clone-specific competitive PCR method, the minimal residual disease (MRD) was determined after 4 weeks of induction therapy in 68 patients who had clonal immune gene rearrangements and for whom DNA was available.18 All patients were followed until December 31, 2001.Controls A total of 250 healthy adult, Danish, white volunteers served as background controls (190 unselected blood donors and 60 from unselected hospital staff).15Mannose-binding lectin The MBL genotypes in patients and controls were determined by PCR as previously described.13,14 We defined 3 MBL genotype subgroups: group I included YA/YA patients (normal structural genes and promoter activities) and YA/XA patients (one high- and one low-expression promoter). Group II included XA/XA patients (2 low-expression promoters) and patients with only one normal structural allele with a high-expression promoter (YA/O). Group II patients will have serum MBL levels that are reduced 2- to 4-fold.13 Group III included the patients with 2 defective alleles (O/O = MBL deficient) and the XA/O patients (those who had one variant gene and a normal gene with a low-expression promoter), of which both subsets have virtually undetectable MBL in the blood.19Statistics Subgroups were compared by the Mann-Whitney U test, Fisher exact test, and the Chi-squared test, including analysis for trend for the distribution of the 3 MBL genotype subgroups. In the event-free survival (EFS) analyses, we included as events death during induction or death in remission, relapse, or the diagnosis of a second malignant neoplasm, whichever occurred first. The Kaplan-Meier method was applied for estimation of probability of EFS. Subgroups were compared with the log-rank test. In all analyses, 2-sided P values less than .05 were regarded as being significant. All statistical analyses were done with SPSS 11.0 software (SPSS, Chicago, IL).
The ALL cases and controls differed in their MBL
genotypes, with a significantly higher frequency of MBL
low-level genotypes among ALL cases (MBL group I/II/III: 63 (46%)/44 (32%)/30 (22%) vs 145 (58%)/65 (26%)/40 (16%);
P = .02, analysis for trend; Table 1). Of the 30 ALL patients (22%) in
MBL group III, 12 (9%) were MBL deficient
(O/O), a significantly higher frequency than that among
controls (P = .009). The odds ratio for ALL
for MBL-deficient versus nondeficient individuals was 3.3 (95% confidence interval, 1.3-8.7). In contrast, the odds ratio for
ALL for individuals with high-level MBL genotypes compared
with the intermediate or low-level individuals was 0.62 (95%
confidence interval, 0.41-0.94).
Nonwhite and white patients did not differ in their MBL group I-III distribution (MBL group I/II/III: 6/7/6 vs 57/37/24; P = .35). The increased frequency of low-level genotypes was found in both pre-B-lineage and T-lineage ALL and seemed to be most pronounced in the 56 patients for whom successful cytogenetic analyses revealed neither t(12;21) positivity nor high-hyperdiploidy (Table 1). The 30 patients classified as MBL group III were diagnosed with ALL at a significantly earlier age than the remaining 107 MBL group I/II patients (median, 3.9 vs 5.2 years; P = .04). The lower age at diagnosis was found in both pre-B-lineage and T-lineage ALL (median age, pre-B-lineage [n = 113]: 3.4 vs 4.6 years; P = .02; T-lineage [n = 24]: 6.5 vs 9.1 years; P = .26). The day-29 MRD levels did not differ between the 3 MBL groups (median MRD, group I: 0.02%, group II: 0.01%, group III: 0.2%; P = .6). After a median follow-up of 5.5 years for patients who stayed in remission, 5 patients died during induction therapy, 18 patients developed a relapse 0.2 to 6.7 years from diagnosis (median, 1.9 years), 2 patients developed a second myeloid malignancy, and one patient died in remission. At 7 years the pEFS is 0.76, which is identical to the overall outcome of the NOPHO ALL-92 protocol in the 5 Nordic countries.16 The 7-year pEFS did not differ significantly between the 3 MBL genotype subgroups (group I: 0.73 ± 0.07, group II: 0.79 ± 0.07, group III: 0.84 ± 0.08; P = .54). Similarly, the 3 MBL groups did not differ significantly in their 7-year risk of relapse (group I: 0.21 ± 0.06, group II: 0.16 ± 0.06, group III: 0.10 ± 0.07; P = .43).
Circumstantial evidence has been provided for a relationship between childhood ALL in general and the pattern of infections during early childhood, but the mechanisms by which these infections may influence the natural history of ALL have been unclear.3-6,20,21 More specifically, the hypotheses put forward suggest that childhood ALL may be caused by a combination of a lack of common infections in infancy (hygiene hypothesis), leading to a failure of normal immune system modulation that could leave the individual susceptible to leukemogenic bacterial or viral infections later in early childhood (delayed infection hypothesis).6 Even if these patterns of childhood infections could influence the risk of leukemia, the biologic mechanisms involved in these 2 settings could be completely unrelated. In addition, each of them may influence only certain subsets of childhood ALL. Although there has been some evidence that HLA class II alleles could influence the risk of childhood ALL,22 there has so far been little to support a link between common polymorphisms in the immune system and the risk of childhood ALL. The present study suggests an MBL gene dose-dependent association to the risk of ALL with a significantly increased leukemia odds ratio for individuals with low-level MBL genotypes. This finding lends support to the proposed theory of an increased risk of ALL subsequent to an abnormal response to infections during early childhood (delayed infection hypothesis).1 Due to more frequent and/or more severe infections, the proliferative stress on the developing immune system, possibly leading to critical leukemogenic DNA damages, would be more pronounced in children with low-level compared with those with high-level MBL genotypes. The mechanisms by which the low-level MBL genotypes lead to an increased risk of deleterious cytogenetic aberrations is unclear and could simply involve random events second to an increased turnover of B- and T-lineage lymphoblasts. It remains to be explored whether the association is specific for MBL or whether other polymorphisms in the immune system may have a similar impact on the risk of childhood ALL. The study indicates that the MBL genotype distribution could be normal, specifically among the ALL subsets that are especially frequent in the high-incidence 2- to 7-years age group (ie, the translocation t(12;21)-positive and high-hyperdiploid leukemias). This is especially intriguing, because t(12;21)-positive and high-hyperdiploid ALL so far are the only noninfant groups of childhood ALL for which a high prevalence of cells with leukemia-associated genetic markers have been demonstrated at birth.23-27 However, future studies are needed to confirm this finding and to explore whether other pathogenic mechanisms are involved in these patient subsets. The differences between cases and controls in MBL genotype distributions found in the present study are unlikely to be due to ascertainment bias of our adult control population. Thus, a previous study of young Danish white cystic fibrosis patients showed the same MBL genotype frequencies as our controls.19 In addition, a study on cord blood from healthy English children was in accordance with the genotype distribution both in healthy adult British controls and in the present control population.28,29 Finally, the younger age at diagnosis for the MBL group III compared with group I/II individuals also supports the theory that the distribution of MBL genotypes in children with ALL is truly skewed compared with the background population. This is the first study that indicates a critical interaction between the developing immune system and the risk of childhood ALL. Hence, further case-control studies are needed both to confirm this finding and to explore in detail whether more frequent and/or severe infections in early childhood may lead to ALL. Such epidemiological studies should be stratified by the MBL genotypes of the individuals as well as by the cytogenetically defined ALL subtypes.
Submitted June 6, 2002; accepted June 25, 2002.
Prepublished online as Blood First Edition Paper, July 5, 2002; DOI 10.1182/blood-2002-06-1627.
Supported by The Lundbeck Foundation (grant no. 38/99), The Danish Medical Research Council, and The Novo Nordisk Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kjeld Schmiegelow, Section of Clinical Hematology and Oncology, Pediatric Clinic II, Juliane Marie Centre, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen; e-mail: kschmiegelow{at}rh.dk.
1.
Rubnitz JE, Downing JR, Pui CH, et al.
TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance.
J Clin Oncol.
1997;15:1150-1157 2. Forestier E, Johansson B, Gustafsson G, et al. Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukaemia Cytogenetic Study Group. Br J Haematol. 2000;110:147-153[CrossRef][Medline] [Order article via Infotrieve]. 3. Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer. 1995;71:1-5[Medline] [Order article via Infotrieve]. 4. Alexander FE, Boyle P, Carli PM, et al. Population density and childhood leukaemia: results of the EUROCLUS Study. Eur J Cancer. 1999;35:439-444[CrossRef][Medline] [Order article via Infotrieve]. 5. Kinlen LJ, Balkwill A. Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK. Lancet. 2001;357:858[CrossRef][Medline] [Order article via Infotrieve].
6.
Greaves M.
Childhood leukaemia.
Br Med J.
2002;324:283-287
7.
Smith MA, Chen T, Simon R.
Age-specific incidence of acute lymphoblastic leukemia in U.S. children: in utero initiation model.
J Natl Cancer Inst.
1997;89:1542-1544 8. Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today. 1996;17:532-540[CrossRef][Medline] [Order article via Infotrieve].
9.
Koch A, Melbye M, Sorensen P, et al.
Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood.
JAMA.
2001;285:1316-1321
10.
Sastry K, Herman GA, Day L, et al.
The human mannose-binding protein gene: exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10.
J Exp Med.
1989;170:1175-1189 11. Taylor ME, Brickell PM, Craig RK, Summerfield JA. Structure and evolutionary origin of the gene encoding a human serum mannose-binding protein. Biochem J. 1989;262:763-771[Medline] [Order article via Infotrieve]. 12. Sumiya M, Super M, Tabona P, et al. Molecular basis of opsonic defect in immunodeficient children. Lancet. 1991;337:1569-1570[CrossRef][Medline] [Order article via Infotrieve]. 13. Garred P, Madsen HO, Svejgaard A. Genetics of human mannan-binding protein. In: Ezekowitz RAB,Sastry K,Reid KBM, eds. Collectins and Innate Immunity. Austin, TX: RG Landes; 1996:139-164. 14. Madsen HO, Garred P, Thiel S, et al. Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol. 1995;155:3013-3020[Abstract].
15.
Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P.
Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America.
J Immunol.
1998;161:3169-3175 16. Gustafsson G, Schmiegelow K, Forestier E, et al. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Leukemia. 2000;14:2267-2275[CrossRef][Medline] [Order article via Infotrieve].
17.
Kirchhoff M, Rose H, Lundsteen C.
High resolution comparative genomic hybridisation in clinical cytogenetics.
J Med Genet.
2001;38:740-744
18.
Nyvold C, Madsen HO, Ryder LP, et al.
Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.
Blood.
2002;99:1253-1258 19. Garred P, Pressler T, Madsen HO, et al. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest. 1999;104:431-437[Medline] [Order article via Infotrieve]. 20. Auvinen A, Hakulinen T, Groves F. Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer. 2000;83:956-958[CrossRef][Medline] [Order article via Infotrieve].
21.
Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ.
Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers.
Int J Epidemiol.
2001;30:1428-1437 22. Taylor GM, Dearden S, Payne N, et al. Evidence that an HLA-DQA1-DQB1 haplotype influence susceptibility to childhood common acute lymphoblastic leukaemia in boys provides further evidence for an infection-related aetiology. Br J Cancer. 1998;78:561-565[Medline] [Order article via Infotrieve]. 23. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999;354:1499-1503[CrossRef][Medline] [Order article via Infotrieve].
24.
Maia AT, Ford AM, Jalali GR, et al.
Molecular tracking of leukemogenesis in a triplet pregnancy.
Blood.
2001;98:478-482 25. Mori H, Xiao Z, Ford AM, et al. TEL-AML1 and AML1-ETO fusion sequence in normal newborn cord bloods [abstract]. Blood. 2000;96:88a. 26. Trka J, Zuna J, Zavacka-polouckova A, Madzo J, Holzelova E, Brabecova A. Evidence for the presence of t(12;21) in cord blood samples of healthy newborns [abstract]. Blood. 2000;96:694a.
27.
Taub JW, Konrad MA, Ge Y, et al.
High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia.
Blood.
2002;99:2992-2996 28. Mead R, Jack D, Pembrey M, Tyfield C, Turner M. Mannose-binding lectin alleles in a prospective recruited UK population: the ALSPAC Study Team: Avon longitudinal study of pregnancy and childhood. Lancet. 1997;349:1669-1670[CrossRef][Medline] [Order article via Infotrieve]. 29. Mullighan CG, Marshall SF, Welsh KI. Mannose-binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol. 2000;51:111-122[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  P. GERGELY Jr, B. PAZAR, Z. B. NAGY, T. GOMBOS, K. RAJCZY, Z. BALOGH, I. ORBAN, K. SEVCIC, and G. POOR Structural Polymorphisms in the Mannose-Binding Lectin Gene Are Associated with Juvenile Idiopathic Arthritis J Rheumatol, April 1, 2009; 36(4): 843 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Pine, L. E. Mechanic, S. Ambs, E. D. Bowman, S. J. Chanock, C. Loffredo, P. G. Shields, and C. C. Harris Lung Cancer Survival and Functional Polymorphisms in MBL2, an Innate-Immunity Gene J Natl Cancer Inst, September 19, 2007; 99(18): 1401 - 1409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dahl, A. Tybjaerg-Hansen, P. Schnohr, and B. G. Nordestgaard A Population-based Study of Morbidity and Mortality in Mannose-binding Lectin Deficiency J. Exp. Med., May 17, 2004; 199(10): 1391 - 1399. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
221 (X or Y genotypes) has a
significant effect on the MBL serum concentration, with the
Y promoter variant being responsible for high and the X variant for low MBL-expressing activity,
respectively.
10 years and/or
WBC = 10 × 109/L-49 × 109/L;
HR, WBC