Introduction
Acute lymphoblastic leukemia (ALL) is the most
common malignancy diagnosed in children, representing one quarter
of all pediatric cancers worldwide (1).
Over 40 years since the first associations between
particular human leukocyte antigen (HLA) profiles and disease
susceptibility were described, the identification of large numbers
of HLA-associated diseases parallels our improved understanding of
the genetic complexity of the HLA system and its extensive
polymorphism. These associations involve malignant as well as
autoimmune diseases, including the well-known association between
HLA-B27 and ankylosing spondylitis. Over time, several hundred
diseases have been reported to occur more frequently in individuals
with particular HLA genotypes (2).
These diseases include a broad spectrum of immune-mediated diseases
involving all major organ systems, certain malignancies, infectious
diseases and, more recently, adverse reactions to particular drugs
(2).
One of the factors that may determine whether a
child develops ALL is how it responds to the candidate infection.
Since immune responses to infection are under the partial control
of HLA genes, an association between an HLA allele and ALL may
provide support for an infectious etiology (3).
The biological significance of the association
between HLA types and acute leukemia is emphasized by the fact that
HLA may be involved in disease susceptibility or resistance. It is
important to investigate the HLA-associated susceptibility to
childhood ALL, as this may provide clues to leukemogenesis in
general and to the role of other risk factors (4).
The present study aimed to determine the association
between the HLA-DRB1 genotype and the susceptibility to ALL in
children and to evaluate the prognostic value of HLA-DRB1 alleles
in these patients.
Patients and methods
Patients
This study was performed on 50 ALL patients who were
consecutively admitted to the Pediatric Oncology Unit of Zagazig
University Hospital and 50 gender-matched healthy volunteers as a
control group.
The patients were subjected to: i) full clinical
history and thorough clinical examination; and ii) routine
laboratory investigations, including complete blood count,
examination of Leishman-stained peripheral blood smear, bone marrow
aspiration with examination of Leishman-and peroxidase-stained
films and immunophenotyping by flow cytometry.
Molecular HLA-DRB1 typing and risk
classification
The patients and controls were subjected to
molecular HLA-DRB1 typing and the patients also underwent risk
classification.
HLA typing
EDTA-anticoagulated whole-blood samples were
collected from patients and controls and processed as follows: i)
DNA extraction using the spin column technique (QIAamp DNA Blood
Mini kits; Qiagen, Hilden, Germany) was performed according to the
manufacturer's guidelines; ii) polymerase chain reaction (PCR)
amplification of the HLA-DRB1 gene (exon 2) target (INNO-LiPA
HLA-DRB1 Amplification Plus kit; Fujirebio Europe, Ghent, Belgium)
was performed and the amplicons were chemically denatured to form
single-stranded DNA. Reverse dot-blotting was performed on a nylon
membrane (INNO-LiPA HLA-DRB1 Plus strips, Fujirebio Europe), which
contains an array of immobilized, sequence-specific oligonucleotide
(SSO) probes. The biotin-labeled amplicons were then bound
(hybridized) to these SSO probes, which contain a complementary
target sequence and, thus, were captured onto the membrane strip;
iii) visualization of the results was achieved by incubating with
an enzyme conjugate (streptavidin and alkaline phosphatase), which
binds to the biotin of the PCR product, followed by the addition of
a substrate. The bands with the captured PCR product turned blue.
Interpretation was achieved by entering the band pattern into a
computer program.
Risk classification
The patients were divided into standard-and
high-risk groups according to the Children's Cancer Group (CCG)
risk stratification (5).
Standard-risk patients were defined as follows: age 1–9 years;
initial total leukocyte count <50,000/mm3; precursor
B-ALL immunophenotype; and no central nervous system (CNS)
manifestations or testicular infiltration. High-risk patients
exhibited any of the following at diagnosis: age ≥10 years; initial
total leukocyte count ≥50,000/mm3; T-ALL
immunophenotype; CNS manifestations; and overt testicular
leukemia.
Children with mature B-ALL were considered to be
among the high-risk patients and were treated separately using the
LMB-96 protocol, which is an international protocol conducted by
three cooperative groups (International Society for Pediatric
Oncology, CCG and United Kingdom Children's Cancer Study Group) and
(6).
Statistical analysis
The data were checked, entered and analyzed using
Epi Info 6 statistical software (Centers for Disease Control and
Prevention, Atlanta, GA, USA). The results are expressed as mean ±
standard deviation for quantitative variables and as number and
percentage for qualitative variables. The differences in the
frequencies of HLA-DRB1 alleles among the investigated groups were
analyzed using the Chi-square test with Yates' correction and the
two-tailed Fisher's exact test for results ≤5. Each allele
frequency in the patients was compared against the same allele in
controls. The odds ratios (ORs) with 95% confidence intervals were
calculated. P≤0.05 was considered to indicate statistically
significant differences.
Ethics
This study was conducted in accordance with the
ethical standards of the Helsinki Declaration of 1964, as revised
in 2000 (7) and was approved by
the Institutional Review Board of the Faculty of Medicine, Zagazig
University. Informed consent was obtained from all the study
participants.
Results
Patient characteristics
The mean age of the patients at diagnosis was
4.9±3.3 years (range, 2–13 years). The patients included 32 males
and 18 females, with a male:female ratio of 1.8:1. The most
frequent clinical manifestation was pallor (88%), followed by fever
(74%), hepatosplenomegaly (72%), lymphadenopathy (54%), purpura
(40%) and bone pain (30%). CNS was involved in only 4% of the
patients. A total of 72% of the patients had a total leukocyte
count <50,000/mm3 and 28% had a total leukocyte count
≥50,000/mm3. A total of 88% of the patients had
precursor B-ALL, 10% had T-ALL and 2% had mature B-ALL.
Allele frequency determination
HLA-DRB1*04, *11, *13, *07 and *03 were the most
frequent alleles in the patients (42, 30, 28, 26 and 20%,
respectively). HLA-DRB1*09 and HLA-DRB1*12 alleles were not
detected in any patients. HLA-DRB1*13, *11, *04, *03 and *15 were
the most frequent alleles in the controls (38, 28, 24, 20 and 18%,
respectively). There was no significant difference between patients
and controls as regards the frequencies of different HLA-DRB1
alleles (P>0.05) (Table I).
 | Table I.HLA-DRB1 allele frequencies in
patients and controls. |
Table I.
HLA-DRB1 allele frequencies in
patients and controls.
| HLA-DRB1 alleles | Patient no. (%)
(n=50)a | Control no. (%)
(n=50)a | OR (95% CI) |
P-value |
|---|
| *01 | 2(4.0) | 5 (10.0) | 0.38 (0.05-2.35) |
0.43 |
| *03 | 10 (20.0) | 10 (20.0) | 1 (0.34-2.96) |
0.80 |
| *04 | 21 (42.0) | 12 (24.0) | 2.29 (0.9-5.93) |
0.13 |
| *07 | 13 (26.0) | 7 (14.0) | 2.16 (0.71-6.76) |
0.21 |
| *08 | 2 (4.0) | 3 (6.0) | 0.65 (0.07-5.11) |
0.99 |
| *09 | 0 (0.0) | 3 (6.0) | 0 (0.0-2.23) |
0.24 |
| *10 | 4 (8.0) | 4 (8.0) | 1 (0.19-5.14) |
1.00 |
| *11 | 15 (30.0) | 14 (28.0) | 1.1 (0.43-2.86) |
1.00 |
| *12 | 0 (0.0) | 3 (6.0) | 0 (0.0-2.23) |
0.24 |
| *13 | 14 (28.0) | 19 (38.0) | 0.63 (0.25-1.6) |
0.39 |
| *14 | 3 (6.0) | 4 (8.0) | 0.73 (0.12-4.18) |
0.99 |
| *15 | 6 (12.0) | 9 (18.0) | 0.62 (0.18-2.13) |
0.57 |
| *16 | 2 (4.0) | 2 (4.0) | 1 (0.1-10.47) |
1.00 |
A total of 8 patients were homozygous for HLA-DRB1,
namely 6 males (homozygous HLA-DRB1*03, *04, *04, *07, *13 and *14)
and 2 females (homozygous HLA-DRB1*11 and *13); in addition, 5
controls were homozygous for HLA-DRB1, namely 2 males (HLA-DRB1*04
and *11) and 3 females (HLA-DRB1*03, *04 and *04).
There was no significant difference between male
patients and male controls as regards the frequencies of different
HLA-DRB1 alleles (P>0.05). However, the HLA-DRB1*04 allele
frequency was significantly higher among female patients compared
to that among female controls (55.6 vs. 16.7%, respectively;
P=0.03) (Table II).
| Table II.HLA-DRB1 allele frequencies in female
patients and female controls. |
Table II.
HLA-DRB1 allele frequencies in female
patients and female controls.
| HLA-DRB1 alleles | Female patients, no.
(%) (n=18) | Female controls, no.
(%) (n=18) | OR (95% CI) | P-value |
|---|
| *01 | 0 (0.0) | 1 (5.6) | 0.0 |
0.95 |
| *03 | 2 (11.1) | 3 (16.7) | 0.63 (0.06-5.64) |
0.99 |
| *04 | 10 (55.6) | 3 (16.7) | 6.25 (1.09-40.4) |
0.03a |
| *07 | 6 (33.3) | 3 (16.7) | 2.5 (0.42-16.32) |
0.44 |
| *08 | 1 (5.6) | 1 (5.6) | 1 (0.0-40.56) |
1.00 |
| *09 | 0 (0.0) | 1 (5.6) | 0.0 |
0.99 |
| *10 | 0 (0.0) | 1 (5.6) | 0.0 |
0.99 |
| *11 | 6 (33.3) | 4 (22.2) | 1.75 (0.32-9.91) |
0.70 |
| *12 | 0 (0.0) | 2 (11.1) | 0.0 |
0.48 |
| *13 | 5 (27.8) | 7 (38.9) | 0.6 (0.12-3.01) |
0.71 |
| *14 | 0 (0.0) | 2 (11.1) | 0.0 |
0.48 |
| *15 | 3 (16.7) | 4 (22.2) | 0.7 (0.1-4.74) |
0.99 |
| *16 | 1 (5.6) | 1 (5.6) | 1 (0.0-40.56) |
1.00 |
Based on the CCG risk classification, the ALL
patients were divided regarding their age at diagnosis into two
groups, namely those aged <10 and those aged ≥10 years. The
HLA-DBR1*04 allele frequency was significantly higher among
patients aged <10 years compared to those aged ≥10 years at
diagnosis (50.0 vs. 0.0%; P=0.01) (Table III).
| Table III.HLA-DRB1 allele frequencies in
relation to patient age at diagnosis. |
Table III.
HLA-DRB1 allele frequencies in
relation to patient age at diagnosis.
| Patient age | | |
|---|
|
| | |
|---|
| HLA-DRB1
alleles | <10 yrs, no. (%)
(n=42) | ≥10 yrs, no. (%)
(n=8) | OR (95% CI) | P-value |
|---|
| *01 | 2 (4.8) | 0 (0.0) | 0.0 |
1.00 |
| *03 | 6 (14.3) | 4 (50) | 0.16
(0.03-0.85) |
0.04 |
| *04 | 21 (50.0) | 0 (0.0) | 0.0 |
0.01a |
| *07 | 10 (23.8) | 3 (37.5) | 0.52
(0.10-2.57) |
0.66 |
| *08 | 1 (2.3) | 1 (12.5) | 0.17 (0-3.05) |
1.00 |
| *10 | 4 (9.5) | 0 (0.0) | 0.0 |
0.60 |
| *11 | 12 (28.6) | 3 (37.5) | 0.66
(0.13-3.2) |
0.68 |
| *13 | 12 (28.6) | 2 (25) | 1.2
(0.21-6.80) |
1.00 |
| *14 | 3 (7.1) | 0 (0.0) | 0.0 |
1.00 |
| *15 | 5 (11.9) | 1 (12.5) | 0.94
(0.09-9.3) |
0.65 |
| *16 | 1 (2.3) | 1 (12.5) | 0.17 (0-3.05) |
1.00 |
There was no significant difference among patients
with different immunophenotypes as regards the frequencies of
different HLA-DRB1 alleles (P>0.05).
The HLA-DRB1*11 allele frequency was significantly
higher in high-risk compared to standard-risk patients (50.0 vs.
14.3%; P=0.01) (Table IV).
| Table IV.HLA-DRB1 allele frequencies in
relation to risk. |
Table IV.
HLA-DRB1 allele frequencies in
relation to risk.
| Risk | | |
|---|
|
| | |
|---|
| HLA-DRB1
alleles | Standard, no. (%)
(n=28) | High, no. (%)
(n=22) | OR (95% CI) | P-value |
|---|
| *01 | 1 (3.6) | 1 (4.5) | 0.78
(0.02-30.61) |
1.00 |
| *03 | 5 (17.9) | 5 (22.7) | 0.74
(0.15-3.61) |
0.73 |
| *04 | 13 (46.4) | 8 (36.4) | 1.52
(0.42-5.58) |
0.67 |
| *07 | 7 (25.0) | 6 (27.3) | 0.89
(0.21-3.78) |
0.88 |
| *08 | 1 (3.6) | 1 (4.5) | 0.78
(0.02-30.61) |
1.00 |
| *10 | 3 (10.7) | 1 (4.5) | 2.52
(0.2-67.98) |
0.62 |
| *11 | 4 (14.3) | 11 (50.0) | 0.17
(0.03-0.75) |
01a |
| *13 | 10 (35.7) | 4 (18.2) | 2.5
(0.56-11.75) |
0.29 |
| *14 | 3 (10.7) | 0 (0.0) | 0.0 |
0.24 |
| *15 | 3(10.7) | 3 (13.6) | 0.76
(0.11-5.47) |
1.00 |
| *16 | 1 (3.6) | 1 (4.5) | 0.78
(0.02-30.61) |
1.00 |
Of the 50 included patients, 10 were referred to
other hospitals prior to treatment initiation and 10 succumbed to
the disease; 1 patient with mature B-ALL succumbed to acute renal
failure prior to treatment initiation, 7 patients died during
treatment due to chemotherapy-related toxicity and infections and 2
patients died following disease relapse.
Following exclusion of the 10 referred patients and
the 1 patient who died prior to treatment initiation, the remaining
39 patients were divided into the remission (n=34) and refractory
(n=5) groups. The HLA-DR1*11 allele frequency was significantly
higher among refractory patients compared to those who achieved
remission (80.0 vs. 23.5%; P=0.02) (Table V).
| Table V.HLA-DRB1 allele frequencies in
relation to induction of remission. |
Table V.
HLA-DRB1 allele frequencies in
relation to induction of remission.
| HLA-DRB1
alleles | Remission group,
no. (%) (n=34) | Refractory group,
no. (%) (n=5) | OR (95% CI) | P-value |
|---|
| *01 | 1 (2.9) | 1 (20.0) | 0.12 (0.0-2.3) |
0.24 |
| *03 | 6 (17.6) | 2 (40.0) | 0.32 (00-2.3) |
0.56 |
| *04 | 15 (44.1) | 0 (0.0) | 0.0 |
0.13 |
| *07 | 9 (26.4) | 1 (20.0) | 1.4
(0.14-14.6) |
1.00 |
| *08 | 1 (2.9) | 0 (0.0) | 0.0 |
1.00 |
| *10 | 3 (8.8) | 1 (20.0) | 0.38 (0.0-4.6) |
0.99 |
| *11 | 8 (23.5) | 4 (80.0) | 0.07
(0.0-0.79) |
0.02a |
| *13 | 10 (29.4) | 1 (20.0) | 1.6
(0.16-16.0) |
1.00 |
| *14 | 2 (5.8) | 0 (0.0) | 0.0 |
1.00 |
| *15 | 6 (17.6) | 0 (0.0) | 0.0 |
0.57 |
Following exclusion of the 10 referred patients and
the 8 patients who died during the study due to causes other than
relapse, the remaining 32 patients were divided into the relapsed
(n=4) and non-relapsed groups (n=28). There was no significant
difference between the two groups as regards the frequencies of
different HLA-DRB1 alleles (P>0.05).
Following exclusion of the 10 referred patients, the
remaining 40 patients were divided into the survivors (n=30) and
those who succumbed to the disease (n=10). There was no significant
difference between the two groups as regards the frequencies of
different HLA-DRB1 alleles (P>0.05).
Discussion
Genetic and environmental factors play an
interactive role in the development of childhood ALL. Since the
demonstration of a major histocompatibility complex effect on mouse
leukemia in 1964, an HLA association has been considered as a
possible genetic risk factor (8).
In the present study, there was no significant
difference between patients and controls as regards the frequencies
of different HLA-DRB1 alleles (P>0.05). In addition, there was
no significant difference between male patients and male controls
as regards the frequencies of different HLA-DRB1 alleles
(P>0.05). However, the HLA-DRB1*04 allele frequency was
significantly higher among female patients compared to female
controls (55.6 vs. 16.7%; P=0.03), indicating that HLA-DRB1*4 is a
female-specific susceptibility allele for childhood ALL.
The putative role of the HLA class-II DR antigen in
ALL risk was first suggested in the late 1970s by de Moerloose
et al (9), who demonstrated
an association with DR7. Additional evidence specifically regarding
childhood ALL was available shortly after the studies conducted by
von Fliedner et al, one of which confirmed the DR7
association (10), whereas the
other revealed a higher sharing of DR antigens among parents of
children with leukemia than expected (11).
By contrast, Dorak et al (8) reported that the frequency of the
HLA-DRB1*04 allele was higher (P=0.0005, OR=2.9), whereas the
frequency of the HLA-DRB1*13 allele was lower in male patients.
In 2002, a study that was performed on an Indian
population demonstrated that the HLA-DRB1*04 and HLA-DRB1*13
alleles are susceptible and protective alleles, respectively, in
ALL patients (12).
In their study on 106 Iranian patients with ALL,
Yari et al (13) concluded
that HLA-DRB1*13, which exhibited a decrease among the patients,
appeared to be protective against ALL, whereas HLA-DRB1*04, which
was moderately increased among the patients, was considered a
susceptibility allele for childhood ALL.
A significant increase in the frequency of the
HLA-DRB1*04 allele in the overall and male ALL patients was
reported in a Turkish study (4).
In addition, a significantly lower frequency of the HLA-DRB1*13
allele was observed among female patients compared to female
controls (4).
The association between HLA class II alleles and ALL
was investigated in 20 Iranian patients with leukemia (14). The results revealed a significant
increase in the frequency of the HLA-DRB1*04 allele in ALL patients
compared to that in controls.
DRB1*15, a risk allele for multiple sclerosis, has
also been implicated in the susceptibility to childhood ALL. At
least two studies have reported such an association; one was
conducted in a Chinese population comprising 162 childhood ALL
cases and 1,000 controls (15),
whereas the other was conducted in a UK population, investigated
the effects by gender and observed an association only in females,
which is consistent with a female-specific effect of the allele
DRB1*15:01, also observed in multiple sclerosis (16).
The discrepancy between the results of different
studies, including our results, may be attributed to the
differences in population race and geographical distribution.
Studies investigating the pathogenic effects of a
gene should include factors such as the differences in the
frequency distributions of the gene between the patient and the
control groups (the stronger the effect of a gene, the more
significant the differences in frequency distribution) and early or
late age at disease onset in gene carriers (the stronger the
effects, the earlier the onset) (17).
In our study, the HLA-DBR1*04 allele frequency was
significantly higher in patients aged <10 years compared to
those aged ≥10 years at the time of diagnosis (50.0 vs. 0.0%;
P=0.01). From these results, it was suggested that the HLA-DRB1
allele may affect the age at onset in ALL.
To the best of our knowledge, there are no studies
in the literature associating the HLA-DRB1 allele frequencies with
the age at onset in ALL. However, this allele has been investigated
in relation to other cancers in adults (17, 18).
The mean age of patients with colorectal cancer who
carry the HLA-DQB1*02 allele was found to be lower compared to that
of subjects without the allele (P<0.05), suggesting that this
allele is associated with colorectal cancer susceptibility
(17). In another study, the
frequency of HLA alleles in 50 chronic myeloid leukemia patients in
relation to age at onset was investigated; the authors concluded
that the frequency of the HLA-DRB1*07 (P=0.03) and DQA1*0201
(P=0.03) alleles was higher among patients aged <35 years
(18).
Our results demonstrated that the HLA-DRB1*11 allele
frequency was significantly higher among high-risk compared to
standard-risk patients (50.0 vs. 14.3%; P=0.01) and in refractory
patients compared to those who achieved remission (80.0 vs. 23.5%;
P=0.02). These results indicated that the HLA-DRB1*11 allele may be
a predictor for prognosis and treatment outcome in children with
ALL. However, there was no significant difference between the
relapsed and non-relapsed groups and between survivors and those
who succumbed to the disease as regards the frequencies of
different HLA-DRB1 alleles (P>0.05).
The significance of the HLA alleles as prognostic
indicators in childhood leukemia has been investigated in a limited
number of studies. Casper et al (19) reported an increased incidence of
relapse associated with HLA-DR5, with a higher rate of disease-free
remission associated with DR7; however, Takeuchi et al
(20) and Lauten et al
(21) did not identify an
association with outcome in childhood leukemia.
In conclusion, the HLA-DRB1*04 allele appears to be
a female-specific susceptibility factor for the development of
childhood ALL and it may affect the age at onset for ALL. In
addition, the HLA-DRB1*11 allele may be of prognostic value in
childhood ALL. However, further larger studies are required to
support our findings.
References
|
1
|
Ribera JM and Oriol A: Acute lymphoblastic
leukemia in adolescents and young adults. Hematol Oncol Clin North
Am. 23:1033–1042. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
2
|
Howell WM: HLA and disease: guilt by
association. Int J Immunogenet. 41:1–12. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Dearden SP, Taylor GM, Gokhale DA, et al:
Molecular analysis of HLA-DQB1 alleles in childhood common acute
lymphoblastic leukaemia. Br J Cancer. 73:603–609. 1996. View Article : Google Scholar : PubMed/NCBI
|
|
4
|
Ozdilli K, Oguz FS, Anak S, Kekik C, Carin
M and Gedikoglu G: The frequency of HLA class I and II alleles in
Turkish childhood acute leukaemia patients. J Int Med Res.
38:1835–1844. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
5
|
Pui CH, Carroll WL, Meshinchi S and Arceci
RJ: Biology, risk stratification, and therapy of pediatric acute
leukemias: an update. J Clin Oncol. 29:551–565. 2011. View Article : Google Scholar : PubMed/NCBI
|
|
6
|
Cairo MS, Gerrard M and Patte C: A new
protocol for treatment of mature B-cell lymphoma/leukemia (BCLL):
FAB LMB 96, a SFOP LMB 96/CCG-5961/UKCCSG NHL 9600 international
cooperative study. Med Pediatr Oncol. 29:357A1997.
|
|
7
|
Christie B: Doctors revise declaration of
Helsinki. BMJ. 321:9132000. View Article : Google Scholar : PubMed/NCBI
|
|
8
|
Dorak MT, Lawson T, Machulla HK, Darke C,
Mills KI and Burnett AK: Unravelling an HLA-DR association in
childhood acute lymphoblastic leukemia. Blood. 94:694–700.
1999.PubMed/NCBI
|
|
9
|
de Moerloose P, Chardonnens X, Vassalli P
and Jeannet M: HL-A D antigens from B-lymphocytes and
susceptibility to certain diseases. Schweiz Med Wochenschr.
107:14611977.(In French). PubMed/NCBI
|
|
10
|
von Fliedner VE, Sultan-Khan Z and Jeannet
M: HLA-DRw antigens associated with acute leukemia. Tissue
Antigens. 16:399–404. 1980. View Article : Google Scholar : PubMed/NCBI
|
|
11
|
von Fliedner VE, Merica H, Jeannet M, et
al: Evidence for HLA-linked susceptibility factors in childhood
leukemia. Hum Immunol. 8:183–193. 1983. View Article : Google Scholar : PubMed/NCBI
|
|
12
|
Jaini R, Kaur G and Mehra NK:
Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the
North Indian population. Hum Immunol. 63:24–29. 2002. View Article : Google Scholar : PubMed/NCBI
|
|
13
|
Yari F, Sobhani M, Sabaghi F, Zaman-Vaziri
M, Bagheri N and Talebian A: Frequencies of HLA-DRB1 in Iranian
normal population and in patients with acute lymphoblastic
leukemia. Arch Med Res. 39:205–208. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
14
|
Atashbeik SM, Akbari MT, Sayad A, et al:
The association of HLA-DRB1 gene polymorphisms with acute
lymphoblastic leukemia (ALL) in Iranian patients. J Biol Today's
World. 2:173–178. 2013.
|
|
15
|
Wang XJ, Ai XF, Sun HY, et al: Relation of
HLA-DRB1*15 with pathogensis in 162 childhood cases of acute
lymphoblastic leukemia. Chin Assoc Pathophysiol. 17:1507–1510.
2009.(In Chinese).
|
|
16
|
Morrison BA, Ucisik-Akkaya E, Flores H,
Alaez C, Gorodezky C and Dorak MT: Multiple sclerosis risk markers
in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific
childhood leukemia risk. Autoimmunity. 43:690–697. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
17
|
Tong F, Yu W and Liu H: Efficient
association analysis between colorectal cancer and allelic
polymorphisms of HLA-DQB1 by comparison of age of onset. Oncol
Lett. 3:517–519. 2012.PubMed/NCBI
|
|
18
|
Amirzargar AA, Khosravi F, Dianat SS, et
al: Association of HLA class II allele and haplotype frequencies
with chronic myelogenous leukemia and age-at-onset of the disease.
Pathol Oncol Res. 13:47–51. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
19
|
Casper JT, Marrari M, Piaskowski V, Lauer
SJ and Duquesnoy RJ: Association between HLA-D region antigens and
disease-free survival in childhood non-T, non-B acute lymphocytic
leukemia. Blood. 60:698–702. 1982.PubMed/NCBI
|
|
20
|
Takeuchi S, Takeuchi N, Tsukasaki K, et
al: Genetic polymorphisms in the tumor necrosis factor locus in
childhood acute lymphoblastic leukaemia. Br J Haematol.
119:985–987. 2002. View Article : Google Scholar : PubMed/NCBI
|
|
21
|
Lauten M, Matthias T, Stanulla M, Beger C,
Welte K and Schrappe M: Association of initial response to
prednisone treatment in childhood acute lymphoblastic leukaemia and
polymorphisms within the tumor necrosis factor and interleukin-10
genes. Leukemia. 16:1437–1442. 2002. View Article : Google Scholar : PubMed/NCBI
|
