Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in childhood, with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. We analyzed the loss of heterozygosity (LOH) of 6q, 9p, 11q and 12p using 31 microsatellite sites to determine their overall frequency and clinical value. We have studied 244 primary ALL samples obtained from the Multicenter Trial ALL-BFM 90 of Childhood ALL group. These patients have now been followed clinically for over 8 years. LOH occurred in 169 (69%) individuals in the following frequencies: 6q, 49 patients (20%); 9p, 97 patients (40%); 11q, 29 patients (12%); 12p, 60 patients (25%). Clinical data showed that those with 6q LOH were younger (P = 0.01) and had lower WBC counts (P = 0.02); patients with 9p LOH more frequently had CNS involvement (P = 0.01) and T cell phenotype (P = 0.0001); individuals with 11q LOH had a good response to induction chemotherapy (P = 0.02); those with 12p LOH were younger (P = 0.005), frequently had precursor B ALL (P = 0.001), and had a longer event-free survival (P = 0.05). Taken together, these data confirm that LOH is a very frequent alteration in childhood ALL.
Cytogenetic studies have been frequently performed in childhood acute lymphoblastic leukemia (ALL) and have identified non-random translocations and deletions.1,2,3,4,5,6 Like other tumors, ALL probably results from accumulation of genetic alterations that affect normal control of cellular growth. Malignant transformation can arise as a result of the increased activity of growth-promoting genes (oncogenes) and/or the inactivation or loss of growth-constraining genes (tumor suppressor genes). Inactivation or deletion of tumor suppressor genes is a pivotal pathway of leukemogenesis in childhood ALL. The paradigm of inactivation of tumor suppressor genes is mutation of one allele and loss of the second allele. This reduction to homozygosity in the region of the tumor suppressor gene can be detected as a loss of heterozygosity (LOH) of informative markers in the region of the tumor suppressor gene. Thus, LOH analysis is an indirect method to search for an inactivated tumor suppressor gene. In addition, LOH analysis can detect areas of allelic loss that result from complex mechanisms involving either duplication of a single mutated chromosome or mitotic recombination leading to homozygosity for loci distal to the site of recombination.
We and others have previously performed extensive LOH analysis of childhood ALL using microsatellite markers and have found that LOH of 6q, 9p, 11q and 12p are frequent in childhood ALL. LOH of the short arm of chromosome 9 was found in 40% of children with ALL and further analysis showed deletions of the CDKN2/INK4A/p16 gene at 9p21 occurred in about 15% of children with precursor-B ALLs and 75% of those with T-ALLs.7,8,9,10 LOH of the short arm of chromosome 12 with concomitant TEL-AML1 fusion was found in 16–33% of childhood B-lineage ALL.7,11,12,13,14,15 LOH of 6q was reported in 15% of childhood ALL at diagnosis.16,17 Furthermore, LOH of 11q was found in 16% of childhood ALL.18 These findings suggest that LOH is an important event in the development of childhood ALL.
Childhood ALL is a heterozygous disease with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. Many investigators have tried to identify useful clinical markers that could divide the ALL patients into several groups. However, useful markers have been difficult to identify. Moreover, little is known about the relationship between the presence of LOH and patient outcome.
We designed a comprehensive set of microsatellite markers for LOH analysis in order to evaluate genomic changes in childhood acute lymphoblastic leukemia. Our objective was to assess the frequency and clinical relevance of genomic aberrations in a very large group of children with ALL.
Materials and methods
Two hundred and forty-four primary DNA samples of childhood ALL were obtained from individuals who participated in the ongoing multicenter trial (ALL-BFM 90) of the German Berlin–Frankfurt–Münster (BFM) group (diagnosis between April 1990 and March 1995).19 These patients were selected by the availability of cryopreserved pre-treatment cell samples in addition to the needs of routine programs. The test panel was comparable with the total group of patients enrolled on the ALL-BFM 90 trial (n = 2780) with respect to the distribution of gender, age at diagnosis, CNS manifestation, immunophenotype, prednisone response, as well as risk group, while the median white blood cell count (WBC) was higher in the test panel (20.1 × 103/μl vs 10.5 × 103/μl). Informed consent was obtained from the patients, their parents, or both, as appropriate. We previously analyzed LOH of 6q, 9p, 11q and 12p using 113 patients.10,12,17,18 These results were incorporated into this study. The techniques of immunophenotyping has been previously described.20 The percentage of blast cells was at least 80%, and usually more than 90% in the cell samples, and DNA was extracted from them. The corresponding normal DNAs from the same individuals were obtained from the bone marrows after complete remission (CR) was achieved (at least 12 months after initial diagnosis). Clinical information for up to 8 years from their initial diagnosis was available for all of the 244 children in this study.
Analysis of LOH using microsatellite markers
The LOH analysis was performed by polymerase chain reaction (PCR)-amplification of microsatellite sequences. We previously performed LOH analysis for 6q, 9p, 11q and 12p, and identified several commonly deleted regions.10,12,17,18 In this study, we selected 31 microsatellites markers which covered all the commonly deleted regions. Microsatellite markers used for 6q LOH analysis were D6S284, D6S286, D6S275, D6S417, D6S300, D6S424, D6S468, D6S283, D6S449, D6S268, D6S278, D6S302, D6S261, and D6S266. Microsatellite markers for 9p analysis were D9S168, D9S1749, D9S1747, D9S1748, D9S171, D9S126, and IFNA. Markers for 11q were D11S901, D11S2179, D11S1391, D11S897, D11S1341, D11S976, D11S614, and D11S924. Markers for 12p were D12S89 and D12S98. The genetic map of chromosomes 6, 9, 11 and 12 was compiled mainly from the Généthon microsatellite map.21,22 Primers were obtained from Reseach Genetics (Huntsville, AL, USA).
Each PCR reaction contained 5–25 ng of DNA, 10 pmole of each of the primers, 2 nmole of each of the four deoxyribonucleotide triphosphates (Pharmacia, Stockholm, Sweden), 0.5 units of Taq DNA polymerase (Boehringer-Mannheim, Indianapolis, IN, USA), 2 μCi [α-32P]dCTP (ICN, Irvine, CA, USA) in 20 μl of the specified buffer with 1.5 mM MgCl2. Samples were amplified using 30–35 cycles of denaturing for 40 s at 94°C, annealing for 30 s at 55°C and extending for 1 min at 72°C in a Programmable Thermal Controller (MJ Research Inc, Watertown, MA, USA). After amplification, PCR samples were diluted five-fold in loading buffer containing 20 mM EDTA, 96% formamide, and 0.05% of both bromophenol blue and xylene cyanol. The products were heated to 95°C for 5 min and 1.5 μl of each sample was electrophoresed through a 6% polyacrylamide gel containing 8.3 M urea for 3–4 h at 85 W. Subsequently, the gels were dried and subjected to autoradiography using Kodak XAR-5 film (Eastman Kodak, Rochester, NY, USA) at −80°C. LOH was determined by densitometry. LOH was inferred only when substantial reduction (>50%) was measured in the ratio of radiographic signal intensities of an allele in the tumor sample relative to that in the corresponding normal sample.
Difference in the distribution of variables among patients either with or without any LOH were analyzed using two tailed Fisher's exact test for categorical variables (age, WBC counts, CNS involvement, immunophenotype, and response to chemotherapy) and Wilcoxon rank sum test for continuous variables (event-free survival). An effect was considered statistically significant if the P value was 0.05 or less.
Analysis of LOH in childhood ALL using microsatellite markers
We analyzed 244 childhood ALL samples for LOH of chromosome arms 6q, 9p, 11q and 12p using 31 microsatellite markers. Figure 1 displays representative autoradiographs showing LOH. One hundred and sixty-nine children (69%) showed LOH at least at one arm indicating that LOH is a frequent event in the development of childhood ALL. Frequencies of LOH for each arm are as follows: 6q, 49 children (20%); 9p, 97 patients (40%); 11q, 29 children (12%); 12p, 60 individuals (25%). One hundred and fifteen patients (47%) had LOH on one chromosomal arm, and 46 individuals (19%) had LOH on two arms, five patients (2%) had LOH on three chromosomal arms, and three children (1%) had LOH on four arms.
Clinical characteristics of children with ALL having LOH at chromosome 6q
Clinical information for up to 8 years from their initial diagnosis was available for all 244 children examined in this study (Table 1). Of the 244 children, 195 (80%) were younger, and 49 (20%) were older than 10 years. LOH of 6q was found more frequently in patients younger than 10 years (45/195; 23%) than those older than 10 years (4/49; 8%) (P = 0.012). Concerning WBC counts at diagnosis for the entire ALL population, 121 children (50%) had counts less than 20 000/μl, and 123 children (50%) had more than 20 000/μl. LOH of 6q was found more frequently in patients with less than 20 000/μl WBC (31/121; 26%) than those with more than 20 000/μl WBC (18/123; 15%) (P = 0.023). No statistically significant associations were found between LOH of 6q and either CNS involvement or immunophenotype.
Clinical characteristics of children with ALL having LOH at chromosome 9p
In the total population, seven patients (3%) had, and 221 (97%) did not have CNS involvement (Table 2). LOH of 9p was found more frequently in patients with CNS involvement (6/7; 86%) than in those without CNS involvement (82/221; 8%) (P = 0.014). The immunophenotype in the total population was 38 children (16%) with T-ALL, and 205 children (84%) with precursor-B ALL. LOH of 9p was found more frequently in patients with T-ALL (26/38; 68%) than those children with precursor-B ALL (71/205; 35%) (P = 0.0001). No statistically significant associations were found between LOH of 9p and either age or WBC counts at diagnosis.
Clinical characteristics of children with ALL having LOH at chromosome 11q
No statistically significant associations were found between LOH of 11q and CNS involvement, WBC counts at diagnosis, age, or immunophenotype (Table 3).
Clinical characteristics of children with ALL having LOH at chromosome 12p
LOH of 12p was found more frequently in children younger than 10 years old (55/195; 28%) than those older than 10 years old (5/49; 10%) (P = 0.005) (Table 4). In addition, LOH of 12p occurred more often in patients with precursor B ALL (58/206; 28%) than those with T-ALL (2/38; 5%) (P = 0.001). No statistically significant associations were found between LOH of 12p and WBC count at diagnosis, or CNS involvement.
Disease outcome of children with ALL having LOH
All of the 244 children were treated uniformly, and none with 11q LOH showed a poor response to initial induction chemotherapy. Poor response was defined as the presence of more than 1000/μl peripheral blood blast cells at day 8 of therapy. In contrast, 29 of 209 (14%) patients without 11q LOH showed a poor response (P = 0.020) (Table 3). No statistically significant associations were found between response to chemotherapy and LOH of 6q, 9p or 12p. Children with LOH of 12p had a better event-free survival over the 8 years of follow-up (84%) as compared to the cohort without the 12p LOH (70%) (P = 0.05) (Figure 2). Children with LOH of 9p had a better event-free survival over the 8 years of follow-up (78%), as compared to the cohort without the 9p LOH (71%). However, this difference was not statistically significant. No statistically significant associations were found between event-free survival and LOH of either 6q or 11q.
We performed detailed LOH analysis of chromosome arms 6q, 9p, 11q and 12p using highly informative microsatellite markers; LOH was detected in 20%, 40%, 12% and 25% of ALL patients, respectively. These frequencies are much higher than the reported frequency of cytogenetic deletions on these chromosomal arms (less than 10 % for each of the chromosomal arms).1,2,3,23,24,25 Thus, cytogenetic studies have probably missed many cases of small interstitial deletions in ALL. Our results show the power of LOH analysis using microsatellite markers.
Genetic alterations of several tumor suppressor genes have been reported in childhood ALL. Deletions of the CDKN2/INK4A/p16 gene occurred in about 15% of children with precursor-B ALLs.7,8,9,10 TEL-AML1 fusion was found in 16-33% of childhood B-lineage ALL.7,11,12,13,14,15 Mutations of the p53 gene were reported in 2-5% of the children.26,27,28 Alterations of these known genes in childhood ALL is less frequent than LOH which appears to be an extremely frequent genetic event in the development of childhood ALL. In fact, 169 of 244 children (69%) had LOH on at least one chromosomal arm. Interestingly, of the 169 ALL patients with LOH, 161 (95%) had LOH at either one or two of these sites.
LOH analysis has been performed in various types of human malignancies. However, most of these studies focused on solid tumors; and LOH analysis in childhood ALL has been limited in scope. We previously performed a limited allelotype analysis of childhood ALL and found LOH of 6q, 9p, 11q and 12p in 15%, 57%, 16%, and 33% patients, respectively.7,10,12,17,18 Cavé et al29 found LOH of 6q in 1/42 (2%), 9p in 8/50 (16%), 11q in 2/36 (6%), and 12p in 3/43 (7%) ALL patients. Also, Heyman et al30 identified LOH of 6q, 9p, 12p and 13q in 17/70 (24%), 32/64 (50%), 10/68 (15%), and 7/68 (10%) patients, respectively. However, the number of microsatellite markers and individuals that were examined in these studies were too few to identify any clinical significance of LOH. This is the first large LOH study ever performed in childhood ALL.
In this study, all the samples were obtained at the time of initial diagnosis. Therefore, the LOH occurred at the early phase of the disease. Since these patients were also enrolled in a minimal residual disease study, DNA samples are available from all these individuals who relapsed, which will allow us to identify regions of LOH associated with relapse of the disease. We suspect that some unique sites will be involved. For example, investigators found that while p53 mutations were rare (3%) at the time of diagnosis of ALL, they occurred more frequently (30%) at the time of relapse.23,24,25 Further LOH studies using relapsed samples are necessary to clarify this issue.
Molecular correlations of these sites of LOH can be associated with two of the four sites. The tumor suppressor genes CDKN2/INK4A/p16 and/or CDKN2B/INK4B/p15 and/or p14(ARF) are affected by the 9p LOH.8,9,10 Recent studies suggest that the TEL gene is translocated in most cases of childhood ALL with 12p LOH.13,14,15 Thus, loss of the normal TEL allele occurs in parallel with the translocation of the other allele to form the TEL-AML1 fusion. No disease-related genes have yet been associated with the other LOH sites.
The main clinical value of this LOH analysis lies in its ability to divide ALL patients into several biologic subgroups. Children with 6q LOH were younger (P = 0.01) and had lower WBC counts (P = 0.02); patients with 9p LOH more frequently had CNS involvement (P = 0.01) and T cell phenotype (P = 0.0001); patients with 12p LOH were younger (P = 0.005), and frequently had precursor B ALL (P = 0.001). In addition, there are data that LOH may be associated with disease outcome. Individuals with 11q LOH had a good response to induction chemotherapy (P = 0.02); patients with 12p had a longer event-free survival (P = 0.05). However, this is likely to be due to the association of 12p LOH with TEL-AML1 fusion.
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This study was supported in part by National Institutes of Health, Lymphoma Foundation, C and H Koeffler Fund, Parker Hughes Trust, Horn Fund (HPK), the Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe (CRB), and Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan (ST). HPK is a member of the Jonsson Comprehensive Cancer Center and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine. We are grateful to Wolf Dieter Ludwig for providing the immunophenotypic data. We thank Ian K Williamson, Harry E Taub and Jeffrey Grewal for technical help.
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Takeuchi, S., Tsukasaki, K., Bartram, C. et al. Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia. Leukemia 17, 149–154 (2003). https://doi.org/10.1038/sj.leu.2402727
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