To study genetic epidemiology of childhood acute lymphoblastic leukemia (ALL) in the Chinese and Malays, we investigated 10 polymorphisms encoding carcinogen- or folate-metabolism and transport. Sex-adjusted analysis showed NQO1 609CT significantly protects against ALL, whilst MTHFR 677CT confers marginal protection. Interestingly, we observed that NQO1 609CT and MTHFR 1298 C-allele have greater genetic impact in boys than in girls. The combination of SLC19A1 80GA heterozygosity and 3'-TYMS -6bp/-6bp homozygous deletion is associated with reduced ALL risk in Malay boys. Our study has suggested the importance of gender and race in modulating ALL susceptibility via the folate metabolic pathway.
This study reviewed the immunophenotyping results of children with acute leukemia in Kelantan, Malaysia. In the 3.5-year period (January 1994 to June 1997), 45 cases were identified. All children were under the age of 12 years and the predominant ethnic group was Malay. Thirty-six cases (80%) were acute lymphoblastic leukemia (ALL) and 9 cases (20%) were acute myeloblastic leukemia (AML). Of the ALL cases, 3% were of B-cell and 22% of T-cell origin, and 96% of the B-lineage ALL were CD10 positive. All the AML cases expressed CD33 and 78% were positive for CD13. The incidence of mixed-lineage leukemias was 13.8% for My+ ALL and 11.1% for Ly+ AML.
Childhood acute lymphoblastic leukemia (ALL) is clinically heterogeneous with prognostically and biologically distinct subtypes. Although racial differences in frequency of different types of childhood ALL have been reported, many are confounded by selected or limited population samples. The Malaysia-Singapore (MA-SPORE) Leukemia Study Group provided a unique platform for the study of the frequency of major subgroups of childhood ALL in a large cohort of unselected multiethnic Asian children. Screening for the prognostically important chromosome abnormalities (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL) using multiplex reverse-transcription polymerase chain reaction was performed on 299 consecutive patients with ALL at 3 study centers (236 de novo, 63 at relapse), with the ethnic composition predominantly Chinese (51.8%) and Malay (34.8%). Reverse-transcription polymerase chain reaction was successful in 278 (93%) of cases screened. The commonest fusion transcript was TEL-AML1 (19.1%) followed by BCR-ABL (7.8%), MLL rearrangements (4.2%), and E2A-PBX1 (3.1%). Chinese have a significantly lower frequency of TEL-AML1 (13.3% in de novo patients) compared with Malays (22.2%) and Indians (21.7%) (P=0.04). Malays have a lower frequency of T-ALL (6.2%) compared with the Chinese and Indians (9.8%). Both Malays (7.4%) and Chinese (5.0%) have significantly higher frequency of BCR-ABL compared with the Indian population (P<0.05) despite a similar median age at presentation. Our study suggests that there are indeed significant and important racial differences in the frequency of subtypes of childhood ALL. Comprehensive subgrouping of childhood ALL may reveal interesting population frequency differences of the various subtypes, their risk factors and hopefully, its etiology.
The purpose of this study was to determine the frequency of thiopurine methyltransferase (TPMT) polymorphisms in a multiracial Asian population and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Six hundred unrelated cord blood samples from 200 Chinese, Malay, and Indian healthy newborns were collected at the National University Hospital, Singapore; an additional 100 children with ALL were analyzed for five of the commonly reported TPMT variant alleles using polymerase chain reaction/restriction fragment length polymorphism and allele-specific polymerase chain reaction-based assays. In the cord blood study, the TPMT*3C variant was detected in all three ethnic groups; Chinese, Malays, and Indians had allele frequencies of 3%, 2.3%, and 0.8%, respectively. The TPMT*3A variant was found only among the Indians at a low allele frequency of 0.5%. The TPMT*6 variant was found in one Malay sample. Among the children with ALL, two white and one Chinese were heterozygous for the TPMT*3A variant and showed intermediate sensitivity to 6-mercaptopurine during maintenance therapy. Three Chinese patients and one Malay patient were heterozygous for the TPMT*3C variant. Mercaptopurine sensitivity could be validated in only one out of four TPMT*3C heterozygous patients. The overall allele frequency of the TPMT variants in this multiracial population was 2.5%. The TPMT*3C was the most common variant allele; TPMT*3A and TPMT*6 were rare. These results support the feasibility of performing TPMT genotyping in all children diagnosed with acute leukemia to minimize toxicity from thiopurine chemotherapy.