TO THE EDITOR
The presence of the major chromosomal translocations, that is, t(12;21), t(1;19), t(9;22) and t(4;11) defines clinicopathological subgroups of childhood precursor B-cell ALL (ALL), which represent about 30% of all cases in USA/Europe.1 Furthermore, these translocations have been used in risk stratification for treatment purposes.2 However, their relative distribution and prognostic value in other geographic regions are sparse.
Stratification of pediatric precursor B-cell ALL in India using standard clinical criteria suggested that an unusually large fraction of these patients fall into a high-risk disease category.3 This may either be a result of late diagnosis or the low-risk subgroups are under-represented in these children or a combination of both. It is possible that the distribution of molecular subtypes is not uniform in different World regions. It is also possible that gene–environment interactions, which are critical in leukemogenesis, may differently contribute in defining the relative proportions of molecular subgroups in different geographic regions.
We have therefore studied 259 newly diagnosed children with precursor B-cell ALL from India. In all, 201 consecutive samples were obtained from Tata Memorial Hospital, Mumbai and 58 ALL samples were available at All India Institute for Medical Sciences, New Delhi. Patients were <1–21 years old (63% were in the 1–9 range) with a median age of 7 years. Male-to-female ratio was 2.9:1. Only 23% of the patients presented with WBC ⩾50 × 109/l (Table 1). cDNAs were prepared from frozen samples; their quality and integrity were tested by RQ-RT-PCR for GAPDH using the LightCycler instrument (Roche, Mannheim, Germany). The presence of the four translocations was assayed by real-time multiplex RT-PCR as described.4 Leukemia-specific chimeric transcripts were detected in 50 of the 259 samples (19%). In all, 18 (7%) carried a t(12;21); only one of them corresponded to the variant isoform that juxtaposes exon 5 of TEL to exon 3 of AML1. A total of 18 samples (7%) demonstrated a t(1;19), while 14 (5%) showed a t(9;22) (ALL-type, p190). The absence of t(4;11) was remarkable since the primers used would amplify 85% of all known MLL-AF4 variants. Of the 209 samples without any of the four translocations analyzed, we had enough DNA from 50 samples to analyze other 11q23 abnormalities. Southern blot analyses identified two patients carrying a rearrangement in the MLL gene (4%).
Table 1 summarizes molecular and clinical data from Indian patients. We compared these results with data compiled from publications from USA/Europe (Table 2). Similar to the West, patients carrying BCR-ABL or E2A-PBX1 are older than patients carrying TEL-AML1 and the latter subgroup was associated with the lowest WBC. However, other differences were evident. The four translocation subgroups together represented 19% of all Indian precursor B-cell ALLs whereas in the West these ALLs, represent as much as 35%. The frequency of the TEL-AML1 subgroup in India was significantly lower than in USA or Europe (P<0.005). In contrast, the other two translocations associated with an intermediate [t(1;19)] or poor prognosis [t(9;22)] are more commonly seen in India than in the West (P<0.005). It is still possible that rare translocations reported in the West, for example involving 11q23, may be more frequent in India. However, the absence of MLL-AF4 together with the preliminary 4% MLL rearrangements suggests that their frequency is not high.
Surprisingly, a notable low proportion of female patients with TEL-AML1 was observed (17M:1F) compared to 2.7–4.7M:1F in other ALLs. Whether this results from a referral bias or is indeed a feature of ALL in India remains unknown. However, it is unlikely that such a referral bias will be observed only for the TEL-AML1 subgroup. Data from USA/Europe does not support a gender dependency.5 TEL-AML1 is associated with young age and it may constitute a significant proportion of the preschool peak, the magnitude of which correlates with socioeconomic status. The increase in the incidence of ALL during socioeconomic transition has been associated more prominently with females,6 and thus the selective reduction of females in this TEL-AML1 cohort (one of 18) is of epidemiological interest.
The data provide support for geographic differences in subgroups of otherwise similar malignancies. Since the etiology of ALL is almost certainly dependent upon gene–environment interactions, it remains possible that differences in both the population and the environment dictate the relative distribution of these subtypes.
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Siraj, A., Kamat, S., Gutiérrez, M. et al. Frequencies of the major subgroups of precursor B-cell acute lymphoblastic leukemia in Indian children differ from the West. Leukemia 17, 1192–1193 (2003) doi:10.1038/sj.leu.2402931
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