• trisomy 21;
  • ETV6/RUNX1;
  • childhood;
  • acute lymphoblastic leukaemia


  1. Top of page
  2. Summary
  3. Acknowledgement
  4. References

Trisomy 21 is common in ETV6/RUNX1-positive acute lymphoblastic leukaemia (ALL); both these aberrations are associated with a favourable outcome. The prognostic impact of +21 as a sole cytogenetic change could be due to a cryptic t(12;21)(p13;q22). The occurrence of ETV6/RUNX1 was determined in 66 childhood ALLs with an acquired +21 and a chromosome number <51. ETV6/RUNX1 was found in 45% of cases and in the majority (10/18; 56%) of ALLs with sole +21. Event-free survival did not differ between the t(12;21)-positive and -negative cases. Thus, the prognostic impact of +21 is not attributable to cryptic ETV6/RUNX1.

Gain of chromosome 21 is the most common chromosomal abnormality in acute lymphoblastic leukaemia (ALL), occurring in approximately 20% of cytogenetically abnormal cases (Mitelman et al, 2006). It is particularly frequent in childhood high hyperdiploid (>50 chromosomes) ALLs, in which the vast majority (>90%) of cases have trisomy or tetrasomy 21, but it is also present in a large proportion (30%) of paediatric B-lineage ALLs with modal chromosome number between 47 and 50 (Forestier et al, 2000; Paulsson et al, 2005; Mitelman et al, 2006). The clinical impact of +21 occurring together with other chromosomal changes is presently unclear. However, as a sole change, which it is in 1–2% of childhood ALLs, trisomy 21 has been associated with a favourable outcome (Raimondi et al, 1992; Watson et al, 1993). Considering that +21 is a common secondary change to the cytogenetically cryptic t(12;21)(p13;q22) [ETV6/RUNX1], occurring in approximately 15% of the cases (Loncarevic et al, 1999; Raynaud et al, 1999; Attarbaschi et al, 2004), and that t(12;21) seems to confer a good prognosis (McLean et al, 1996; Borkhardt et al, 1997; Jamil et al, 2000), it is tempting to speculate that the prognostic impact of +21 as a ‘sole’ change in fact reflects the simultaneous presence of a cryptic ETV6/RUNX1 fusion. If so, one could postulate that most ALLs with +21 as the seemingly only abnormality would harbour t(12;21). In order to investigate this possibility, we analysed the frequency of the ETV6/RUNX1 fusion gene in a large series of childhood ALLs with acquired +21. Furthermore, the prognostic impact of +21, with and without t(12;21), was ascertained.

All paediatric ALLs diagnosed in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) between 1989 and 2005 that fulfilled the following criteria were included in the study: age below 15 years, presence of an acquired +21 identified by G-banding, modal chromosome number below 51, and investigated for the presence of t(12;21)(p13;q22) [ETV6/RUNX1] by fluorescence in situ hybridisation (FISH) and/or reverse transcription-polymerase chain reaction (RT-PCR). ALLs in children with Down syndrome, i.e. with a constitutional trisomy 21, were not included, nor were high hyperdiploid cases. The reason for the latter exclusion was that high hyperdiploidy and t(12;21) are virtually mutually exclusive (Raynaud et al, 1999; Mitelman et al, 2006).

In total, 66 ALLs with +21, either as a single karyotypically visible change or together with other abnormalities, were identified. The basic clinical, immunophenotypic and genetic features of these cases are summarised in Table I. The male/female ratio among the 66 patients was 0·47 (21/45), which was significantly different (P < 0·001) from that seen in all childhood ALLs in the Nordic countries (592/486; 1·22). The median age was 4·7 years, and the median white blood cell count was 11 × 109/l. Apart from one T-cell ALL, all cases were precursor B-cell ALLs. Whereas there was no over-representation of MLL rearrangements and BCR/ABL1 and TCF3/PBX1 chimaeras, the frequency of the ETV6/RUNX1 gene fusion was clearly higher than expected (45% vs. 25% in all B precursor childhood ALLs in the Nordic countries; P < 0·001). In the subgroup with +21 as the sole karyotypic change, more than half of the cases (56%) harboured the cytogenetically invisible t(12;21). Thus, +21, both as a ‘single’ anomaly and together with other chromosomal abnormalities in non-high hyperdiploid ALLs, is strongly associated with the presence of ETV6/RUNX1. Among the ten t(12;21)-positive cases with +21 as the sole change, five had been analysed by FISH, revealing +der(21) in one of them, and among the 20 ALLs with +21 together with other aberrations, +der(21) was found in four of the 11 cases investigated by FISH.

Table I.   Clinical, immunophenotypic, and genetic data on 66 ALL cases with +21.
ParametersTrisomy 21
Total (n = 66) Sole (n = 18)Other changes (n = 48)
  1. *Not investigated by FISH, RT-PCR, or Southern blot for the presence of the abnormality.

 Male (%)21 (32)8 (44)13 (27)
 Female (%)45 (68)10 (56)35 (73)
Age in years, median (range)4·7 (1·4 – 14)4·6 (2·2 – 13)4·8 (1·4 – 14)
Leucocytes × 109/l, median (range)10 (1·0 – 272)8·5 (2·0 – 272)10 (1·0 – 225)
 B precursor (%)65 (98)18 (100)47 (98)
 B-cell mature (%)0 (0)0 (0)0 (0)
 T cell (%)1 (1·5)0 (0)1 (2·1)
Genetic subgroup
MLL rearrangement [der(11)(q23)]
 Yes (%)0 (0)0 (0)0 (0)
 No (%)31 (47)10 (56)21 (44)
 Not determined* (%)35 (53)8 (44)27 (56)
BCR/ABL1 [t(9;22)(q34;q11)]
 Yes (%)2 (3·0)0 (0)2 (4·2)
 No (%)52 (79)15 (83)37 (77)
 Not determined* (%)12 (18)3 (17)9 (19)
TCF3/PBX1 [t(1;19)(q23;p13)]
 Yes (%)2 (3·0)0 (0)2 (4·2)
 No (%)37 (56)13 (72)24 (50)
 Not determined* (%)27 (41)5 (28)22 (46)
ETV6/RUNX1 [t(12;21)(p13;q22)]
 Yes (%)30 (45)10 (56)20 (42)
 No (%)36 (55)8 (44)28 (58)
Risk stratification
 Standard (%)25 (38)8 (44)17 (35)
 Intermediate (%)25 (38)5 (28)20 (42)
 High (%)16 (24)5 (28)11 (23)
 Yes (%)65 (98)17 (94)48 (100)
 No (%)1 (1·5)1 (5·6)0 (0)
 Yes (%)11 (17)3 (17)8 (17)
 No (%)55 (83)15 (83)40 (83)
 Yes (%)62 (94)16 (89)46 (96)
 No (%)4 (6·1)2 (11)2 (4·2)

With regard to the prognostic impact of +21, 16 (89%) of the 18 patients with this change as the sole aberration are still alive; the corresponding frequency was 96% for the ALLs with +21 together with other abnormalities (Table I), with the mean follow-up time of the entire patient cohort being 52 months. Thus, this karyotypic pattern is clearly not associated with poor risk ALL, in good agreement with Raimondi et al (1992) and Watson et al (1993). Interestingly, the seemingly favourable prognostic impact of +21 could not be ascribed to the high frequency of t(12;21). Among the 66 cases analysed, 30 (45%) harboured the ETV6/RUNX1 fusion (Table I). The 5-year event-free survival (EFS) estimate for this group was 81 ± 8·8% and 76 ± 8·0% for the t(12;21)-negative group (P > 0·30). Moreover, there was no significant difference in EFS between ETV6/RUNX1-positive and -negative cases (68 ± 21% vs. 80 ± 18%, respectively, P > 0·30) in the subgroup with +21 as the sole change.

In conclusion, the ETV6/RUNX1 fusion occurs in a high frequency (56%) of childhood ALLs with trisomy 21 as the sole visible chromosomal change but does not explain the seemingly good prognosis of this karyotypic subgroup.


  1. Top of page
  2. Summary
  3. Acknowledgement
  4. References

This study was supported by grants from the Swedish Children's Cancer Foundation.


  1. Top of page
  2. Summary
  3. Acknowledgement
  4. References
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