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Keywords:

  • acute myeloid leukaemia;
  • children;
  • cytogenetics

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

Summary. Between 1993 and 2001, 318 children were diagnosed with acute myeloid leukaemia (AML) in the Nordic countries. The patient group comprised 237 children < 15 years of age with de novo AML, 42 children < 15 years with Down syndrome (DS) and de novo AML, 18 adolescents 15–18 years of age with de novo AML, and 21 children < 15 years with treatment-related AML (t-AML). The first group was all-inclusive, yielding an annual childhood de novo AML incidence of 0·7/100 000. Cytogenetic analyses were successful in 288 cases (91%), and clonal chromosomal abnormalities were detected in 211 (73%). The distribution of ploidy levels were pseudodiploidy (55%), hyperdiploidy (34%) and hypodiploidy (11%). The most common aberrations (> 2%) were + 8 (23%) (as a sole change in 6·2%), 11q23-translocations, including cryptic MLL rearrangements (22%) [t(9;11)(p21–22;q23) in 11%], t(8;21)(q22;q22) (9·0%), inv(16)(p13q22) (6·2%), −7/7q– (5·2%), and t(15;17)(q22;q12) (3·8%). Except for +8, these abnormalities were rare in group 2; only one DS patient had a t(8;21) and none had 11q23-translocations, t(15;17) or inv(16). In the t-AML group, three cases displayed 11q23-rearrangements, all t(9;11); and there were no t(8;21), t(15;17) or inv(16). Overall, the observed frequencies of t(8;21) and t(15;17) were lower, and frequencies of trisomy 8 and 11q23-translocations higher, than in previous studies. Furthermore, seven abnormalities that were previously reported as only single AML cases were also seen, meaning that der(4)t(4;11)(q26–27;q23), der(6)t(1;6)(q24–25;q27), der(7)t(7;11)(p22;q13), inv(8)(p23q11–12), t(11;17)(p15;q21), der(16)t(10;16)(q22;p13) and der(22)t(1;22)(q21;q13) are now classified as recurrent abnormalities in AML. In addition, 37 novel aberrations were observed, 11 of which were sole anomalies.

During the last two decades, the clinical importance of both cytogenetic and molecular genetic analyses of acute myeloid leukaemia (AML) patients has become increasingly appreciated (Look, 1998; Mrozek et al, 2001). However, much of the available information has been, and still is, based on studies of adult AML. In fact, the vast majority of the more than 10 000 cytogenetically abnormal AML cases described in the literature to date have been patients aged above 15 years. Furthermore, most published childhood AML cases are either single case reports or members of relatively small series (Mitelman et al, 2003), precluding detailed and quantitative analyses of the types and frequencies of chromosomal aberrations in this patient cohort. In the larger series of cytogenetically characterized childhood AML, somewhat conflicting findings have been reported regarding the prognostic implications as well as the frequencies of specific abnormalities, such as t(1;22)(p13;q13), t(8;21)(q22;q22) and 11q23-translocations (Leverger et al, 1988; Hayashi et al, 1991; Lampert et al, 1991; Martinez-Climent et al, 1995; Grimwade et al, 1998; Raimondi et al, 1999).

Some of the observed differences in the incidences of chromosomal aberrations in childhood AML among various studies may well be fortuitous, or related to methodological differences and/or different inclusion criteria. For example, the frequencies of abnormalities that are difficult to identify by conventional banding techniques alone, such as some 11q23-translocations and inv(16)(p13q22) (Kobayashi et al, 1993; Krauter et al, 1998), may have been underestimated in earlier studies, in which fluorescence in situ hybridization (FISH) or molecular genetic analyses were not available. In addition, the age groups included have varied from below 15 to below 21 years, and some studies have excluded children with Down syndrome (DS) or with treatment-related AML (t-AML). Considering the well-known impact of age, even among infants, children and adolescents, as well as of iatrogenic genotoxic exposure on the karyotypic features of haematological malignancies (Pedersen-Bjergaard & Rowley, 1994; Johansson et al, 1998; Mauritzson et al, 2002), such different inclusion criteria may well lead to the different results observed in previous studies.

The above notwithstanding, true geographical frequency differences of chromosomal abnormalities, strongly implicating ethnic and/or environmental factors in the genesis of AML-associated genetic aberrations (Johansson et al, 1991; Arana-Trejo et al, 1997), cannot be excluded. Consecutive and population-based series are needed in order to address the possibility of geographical variations in the types and frequencies of neoplasia-associated chromosomal abnormalities. We herein present a cytogenetic study of all children, including DS patients, below the age of 15 years with de novo AML treated in the Nordic countries between 1993 and 2001. Apart from establishing the frequencies of karyotypic subgroups and specific AML-associated chromosomal abnormalities in this population-based patient cohort, new recurrent aberrations, as well as novel changes, were identified.

Patients.  The present study comprises all the children diagnosed with AML during the 9-year period between 1993 and 2001 in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) who were treated according to the Nordic Society of Paediatric Oncology & Haematology 1993 AML (NOPHO-93-AML) trial. This protocol was originally designed for patients, including DS children, below the age of 15 years with de novo AML. Older children and patients who had had prior chemotherapy and/or radiotherapy for a malignant disorder were excluded. However, some patients ≥ 15 years or with t-AML have received therapy according to this protocol, and for the sake of completeness they are also included in this consecutive Nordic series. All diagnoses were performed according to the French–American–British (FAB) criteria (Bennett et al, 1985a,b).

Cytogenetic investigations.  Chromosome banding analyses of bone marrow and/or peripheral blood samples were performed using standard methods in 15 cytogenetic laboratories in the Nordic countries. The definition and description of clonal abnormalities followed the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN, 1995). In general, the karyotypes were not centrally reviewed during the investigated time-period, but since 1996 (Sweden) and 2000 (all five Nordic countries) such reviews were performed annually. To date, these annual reviews have not resulted in the detection of abnormalities resulting in a change of cytogenetic subgroup but rather in more precise descriptions of the involved chromosome bands and regions. FISH, Southern blot and reverse-transcriptase polymerase chain reaction analyses have, during recent years, been increasingly applied to either verify or, more precisely, characterize the chromosomal abnormalities found, as well as to detect MLL rearrangements (11q23-translocations) and RUNX1/CBFA2T1 [t(8;21)(q22;q22)], PML/RARA [t(15;17)(q22;q12)] and CBFB/MYH11 [inv(16)(p13q22)] gene fusions. For the identification of either new recurrent or novel AML-associated abnormalities, the Mitelman Database of Chromosome Aberrations in Cancer (Mitelman et al, 2003) was used.

Patients

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

Between 1993 and 2001, 318 children were diagnosed with AML and were treated according to the NOPHO-93-AML protocol (Table I). The patient group comprised 237 children aged < 15 years with de novo AML (group 1), 42 children aged < 15 years with DS and de novo AML (group 2), 18 adolescents aged 15–18 years with de novo AML (group 3), and 21 children < 15 years with t-AML (group 4). The age distribution is shown in Fig 1. Groups 1 and 2, i.e. the 279 patients aged < 15 years with de novo AML, are all-inclusive and hence population-based, yielding an annual childhood de novo AML incidence of 0·7/100 000 in the Nordic countries. Groups 3 and 4, on the other hand, are not necessarily representative of Nordic adolescents with AML or children with t-AML, respectively, and hence are not truly population-based. For this reason, the cytogenetic features of these four patient groups are also presented (Table I) and, when pertinent, discussed separately.

Table I.  The clinical and cytogenetic features in the present study and in previously reported larger series of childhood AML.
FeaturesPresent studyLeverger et al (1988)Hayashi et al (1991)Lampert et al (1991)Martinez- Climent et al (1995)Grimwade et al (1998)Raimondi et al (1999)
All casesGroup 1*Group 2Group 3Group 4§
  • *

    Group 1: de novo childhood AML, excluding patients with Down syndrome (DS).

  • Group 2: de novo AML in children with DS.

  • Group 3: de novo AML in adolescents.

  • §

    Group 4: children with treatment-related AML (t-AML).

  • Refers to cytogenetically analysed cases.

  • **

    The frequencies refer to cytogenetically abnormal cases. In group 2, hypodiploidy, pseudodiploidy and hyperdiploidy were defined as < 47 chromosomes, 47 chromosomes and > 47 chromosomes respectively.

  • ††

    Also includes four cases with MLL rearrangements without cytogenetically identifiable involvement of 11q23.

  • ‡‡

    Also includes cases with t(16;16)(p13;q22).

Total number of cases318237421821?134?120364666
 Age group (years)< 18< 15< 1515–18< 15< 16< 15?< 20< 15< 21
 Median age (years)5·26·02·116116·78·7?8·4?7·8
 Ratio of males:females1·01·10·51·01·21·1??1·2?1·2
 t-AML includedYesNoNoNoYesNo?YesNoYesNo
 DS includedYesNoYesNoNoYesYesYesYesYesNo
Number of cases   analysed (%)288 (91)221 (93)38 (90)18 (100)11 (52)130 (?)106 (79)217 (?)115 (96)340 (93)478 (72)
 Normal karyotype77 (27)59 (27)8 (21)8 (44)2 (18)41 (32)19 (18)70 (32)17 (15)91 (27)109 (23)
 Abnormal karyotype211 (73)162 (73)30 (79)10 (56)9 (82)89 (68)87 (82)147 (68)98 (85)249 (73)369 (77)
Ploidy levels (%)**
 Hypodiploidy24 (11)16 (9·9)5 (17)1 (10)2 (22)17 (19)9 (10)?13 (13)?47 (13)
 Pseudodiploidy116 (55)95 (59)11 (37)5 (50)5 (56)49 (55)53 (61)?61 (62)?245 (66)
 Hyperdiploidy71 (34)51 (31)14 (47)4 (40)2 (22)23 (26)25 (29)?24 (24)?77 (21)
Specific abnormalities   (%)**
 t(1;22)(p13;q13)3 (1·4)3 (1·9)000??1 (0·7)4 (4·1)?4 (1·1)
 −5/del(5q)2 (0·9)2 (1·2)0002 (2·2)03 (2·0)?6 (2·4)6 (1·6)
 t(6;9)(p23;q34)2 (0·9)2 (1·2)000?????6 (1·6)
 −7/del(7q)11 (5·2)7 (4·3)2 (6·7)1 (10)1 (11)6 (6·7)6 (6·9)8 (5·4)6 (6·1)19 (7·6)21 (5·7)
 +848 (23)35 (22)8 (27)4 (40)1 (11)7 (7·9)?18 (12)12 (12)46 (18)40 (11)
 +8 as sole change13 (6·2)9 (5·6)2 (6·7)2 (20)02 (2·2)??1 (1·0)?10 (2·7)
 t(8;21)(q22;q22)19 (9·0)17 (10)1 (3·3)1 (10)017 (19)21 (24)24 (16)9 (9·2)41 (16)56 (15)
 t(9;22)(q34;q11)1 (0·5)1 (0·6)000??????
 11q23-translocation††47 (22)42 (26)02 (20)3 (33)12 (13)14 (16)17 (12)21 (21)26 (10)88 (24)
 t(9;11)(p21–22;q23)††24 (11)21 (13)003 (33)??17 (12)10 (10)?35 (9·5)
 other t(11q23)22 (10)20 (12)02 (20)0??011 (11)?53 (14)
 t(15;17)(q22;q12)8 (3·8)8 (4·9)00010 (11)5 (5·7)8 (5·4)12 (12)31 (12)55 (15)
 inv(16)(p13q22)‡‡13 (6·2)11 (6·8)02 (20)04 (4·5)5 (5·7)10 (6·8)9 (9·2)16 (6·4)28 (7·6)
image

Figure 1. The age distribution of all 318 childhood AML diagnosed in the Nordic countries 1993–2001. Dashed line denotes de novo AML in children < 18 years of age without DS (groups 1 and 3), solid line DS-AML (group 2) and shaded line t-AML (group 4). No, number of cases.

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Basic cytogenetic features (Table I)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

Cytogenetic analyses were successfully performed in 288 (91%) of the 318 AML cases, revealing clonal abnormalities in 211 (73%) patients. In groups 1–4, the corresponding frequencies were 93% and 73%, 90% and 79%, 100% and 56%, and 52% and 82% respectively. Chromosomal breakpoints that were involved in structural rearrangements and genomic imbalances resulting from unbalanced aberrations are depicted in Figs 2–4.

image

Figure 2. The breakpoint map of structural abnormalities in 211 cytogenetically abnormal childhood AML. Closed circles represent breakpoints involved in the well-known and molecularly characterized AML-associated t(1;22)(p13;q13), t(1;11)(q21;q23), t(3;21)(q26;q22), t(6;9)(p23;q34), t(6;11)(q27;q23), t(8;21)(q22;q22), t(9;11)(p21–22;q23), t(9;22)(q34;q11), complex t(10;11)(p11–13;q23), t(11;17)(q23;q21), t(11;17)(q23;q25), t(11;19)(q23;p13), t(15;17)(q22;q12–21), inv(16)(p13q22), t(16;16)(p13;q22) and t(16;21)(p11;q22). Open circles represent other balanced chromosomal rearrangements, whereas closed squares represent genomically unbalanced changes.

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image

Figure 3. An imbalance map of the genomic gains in 211 cytogenetically abnormal childhood AML. Each line represents the area gained on a specific chromosome.

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image

Figure 4. An imbalance map of genomic losses in 211 cytogenetically abnormal childhood AML. Each line represents the area lost on a specific chromosome.

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Modal number (Table Iand Fig 5)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References
image

Figure 5. The distribution of modal numbers in 211 cytogenetically abnormal childhood AML.

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Among the 211 cytogenetically abnormal AML cases, 116 (55%) were pseudodiploid, 71 (34%) hyperdiploid and 24 (11%) were hypodiploid. The distributions of ploidy levels were similar in groups 1, 3 and 4. In group 2, hyperdiploidy (defined as > 47 chromosomes in DS children) was more common than pseudodiploidy. Among the hyperdiploid cases, the vast majority harboured 47–49 chromosomes, and among the hypodiploid AML a modal number of 45 was most commonly observed.

Common recurrent unbalanced chromosomal abnormalities (Table IandFigs 3 and 4)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

The most common trisomies, in decreasing frequency of order, were +8 (48 cases, 23%) (as a sole change in 6·2%), +21 (18 cases, 8·5%), +19 (10 cases, 4·7%), +4 (9 cases, 4·3%), and both +6 and +11 (7 cases each, 3·3%); the most frequent monosomies were loss of a sex chromosome (12 cases, 5·7%), −7 (10 cases, 4·7%), and −11, −12 and −14 (4 cases each, 1·9%). The most common partial gains involved 1q (14 cases, 6·6%) and 11q (7 cases, 3·3%), whereas the most frequent partial losses involved 7q (10 cases, 4·7%), 9q and 17p (7 cases each, 3·3%), 10p (6 cases, 2·8%) and 1p (5 cases, 2·4%).

Common recurrent structural chromosomal abnormalities (Table IandFig 2)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

Abnormalities that involved chromosome band 11q23, including cytogenetically cryptic MLL rearrangements, were the most frequent (47 cases, 22%). Among these, the t(9;11)(p21–22;q23) occurred in 24 cases (11%), followed by t(11;19)(q23;p13) (6 cases, 2·8%), complex t(10;11)(p11–13;q23) (4 cases, 1·9%), t(6;11)(q27;q23) (2 cases, 0·9%), t(11;17)(q23;q21) (2 cases, 0·9%), and single cases of t(X;11)(q26;q23), t(1;11)(q21;q23), der(4)t(4;11)(q26–27;q23) (no MLL rearrangement identified by FISH), t(11;17)(q23;q25), and r(?;11)(?;q23q23). FISH and/or Southern blot analyses identified MLL rearrangements in four cases without cytogenetically identifiable 11q23 abnormalities, namely t(X;11)(q24;q21), t(X;11)(q22q26;q25q11), t(1;10)(p11;p15) and del(11)(q21). Almost all 11q23(MLL)-translocations occurred in group 1; only a handful such rearrangements were found in groups 3 and 4 and none were seen in group 2.

The second most frequent structural abnormality was t(8;21)(q22;q22), which was found in 19 cases (9·0%). All but two of these occurred in group 1; the remaining two t(8;21) were seen in groups 2 and 3, while no t-AML patients had a t(8;21). The third most common change was inv(16)(p13q22)/t(16;16)(p14;q22), which occurred in 13 cases (6·2%). Two of these were found in group 3, whereas the remaining 11 cases belonged to group 1. No inv(16) or t(16;16) was seen in groups 2 and 4. The t(15;17)(q22;q12–21) was found in eight cases (3·8%), which were all acute promyelocytic leukaemias in group 1.

Rare recurrent balanced structural chromosomal abnormalities (Table IandFig 2)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

The t(1;22)(p13;q13) was observed in three cases of acute megakaryoblastic leukaemia, occurring in children without DS aged between 19 and 27 months. The t(6;9)(p23;q34) was found in two cases, both in group 1. Other balanced abnormalities known in the literature to be recurrent in AML, but found in only single cases in the present study, were t(3;21)(q26;q22), t(8;19)(p11;q13), t(9;22)(q34;q11), t(16;21)(p11;q22) and t(12;22)(p13;q13).

Rare translocations and inversions previously reported in only single AML cases (Table II)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References
Table II.  Newly identified recurrent abnormalities, i.e. previously reported in only single cases of AML and made recurrent by the present study. *
AbnormalitySex/age (years)DiagnosisSole changeDS
  • *The Mitelman Database of Chromosome Aberrations in Cancer (Mitelman et al, 2003) was used to identify previously published cases.

  • The der(4)t(4;11) in the present series did not involve the MLL gene.

  • The t(1;6) was balanced in the previously published case.

  • §The t(11;17) was an unbalanced der(11)t(11; 7) in the previously published case. One additional AML with t(11;17)(p15;q21) has been observed in the Nordic countries (Lund, 1979): a 4-year-old boy with de novo AML M4 and 46,XY,t(11;17)(p15;q21)/46,idem,dup(1)(q25q44)/47,idem, + del(1)(p11).

  • For every abnormality, the first row refers to the single case reported in the literature, the second row to the case observed in the present study. Diagnosis was made according to the FAB classification. AML, acute myeloid leukaemia; DS, Down syndrome; NOS, not otherwise specified.

der(4)t(4;11)(q26–27;q23)M/1AML M5aNoNo
F/2AML M7NoNo
der(6)t(1;6)(q24–25;q27)F/1AML M7NoNo
M/2AML M7NoYes
der(7)t(7;11)(p22;q13)F/82AML NOSNoNo
M/2AML M7NoYes
inv(8)(p23q11–12)F/??AML NOSNoNo
F/5 monthsAML M4YesNo
t(11;17)(p15;q21)§F/18AML M0NoNo
F/3AML M4YesNo
der(16)t(10;16)(q22;p13)F/68AML M2NoNo
F/4AML M5aNoNo
der(22)t(1;22)(q21;q13)F/1AML M0YesYes
F/1AML M4YesNo

The present study identified seven changes that should now be considered recurrent in AML. Among these, three abnormalities, namely inv(8)(p23q11–12), t(11;17)(p15;q21) and der(22)t(1;22)(q21;q13), were found as the sole change and three others, namely der(6)t(1;6)(q24–25;q27), der(7)t(7;11)(p22;q13) and the der(22)t(1;22), occurred in DS children.

Rare translocations and inversions previously never reported in AML (Table III)

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References
Table III.  Abnormalities previously never reported in AML found in the present study.
AbnormalitySex/age (years)DiagnosisSole changeDS
  • *

    The der(5)t(1;5)(q21;q32–33) was observed in mosaic form in bone marrow samples from a pair of twins who were diagnosed with AML a few days apart.

  • Diagnosis was made according to the FAB classification. NOS, not otherwise specified.

der(X)t(X;1)(q26;q23)F/4AML M7NoNo
t(X;11)(q22q26;q25q11)M/3AML M0YesNo
t(X;11)(q24;q21)M/4AML M4YesNo
t(X;11)(q26;q23)M/1AML NOSYesNo
t(X;12)(q?13–21;p13)F/1AML M7NoNo
der(1)t(1;1)(p13;q25)F/2AML M5bNoNo
der(1;14)(q10;q10)M/6AML M5NoNo
inv(1)(p36q32)F/4AML M2NoNo
t(1;10)(p11;p15)F/1AML M0YesNo
t(2;5)(p11;p15)F/3AML M7YesYes
t(2;5)(q35;q31)F/3AML M1YesNo
t(2;7)(p13;p22)M/3AML M5bYesNo
t(2;8)(p13;p21)F/4 monthsAML M5aNoNo
t(2;10)(q35;p12)F/4 monthsAML M5aNoNo
t(2;14)(q22;q13)F/10AML M2NoNo
t(2;16)(p11–12;q24)F/10AML M2NoNo
t(3;13)(q25;q14)M/2AML M1/M2YesYes
t(3;17)(q25;q21)F/2AML M1YesYes
der(4)t(1;4)(q21;p13)M/1AML M7NoYes
t(4;17;22;8;13)(p12;q23;q13;p21;q14)F/4 monthsAML M5bNoNo
der(5)t(1;5)(q21;q32–33)*F/4 monthsAML M5YesNo
der(5)t(1;5)(q24–25;p15)M/2AML M7NoYes
der(6;15)(p10;q10)F/2AML M7NoYes
der(7)t(1;7)(q24;p21)M/3AML M7NoNo
der(7)t(6;7)(p23;q11)F/14AML M2NoNo
t(7;10)(p13;p11)F/4AML M5aNoNo
t(8;11)(q24;p11)M/2AML M1NoNo
t(8;12)(p10;q10)F/6AML M4NoNo
der(9)t(7;9)(q11;q34)F/14AML M2NoNo
der(10;22)(q10;q10)M/1AML M7NoNo
der(11)t(4;11)(q26–27;q13)F/2AML M7NoNo
t(11;18)(q13;q21)F/2AML M2YesYes
der(12)t(12;15)(p12;q22)M/17AML M4NoNo
dic(12;18)(p11;p11)M/14AML M4NoNo
der(13)t(13;14)(q32;q24)F/1AML M4NoNo
der(14)t(5;14)(q22;q13)F/1AML M4NoNo
der(17)t(3;17)(q21;q25)F/3AML M5NoNo

A total of 37 novel abnormalities were observed. Among these, 11 occurred as the sole aberration and seven were found in children with DS.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References

The present series, based on all childhood AML cases diagnosed in the Nordic countries between 1993 and 2001, is one the largest cytogenetic studies of AML in children reported to date. In general, the karyotypic patterns and the frequencies of specific AML-associated chromosomal abnormalities in this population-based patient cohort were, with some notable exceptions discussed below, similar to those found in previous larger series (Table I). For example, clonal aberrations were detected in 73% of the cases, an incidence in agreement with the abnormality rates between 68% and 85% described in similar-sized studies from Europe, Japan, and the USA (Leverger et al, 1988; Hayashi et al, 1991; Lampert et al, 1991; Martinez-Climent et al, 1995; Grimwade et al, 1998; Raimondi et al, 1999). In addition, the distributions of ploidy levels, with pseudodiploidy being the most common modal number followed by hyperdiploidy and hypodiploidy (Fig 5), were similar in the various series (Table I). The salient features of the present study are: (1) the differences noted with regards to specific aberrations both among the childhood AML series and between paediatric and adult AML cases; (2) the large proportion of children with DS; and (3) the identification of several novel chromosomal abnormalities.

The total or partial losses of chromosome 5, which are quite common in adult AML, are notably rare in childhood AML, occurring in only 1–2% of the cytogenetically abnormal cases. In addition, losses involving chromosome 7, observed in approximately 5% of paediatric AML cases (Table I, Fig 4), seem to be less frequent than in adult AML patients (Mauritzson et al, 1999; Mitelman et al, 2003). Because these changes are significantly more common in t-AML, in particular after radiotherapy and treatment with alkylating agents (Pedersen-Bjergaard & Rowley, 1994; Mauritzson et al, 2002), their low incidence in childhood AML may, to some extent, be explained by the relative paucity of t-AML in children. Furthermore, among the 21 t-AML cases included in our series, 14 (67%) had previously been treated for either acute lymphoblastic leukaemia (ALL) or non-Hodgkin's lymphoma, the treatment of which in the Nordic countries generally does not include irradiation or large doses of alkylators. However, because the frequencies of −5, del(5q), −7 and del(7q) are also higher in de novo adult AML (Mauritzson et al, 2002) than in de novo paediatric AML, factors other than prior radiotherapy and chemotherapy must be sought to explain these differences in incidence. Occupational and/or leisure-time exposures may play a role, although epidemiological studies focused on this issue have yielded somewhat conflicting results concerning the associations between such exposures and both karyotypic patterns and specific abnormalities (Albin et al, 2000; Björk et al, 2001).

The frequencies of t(8;21), t(15;17) and inv(16) do not seem to differ substantially between children and younger or middle-aged adults, occurring in approximately 10–20%, 5–10% and 5% of the cytogenetically abnormal cases respectively. In contrast, their incidences are clearly decreased in elderly AML patients (Grimwade et al, 1998; Mauritzson et al, 1999, 2002; Nakase et al, 2000). However, the frequencies of t(8;21) and t(15;17) in the present Nordic series were lower than in previous larger studies from France, Germany, Great Britain, Japan and the USA (Table I). Obviously, the observed differences may be fortuitous, but they could also indicate that geographical/ethnic origin may be of importance in the genesis of such abnormalities. In fact, several previous studies have revealed a quite pronounced geographical heterogeneity in the frequency of these two translocations (Johansson et al, 1991; Biondi et al, 1994; Douer et al, 1996; Ruiz-Arguelles, 1997; Nakase et al, 2002). The possibility that constitutional and/or exogenous factors may have an impact on karyotypic patterns has also been postulated for childhood ALL. In the Nordic countries these are more often highly hyperdiploid and less often harbour ALL-specific translocations compared with other geographical regions (Forestier et al, 2000).

The rearrangement of 11q23 and the MLL gene is undoubtedly more common in childhood AML (Fig 2), where it is observed to occur in 10–24% of the cases (Table I), than in adult AML, in which its frequency is less than 5% (Grimwade et al, 1998; Mauritzson et al, 2002; Nakase et al, 2002). The reasons for this age-related difference are unknown, but chemical exposures, even of a trans-placental nature, to certain chemicals has been suggested both to cause MLL gene fusions and to increase the risk of 11q23-positive leukaemias, particularly in infants (Alexander et al, 2001). Because the incidence of 11q23-translocations in the present series was higher than in most other childhood AML studies (Table I), it is tempting to speculate that there is a higher exposure to chemicals that induce MLL fusions in the Nordic countries. This hypothesis, which is admittedly speculative, could be tested in prospective case–control studies. However, one should bear in mind that certain 11q23-translocations, such as t(6;11)(q27;q23) and t(11;19)(q23;p13), can escape recognition with conventional banding techniques (Martineau et al, 1998; Moorman et al, 1998) and may well have been missed in earlier studies. In fact, the two cases with t(6;11) in the present study were both identified in 2001, partly with the help of FISH. Thus, the apparent geographical differences in the frequency of 11q23-rearrangements should be interpreted with caution.

The single most common aberration in the present study was trisomy 8 (Fig 3), which occurred in 23% of the cases and as the sole change in 6%. These frequencies are higher than those observed in previous studies (Table I), again emphasizing the possibility of a geographical variation in AML-associated karyotypic patterns. However, considering that the incidence of +8 in AML and other myeloid malignancies has been shown to vary in relation to several other parameters, such as sex, age and prior toxin exposure (Albin et al, 2000; Paulsson et al, 2001), such factors should be taken into account when comparing different studies. In this context it may be worth noting that trisomy 8 was the only frequent chromosomal abnormality in the present series that was equally common in the various patient groups; all other frequent aberrations were mainly found in groups 1 and 3, i.e. in de novo AML in children without DS (Table I). This may suggest that the occurrence of +8 in childhood AML is not strongly influenced by constitutional factors and iatrogenic exposures.

In the present study, groups 1 and 2, i.e. de novo AML in children below the age of 15 years with or without DS, were all-inclusive and hence truly population-based. Among these 279 patients (Table I), 42 (15%) had DS, which is a frequency clearly higher than the 2–10% reported in the series by Leverger et al (1988), Lampert et al (1991), Creutzig et al (1996), Grimwade et al (1998) and Lange et al (1998). It was deemed highly unlikely that either the incidence of DS is higher in the Nordic countries or that children with DS in the Nordic countries have a higher risk of developing AML than in other parts of the world (Hasle et al, 2000). Alternatively, the most likely explanation for this discrepancy in frequency is an under-reporting/exclusion of DS patients in previous studies. In fact, our present knowledge of chromosomal abnormalities in DS-associated AML is restricted to approximately 100 published cases only (Mitelman et al, 2003). However, based on the present report and a few previous studies, it seems safe to conclude that this AML group is characterized more greatly by miscellaneous abnormalities than by the well-known AML-associated translocations (Table I). We observed only one case with t(8;21) in group 2, and it should be noted that this patient was older (11 years) than all other DS patients (median age 2 years, range 3 weeks – 5 years). The fact that AML in children with DS rarely harbour t(8;21), 11q23-translocations, t(15;17) or inv(16) has previously been stressed (Lampert et al, 1991; Martinez-Climent et al, 1995; Lange et al, 1998). Furthermore, the AML M7-specific t(1;22)(p13;q13) (Bernstein et al, 2000; Mitelman et al, 2003) has, to date, only been reported in two children with DS (Trejo et al, 2000). In contrast, numerical abnormalities, mainly gains, seem to be a characteristic feature of DS-AML (Kaneko et al, 1981; Hecht et al, 1986; Wang et al, 1987; Ravindranath et al, 1992; Litz et al, 1995; Creutzig et al, 1996). In the present series, high hyperdiploidy, i.e. 51–57 chromosomes, was very rare (Fig 5), but all three high hyperdiploid AML cases without additional structural abnormalities occurred in DS patients. High hyperdiploidy in DS-AML patients has also been previously noted by Hayashi et al (1991). Further support for an association between high hyperdiploidy without structural aberrations and DS-AML was obtained by reviewing the Mitelman Database of Chromosome Aberrations in Cancer (Mitelman et al, 2003). To date, seven high hyperdiploid childhood AML cases with numerical changes only have been reported, and three of these had DS. The fact that trisomies, hyperdiploidy (Table I) and high hyperdiploidy are common in DS-AML may indicate that DS patients are more susceptible to non-disjunctional events during cell division (Fong & Brodeur, 1987), but further studies and more cytogenetic data are needed to address this issue.

Seven new recurrent AML-associated abnormalities were identified in the present study (Table II). Among these, three occurred as sole anomalies, of which two were cytogenetically balanced – inv(8)(p23q11–12) and t(11;17)(p15;q21). The molecular genetic consequences of the inv(8) remain to be elucidated, but t(11;17) has previously been shown to involve the NUP98 gene in a case of treatment-related myelodysplastic syndrome (Nishiyama et al, 1999). Considering the frequent formation of NUP98/HOX chimaeras in haematological malignancies with 11p15-translocations, i.e. t(2;11)(q31;p15) with NUP98/HOXD11 or NUP98/HOXD13, t(7;11)(p15;p15) with NUP98/HOXA9 or NUP98/HOXA13, and t(11;12)(p15;q13) with NUP98/HOC11 or NUP98/HOXC13 (Lam & Aplan, 2001; Taketani et al, 2002a,b,c; Panagopoulos et al, 2003), and the fact that the HOXB gene cluster maps to 17q21 (Apiou et al, 1996), it seems reasonable to suggest that the t(11;17) generates a NUP98/HOXB fusion gene.

The present compilation of cytogenetically analysed childhood AML cases from the Nordic countries also revealed 37 novel changes, 11 of which occurred as sole anomalies (Table III). These abnormalities are obviously rare, and some may well be of less importance in initiating leukaemogenesis, at least those that were not primary chromosomal aberrations. However, those observed as single abnormalities, all of which except one were balanced translocations (Table III), are likely to result in fusion genes intimately associated with the leukaemogenic process. The fact that seven novel changes were found in DS-AML and that four of these may be considered primary aberrations, emphasizes the need to investigate more DS-AML cases, with the ultimate goal of identifying abnormalities of both biological and clinical significance in this large patient cohort.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Basic cytogenetic features ()
  7. Modal number (and )
  8. Common recurrent unbalanced chromosomal abnormalities (and)
  9. Common recurrent structural chromosomal abnormalities (and)
  10. Rare recurrent balanced structural chromosomal abnormalities (and)
  11. Rare translocations and inversions previously reported in only single AML cases ()
  12. Rare translocations and inversions previously never reported in AML ()
  13. Discussion
  14. Acknowledgments
  15. References
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