Cytogenetic survey of 53 Moroccan patients with acute myeloblastic leukemia

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ELSEVIER

Cytogenetic Survey of 53 Moroccan Patients with Acute Myeloblastic Leukemia

N. Hda, B. Chadli, A. Bousfiha, A. Trachli, M. Harif, A. Benslimane

ABSTRACT: We present a cytogenetic survey o f chromosome aberrations for 53 Moroccan patients with acute myeloblastic leukemia (AML). Our 53 patients were 2 to 70 years old with 31 m e n a n d 22 women. The cytogenetic study was performed with the following three methods: first, relative propor- tion o f normal (N) or abnormal (A) metaphases; second, presence o f specific or random abnormalities;

a n d third, karyotype complexity, A m o n g 36 patients (67%) with a chromosomal abnormality, 18 (34%) s h o w e d a specific aberration. We have f o u n d t(9;22) in three patients (5%), chromosome 5 or 7 abnor- mality in six (i i %), del(11)(q23) in three (6%), +21 in four (8%), and +8 h~ two (4%). Specific translo- cations associated with the FAB type were found: t(8;21) with AML2 in 12 patients (23%) and t(9;11) with AML5 in one (2%). Rare abnormalities were also found: one patient with t(7;21) associated with

• AML2 and another patient with r(1) ring associated with AML1. We concluded that our study in a Moroccan population confirmed the relation between some specific abnormalities and the FAB classifi- cation. We have f o u n d a higher incidence for t(8;21) than usually described. Finally, we have identified chromosomal abnormalities t(7;21)(q22;p l 1) a n d r(1), rarely described before.

INTRODUCTION

In the past 20 years cytogenetic studies have shown that a number of hematologic disorders are often caracterized by clonal nonrandom abnormalities [1]. Some of these abnormalities are often specifically associated with morphologic types of the FAB classification or with certain immunologic hematologic disorders [18], and the prognostic value of these chromosomic changes has been evaluated [26].

In some cases it was shown that the chromosomal abnormalities observed modified the gene expression at the chromosomes breaks. These genes often participate in cellular differentiation and proliferation processes leading to tumorigenesis. Several methods were designed to study the relationship between chromosomal aberrations and prognosis [1, 24, 36]. However, despite such studies, the diagnostic and prognostic significance of rare chromosomal absnormalities is not well elucidated today.

In this paper, we report the cytogenetic study of 53 Moroccan patients suffering from AML, we discuss the usual epidemiologic profile found, and we identify chromosomal abnormalities never described before.

From the Institut Pasteur du Maroc (N. H., B. C., A. B.), Place Charles Nicolle, Casablanca; and H6pital Ibn Rochd (A. B., A. T., M. H.), Service de P~diatrie 3, Casablanca, Morocco.

Address reprint requests to: Dr. N. Hda, Institut Pasteur du Maroc, Casablanca, Morocco.

Received February 10, 1995; accepted June 27, 1995.

Cancer Genet Cytogenet 86:124-128 (1996)

655 Avenue of the Americas. New York. NY 10010

MATERIALS A N D METHODS

Fifty-three patients with primary AML were studied, including 31 men and 22 women, 2 to 70 years old, with an average age of 22 years old; there were 38 adults and 15 infants. The diagnosis was based on the FAB classification with the aid of cytochemical and immunologic reactions.

The cytogenetic study was performed using three methods [21]. In the first, the relative proportions of normal (N) and abnormal (A) metaphases were evaluated and classified as AA for patients with all abnormal metaphases, NN for patients with all normal metaphases, and AN for patients with a mixture of normal and abnormal metaphases [1, 21, 24]. In the second method, the patients were assigned to the following categories according to certain specific or nonrandom (recurrent) abnormalities: t(8;21), abnormal 16, abnormal 5 or 7, 11q rearrangement, hypop- loidy, hyperdiploidy [24]. The third method was based on the complexity of the abnormal leukemic clones.

The patients were classified into four groups: those with normal karyotypes; simple abnormal clones carrying rearrangement of one or two chromosomes in a simple translocation; complex karyotypes involving two to five chromosomes; and patients with very complex karyotypes involving more than five chromosomes [24].

The karyotype was performed following the FUdR reverse-hand synchronization technique as described by Lorma and Webber [13]. Chromosomes were classified according to the international nomenclature [28].

0165-4608/96/$15.00 SSD10165-4608(95)00188-U

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Cytogenetics of Moroccan AML Patients 125

Table I Classification of patients with normal (N) or abnormal (A) metaphases

Number of

Classification patients Percentage

NN 17 33

NA 4 7

AA 32 60

RESULTS

Seventeen patients were NN (33%), three were NA (7%), and 33 were AA (60%, as s h o w n in Table 1. Following the FAB group (Table 2), 23 patients belonged to M1 (46%), 20 to M2 (37%), two to M4 (4%), 6 to M5 (12%), and 2 to M6

(4%).

The clone with t(8;21) was detected in 12 patients (23%) an abnormal 5 or 7 was observed in six patients (11%) and 11q rearrangements were seen in three patients (6%) (Table 3). Hypodiploidy, hyperdiploidy, and pseudodiploidy were observed equally in four patients (8%). A total of 34% of our patients s h o w e d a specific abnormality.

Seventeen patients (33%) s h o w e d a normal karyotype, 19 a simple karyotype (36%), 10 a complex karyotype (19%), and seven a very complex karyotype (12%) (Table 4). We have observed two different forms of t(8;21), t(8;22) and del(8)(q22), in patients with AML2. Trisomy 8 was observed in two patients (4%), trisomy 21 in four (8%), and abnormal 9 in four (8%).

A total of 36 patients (67%) s h o w e d chromosomal aberrations and the specific t(8;21) abnormality was observed with an u n u s u a l l y high {requency, including 18 patients with a specific abnormality (Table 5) and 12 patients with a recurrent clonal abnormality (Table 6).

DISCUSSION

Specific chromosomal aberrations have been recognized in different hematologic disorders and often considered important factors associated with diagnostic and pronostic import, allowing for the follow-up of the patients [23].

Numerous studies have ,~xamined the cytogenetic abnormalities found in AML [12, 14, 26, 27].

Our study was concerned with cytogenetic investiga- tions on a Moroccan AML population. We have seen the well-recognized associations t(9;11) with M5 and t(8;21) with M2 (26, 28). However, we observed an u n u s u a l l y high frequency (23%) of'L(8;21), w h i c h is notably different from what was described previously (Table 7) [11, 15, 27, 28, 31, 34]. We also ob.~erved that 60% of AML2 were Table 2 Classification of patients in FAB groups

Number of

FAB group patients Percentage

M1 23 43

M2 20 37

M4 2 4

M5 6 11

M6 2 4

Table 3 Abnormal clones among 53 AML patients Number of patients Percentage

Normal 17 33

Translocation (8;21) 12 23

del(11)(q23) 2 4

Abnormal 16 2 4

Abnormal 5 or 7 6 11

Abnormal 11 3 6

+8 2 4

Abnormal 9 4 8

+21 4 8

Pseudodiploidy 4 8

Hypodiploidy 4 8

Hyperdiploidy 4 8

t(8;21) and this was in contrast with the usual 30% indi- cated in the literature [15, 25]. The t(9;22) abnormality was ob-served in three patients (5%); Schiffer et al.

reported two cases (1%) and the GFCH six (1; 8%) cases.

The abnormal 11q23 was observed in 6% of our patients and this was in accordance with the previous 1 - 8 % found in earlier studies [14, 26, 31]. The other abnormalities were r a n d o m l y distributed among the FAB groups. In our study chromosomal aberrations were observed mostly in FAB M1 and FAB M2 cases, as shown previously in the 4th Workshop Report [15]. The t(8;21) was usually s h o w n more frequently in infants [25, 34], and this was the case in our study, with five of 16 infant AML cases.

We have observed two isolated cases of t(8;22) and del(8)(q22) associated with M2. These abnormalities m a y be t(8;21) variants and this confirms that the 8q22 region is a gene breakpoint [16, 32]. Pasquali and Casalone [10] pos- tulated in 1981 that rearrangement of 21q22 to 8q22 was necessary for the development of the M2 subtype of AML [28]. Other authors [2], from analysis of cases with complex translocations, had previously suggested the importance of the 21q and 8q juxtaposition in AML. Kondo et al.

[3] had suggested that the breakage 8q22 b a n d m a y be the most essential event associated with this malignancy.

Sakurai et al. [12] also suggested that the break or translocation involving 8q22, not 21q22, might be essential for expression of the AML p h e n o t y p e [6, 12], although other authors [22], by contrast, argued that c h r o m o s o m e 21 plays an important role in AML pathogenesis. Recent molecular analyses indicate that the t(8;21) yields an abnormal chimeric gene and a protein product, A M L 1 - ETO [29, 32].

Recently, authors claimed that chromosomes 21 are m u c h more important than chromosomes 8 in AML gene- Table 4 Classification of patients on the complexity of

the leukemic clones

Clone Number of patients Percentage

Normal 17 33

Simple 19 36

Complex 10 19

Very complex 7 12

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126 N. H d a et al.

T a b l e 5 C h r o m o s o m a l findings in p a t i e n t AML w i t h r e c u r r e n t c h r o m o s o m a l a b n o r m a l i t i e s

Chromosome Number of

group patients FAB Karyotypes

t(8;21) 1-6 M2 46,XX or XY,t(8;21)(q22;q22)

7,8 M2 45,X,-Y,t(8;21)(q22;q22)

9 M2 45,X,-X,t(8;21)(q22;q22)

10 M2 47,XY,t(8;21)(q22;q22),+8,del(9)(q22)

11 M2 46,XY,t(8;21)(q22;q22),del(9}(q22)

12 M2 46,XY,t(8;21)(q22;q22),inv(9)(pl 1;q13)

t(9;11) 13 M5 46,XX,t(9;11}(p21;q23)

del(11)(q23) 14 M2 46,XY,del(11)(q23)

15 M5 47,XX,+8,del(11)(q23}/47,XX,+mar

16 M5 46,XY,del( 5 )(q13 ),del(11)( q2 3 ) , - 1 0 , + mar/ 4 7 ,XY,

del(5)(q13),- 10,del(11)(q23),+21,+mar 47,XY,- 7,del(13)(q21;q31),+ 21,+ 22

46,XX,del(1)(q21;q44),- 7,dup(12)(q13;q21),der(12)t(12;?) (p13;?),+mar

Abnormal 7 17 M6

18 M4

sis. We have d e s c r i b e d a n e w u n e x p l a i n e d a n d u n u s u a l t(7;21)(q22;p11) a b n o r m a l i t y associated w i t h AML2.

One case of t(9;11) was o b s e r v e d in an infant in our s t u d y a n d it was a l r e a d y s h o w n that this a b n o r m a l i t y was m o r e frequent in infants t h a n in a d u l t s due to the high i n c i d e n c e of AML5 in infants [4, 7, 8].

A b n o r m a l t(11;V) was a s s o c i a t e d w i t h M4 or M5, i n d u c i n g us to suggest that 11q23 bears a gene r e s p o n s i b l e for m y e l o m o n o c y t a r y differentiations. The other chromosomes i n v o l v e d in the t r a n s l o c a t i o n h e l p d e t e r m i n e the proliferating c e l l u l a r t y p e [16, 17, 33].

In our study, as in p r e v i o u s ones, 11% of cases s h o w e d c h r o m o s o m e 5 or 7 r e a r r a n g m e n t s [30, 32]. A 16-year-old p a t i e n t w i t h M2 s h o w e d a b n o r m a l del(5)(q13q32), w h i c h is u n u s u a l in AML [5]. In contrast, a b n o r m a l - 7 / 7 q - a n d - 5 / 5 q - o b s e r v e d after e x p o s u r e to a n t i m i t o t i c agents are not rare in a d u l t s [9].

The P h i l a d e l p h i a c h r o m o s o m e was f o u n d in three

patients, all AML1 (5%), a n d Shifter et al. r e p o r t e d two cases (1%). A b n o r m a l t(9;22) was f o u n d in 1% of AML [26], m o r e often M1 t h a n M2.

H y p e r d i p l o i d y greater t h a n 50 was f o u n d in four patients (8%) a n d this was in a g r e e m e n t w i t h other studies, as Palka et al., A r t h u r et al., a n d Bloomfield et al.

f o u n d this a b n o r m a l i t y in 15%, 16%, a n d 15% of patients, respectively.

In our study, A A k a r y o t y p e s were m o r e frequent (64%) t h a n in the p r e v i o u s studies of A r t h u r et al. a n d Bloom- field et al. [14], w h o f o u n d 16% a n d 22%, respectively. In contrast, the A N k a r y o t y p e was less frequent (4%) in our s t u d y t h a n the 30% frequency p r e v i o u s l y observed in earlier studies [24, 31]. Finally, the s i m p l e , c o m p l e x , a n d v e r y c o m p l e x classification of our results are again in com- plete agreement w i t h the literature [24, 31].

We can c o n c l u d e that in our s t u d y 70% of patients s h o w e d c h r o m o s o m e aberration a n d h a l f of these were T a b l e 6 C h r o m o s o m a l finding in p a t i e n t AML w i t h c l o n a l m i s c e l l a n e o u s a b n o r m a l i t i e s

Patient

number FAB Karyotype

18 M~

19 M 2

20 M 2

21 M 1

22 M~

23 M 1

24 M~

26 M~

27 M 2

28 M4

29 M 1

30 M 2

31 M1

32 M 5

33 M1

34 M1

35 M 1

36 M 6

46,XY/46,XY,del(22)(q22) 47,XY,t(8;22)(q22;ql 2),+ 8 46,XX/46,XX,t(7;21)(q22;q11) 47,XX/47,XX,del(9)(q22),+21

46,XX,der(5)t(5;?)(q35;?),del(9)(q22),-12, 17 46,XY/46,XY,t(9;22) (q34;q11)

47,XX,t(9;22)(q34;q11),+ 17 46,XY,t(9;22)(q34;q11) 47,XX,+5

46,XY,+7,-19 47,XX,+8 47,XY,+16 46,XY,del(15)(q23)

45,XY,inv(1)(q31p36),del(3)(p22),- 12,- 15,+mar1/45,Y,-X,inv(1)(q31p36) del(3)(p22),- 12,- 15,+mar2,+mar3

46,XX,dup(13)(q21q24),+mar/44,XX,dup(13)(q21q24),-8,- 19,+mar2,+mar3 46,XY,r(1)(p35;q41)

4 6 , X Y / 7 2 - 8 3 < 4 N > ,XY,inc

48,XY,+6,der(13)del(13)(q13p21)del(13)(q31q33),+21

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Cytogenetics of M o r o c c a n AML Patients 12 7

Table 7 F r e q u e n c y of t(8;21) in the literature c o m p a r e d to this study

Number Percentage Reference Patient no. with t(8;21) with t(8;21)

Rowley et al. [11] 503 29 6

Palka et al. [21] 80 5 6

Arthur etal. I24) 656 44 7

Bloomfield et al. [14] 660 44 7

Schiffer et al. [26] 398 13 7

GFCH [27] 325 15 4,6

Gallego et al. [34] 638 74 11,6

This study 53 12 23

s i m p l e c h r o m o s o m e changes. A m o n g 36 abnormal karyotypes, 85% harbored r e c u r r e n t abnormalities. Our study confirms the established r e l a t i o n s h i p b e t w e e n certain specific abnormalities and FAB groups, but the P h i l a d e l p h i a c h r o m o s o m e appeared more frequently, We have also identified u n u s u a l abnormalities s u c h as t(7;21)(q22;p11), r(1).

Finally, w e n o t e d a high f r e q u e n c y of t(8;21) in our M o r o c c a n p o p u l a t i o n w i t h AML2, i n d u c i n g us to raise questions c o n c e r n i n g the p r e d i s p o s i n g factor of this abnormality, as w e l l as the nature of the m o l e c u l a r rear- r a n g e m e n t s in the c h r o m o s o m e regions concerned, keep- ing in m i n d that the role of 8q22 and 21q22 in AML genesis is always u n d e r consideration.

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