Document 0LKkx2zeOMkMyMnk020wd1o1O

Scand J Haematol 1986;36,Suppl45: 74- 77 Key words a c u t e non.lymphocytlc ieukaemiachromosomes-myelodysplastic syndromes-survlval Cytogenetics of the myelodysplastic syndromes Georg H. Borgstrom Department of Medical Genetics, University of Helsinki. Helsinki, Finland C h r o m o s o m e aberrations occur in 30-50 Go of patients Hith myelodysplastic syndromes (.WDS). C h r o m o s o m e aberrations found in \1DS a r e generally fognd in acute nonlymphocytic leukaemia (ANLL). while certain aberrations of ANLL d o nor occur in MDS. T h e clinical significance of these aberrations has been eLaluated on the basis of several series from literature and a large series from Helsinki University Central Hospital. The presence o f a n aberrant clone \rith m a j o r karyotypic a b e r r a t i o n (MAK~Ao) r m o n o s o m y 7 in a patient {rith MDS indicates a higher risk of transformation io acute leukaemia and a shorter survival. Acquired chromosomal aberrations occurring clonally are generally considered to be a sign of a malignant or premalignant state. Thus :he fact that patients with myelodysplastic syndromes (hIDS) have aberrations in their bone marrow cells is compatible with the neoplastic nature of these disorders. In leukaemias certain cytogenetic aberrations correlate with prognosis and with specific haematological features, thus being of clinical significance. Clonal evolution often marks a change to a more malignant form of leukaemia. Consequently, it is relevant to ask whether such correlations exist in the myelodysplastic syndromes and whether chromosome analysis can be used in monitoring and evaluating these disorders. Cytogenetic findings The incidence of chromosomal aberrations in \IDS varies bet\r.een 32 To and 51 "0 (Table I ) . Th1>'.;riation could be explained by the different c! :LTgenetic techniques as well as by the diagno.;.; criteria f o r the MDS. From a diagnostic point view, the presence of an aberrant clone confirm. the diagnosis o f MDS while a normal result doc. not exclude this possibility. The most common aberrations in MDS .I-:' also found in de novo ANLL (-5,5q-,-7,7q-. - '. + 19,20q-)(3).On the other hand, some of the m-"' characteristic translocations of acute non-lymFk.'- The literature o n cytogenetics in the myelodysplastic syndromes is difficult to interpret due to varying nomenclature and the different criteria used for the inclusion of cases. Only in a few reports the patients have been classified according t o the FABproposals (I). The present review is based on several large series and some unpublished data from Helsinki University Central Hospital (2-5$ IO, Todd & Pierre and Bloomfield, in this number). TABLE I Frequenci OJ. chromosome oberrartons in [he mielodi,:' * 5 )ndromes cytic leukaemia ( A N L L ) , i.e. ' ANLL M2 and t( 15; 17)(q22;qI 2 not found in de novo MDS. Thisomc leukaemias pass throu: phase with characteristic chrorr. while others develop "direct]! Certain aberrations correlate lodysplastic syndromes, appear. cer treatment (Bloomfield. in tt ly 5q- and - 5 , and 7q- and -7. 7 also appear in primary MDS. Among recurring numerical my 8 and trisomy 19 are espec tion of the long a r m of chror: been found in MDS but also in (3, 6). In o u r series as well as I derson and Bagby (10) deletion at q14 has been found in sever also a recurring breakpoint in :. in this numberj. Only a few r e a have been described in MDS. (7) and t(1;7) which results in and a partial monosomy 7 (8). 5 present with major karyotqpic a t i.e. they have 3 or more karyor the same clone. In addition, se\ ported only in a single patient iin MDS. Clinical correlations with chr For the evaluation of the clini Helsinki series was grouped as common aberrations: 5q-, -7. TABLE 2 .Worphoiogrcoi clacsrficarron o f ceria! FAB-group Yormal RA RARS RAEB CMML RAEB~ Total 21 21 19 11 1 -7 986:36,Suppl45: 74-77 1phocytic leukaemla. astic syndromes-suwlval -,Tomes Genetics. University of and 0- n- 1s. -a1 he yL l iia S iosomal aberrations in MDS nd 51 mo (Table 1). This va,ined by the different cytowell as by the diagnostic `rom a diagnostic point of - ` -rrant clone confirms w d normal result does dity. aberrations in MDS are ANLL (-5,5q-,-7,7q-,+ 8, her hand, some of the most ions of acute non-lympho- irrrorions in rhe m.velodwplosr~c Total 1 24-4 80 88 158 Abnormal Normal clones ( m o ) kar)'ot)p 125 (51) 31 (39) 28 (32) 81 (SI) 119 49 60 7 CYTOGENETICS OF \IDS 75 Lyric leukaemia (ANLL), i.e. t(8;21)(qZZ;q22) in aberrations and cases with only normal mitoses in A ~ L 4L12 and t(15;17)(q22:q12) in A N L L M3, are the bone marrow (BM). The distribution of the found in de novo MDS. This could indicate that FAB-subtypes of MDS in the different chromo- ,ome leukaemias pass through a preleukaemic some groups is presented in Table 2. No significant nhase with characteristic chromosome aberrations difference was found which is of interest in view ,I bile others develop "directly". of the differences in survival among the groups Certain aberrations correlate to secondary mye- noted below. I !dysplastic syndromes. appearing after prior can- Among haematological parameters, the presence Lcr treatment (Bloom field, in this number), name- of blasts in the blood and the increase in the per- 1) i q - and - 5 , and 7q- and -7 . They can, however, centage of blasts in the bone marrow, respective- J],O appear in primary MDS. ly, were studied (Tables 3 and 4). The MAKA group .Among recurring numerical aberrations, triso- had blasts in the blood more often than the other m? Y and trisomy 19 are especially notable. Dele- cytogenetic groups (38 To vs. 10-13 To) and this tion of the long arm of chromosome no. 20 has difference was statistically significant (p < 0.05). been found in MDS but also in polycythaemia vera There was no significant difference in the chromo- (3. 6). In our series as well as in the series of An- somal aberrations in patients with < 5 Cn, VS. derson and Bagby (10) deletion of chromosome 11 > 5 "0 of blasts in the BM. at q14 has been found in several patients. This is also a recurring breakpoint in ANLL (Bloomfield, Correlations of cytogenetics to specific haema- in this number). Only a few recurring translocations tological features have been sought for and found, have been described in MDS. Of note are t(2;Il) at least, for one aberration. Among MDS there is (-) and t(1;7) which results in a partial trisomy 1 an entity called the 5q- syndrome with the same and a partial monosomy 7 (8). Some >IDS patients chromosomal marker as in some secondary mye- present t\ith major kar)ot>-pic aberrations (%w(A), lodyspiastic syndromes, an interstitial deletion of i.e. they hate 3 or more karyotypic aberrations in the long arm of chromosome 5 , but, in these pa- :he same clone. In addition, several aberrations re- tients, a prior exposure history is lacking. The 5q- ported only in a single patient have been described syndrome is a distinct clinico-haematological enti- in 41DS. ty which occurs in elderly females (Van den Berghe, in this number) and includes refractory macrocytic anaemia, normal platelet count, a normal or low Clinical correlations with chromosome groups number of erythroid precursors in the BM and hy- For the evaluation of the clinical correlations the polobulation of megakaryocytes. The clinical -Helsinki series was grouped according to the most course is benign as compared to patients with Zomrnon aberrations: 5q-, - 7 , 8, MAKA, other secondary myelodysplastic syndromes. In patients TABLE 2 Ilorpholopcal clussihsiion oj ter'oin chromosome groups according 10 ;he FA B-criierio r iB-group Uormal 5q- other +8 -~ -7 MAKA Total Ri R ARS RAEB C\I\IL K iEBi rotai 21 4 7 22 0 I ? 19 6 I1 0 8 > --4 0 2 , I I O 31 44 20 I3 1I 00 ~ ~~~ 88 4 4 6 0 2 ~~ IO 44 40 43 I5 8 ~~~ 150. kA = refractor) anaemia. R.ARS = refrairor! acquired sideroblastic anaemia, RAEB = refractor> anaemia with excess of blasts. C \ l \ l L = chronic r n ~ e l o m o n o i ) r ~le; uhsemia. R.AEB[ = refractor) anaemia with excess of blasts in transformarion. * FiB-clatsiiiiarrsn not a ~ a i l a a l efor 8 pts. 76 BORGSTROXI TABLE 3 Blasts in peripltrrul blood' Blaris in PB Xornial f n = -8) \O 90 \ es 10 * Dara from Teerenhovi el 31 ( 5 1 '9. in = IO) 90 10 Percent o i a:h c?ro$:neri< group other (n = 36) -8 In = 81 - (n= 8) ST 87 8: I3 I 3 13 TABLE 4 Presence 0.f blusis in ihe bone niurroit in [he di.fferrnt chromosome groups in;,,* vo hlast, in 5x1 Normal < 5 40 > j 60 * Dara irom Teeienhmi er ill ( 5 1 5q. 64 36 orher 67 33 -8 S6 1.1 - 62 38 51.AE.A I n = 16) 62 38 T o ;. s , I n = 1;- s- I! \!.AKA 56 44 Tau hi 3- with 54- syndrome the chromosome abnormality appears as the sole aberration bvhile in those with secondary MDS it is usually accompanied by other aberrations. Our experience is that the 5q- syndrome can be separated from the other forms of MDS using rhe four haematological features men- tioned abo\e (9). 4 n essential question is ivhether there is a dif- ference in the course of the disease between patients with a chromosome aberration in rhe bone marrow cells and patients with normal karyotype. This has been evaluated at the Second International Workshop on Chromosomes in Leukemia (3). Patients without an aberration showed a lower frequency of development of ANLL than those with only abnormal cells 0: those with a mixture of normal and abnormal cells. This has also been found in the series of Todd and Pierre (in this number), No\vell et a1 (2) and .4yraud et a1 (4). In our series there was a tendency towards this direction, but the difference was not statistically significant (Table 5 ) . However, when the cytogenetic subgroups Lvere analyzed, the patients with Xl.4K.4 and monoso- my 7 tended td have a higher likelihood to develop acute leukaemia (Table 6 ) . Thi, :> in line w i t h !he findings of Anderson and Bagtr! ( I O ) . The overall survival evaluared in our material with regard ro the chromosome groups is presented in Table 7 . .At present there is no sigificant diiference in survival among patients with normal LT abnormal karyotype (Kaplan-Xleier product Iitii:: survival method, p = 0.06). This is in contrabt : ~ 1 T.ABLE 5 Chrotnosotnez 0.' prrcficior o.f acuie ieirkaetvio Source cqOther IO 1 3 1 -7' . 18 8 4 -, MAE.4 16 15 the findings of Todd and Pierrc who found sur\ i \ a1 significantl! with normal karyotype. Houe\tr MAKA or monosomy 7 had a pc? all the other patients ( p < 0.01). there was not a significant differs: tion of the FAB-groups in the dii groups, and. thus, the survi\al ! of a difference of the stage o f . Conclusions Chromosome aberrations occur 11 of patients with myelodysplastiL Chromosome aberrations foL generally found in ..ZNLL, M hile L of ANLL d o not occur in %ID> At least one aberration of hlDS a specific clinical picture, the 51 The presence of certain chromi (MAKA and monosomy 7) prei ment of leukaemia and shorter P 51.A K.A Total 56 63 i 11 3? m t there is no significant diftmong patients with normal or 5 (Kaplan-iMeier producr Iimjt = 0.06). This is in contrast to References :he findings of Todd and Pierre (in this number) ',,ho found survival significantly longer for patients 1rh normal karyotype. However, our patients with \ [ . \ L A or monosomy 7 had a poorer survival than 211 the other patients (p < 0.01). It is notable that :here was not a significant difference in the distribu:ion of the FAB-groups in the different c>Togenetic croups. and, rhus, the survival is not a reflection o f a difference of the stage of the .LlDS. conclusions Chromosome aberrations occur in about 30-50 "0 sf patients with myelodysplastic 'syndromes. Chromosome aberrations found in \IDS are senerally found in ANLL, tvhile certain aberrations of ANLL do not occur in MDS. At least one aberration of LIDS is connected with ;I specific clinical picture, the jq- syndrome. The presence of certain chromosome aberrations (\1.4K.A and monosomy 7) predicts rhe decelopment of leukaemia and shorter jurvi\al. I . Bennett J51.Caiwsh! D. Daniel LIT. et 31. Proporals Cor the Jasiiiicstion O i t h e m)clndysplastic s)ndrome\. Br J Haemarol 1982: 51: 159-99. -. L'owell PC. Cytogenetics of preleuhsmia. Cancrr Genet Cytogenet 1981: 5 : 165-78. t1 Second International Workshop on Chromos mer in Leukemia. Chromosomes in preleuhemia. Cmser enel Cytogenet 1980; 2 : 108-13. 4. Ayraud N. Donzeau Ll. Rabnaud 5. Lambert J-C. C>to- genetic study of 88 iases of relracror) anemia. Cancer Cenet Cytogenet 1983: 5: 243-48. .. Teerenhwi L. Borgstrom GH. Linruls R. Clinical signitiante o i i>logeneticsin myelod)splastic syndromes. L'npublished. 6 . \litelman F. Catalogue o i chromosome aberrations in cancer. Cytogener Cell Genet 1983; 36: 1-515. de la Chapelle A , Knuutila S, Elonen E: Trandocarion (?;l)I(p?l;q?3) in acute non-lymphoc);ric leukaemia. .A non:andom association. Scand J Haematol (in press). 8. Borgstrdm GH. Bloomfield CD. de la Chapelle A . Translocation 1;7 uith resulting monosomy 7q and trisomy Iq; a common recurring abnormality in myelod)splastic jyndromes. Cktogenet Cell Genet 1985; 10: 584. 9. Teerenhovi L . Borgstrom GH. Lintula R , Elonen E. Knuutila S . Vuopio P. Specificliy of some haematoloyical features for 5q- chromosome in preleukemic patients. Meeting abstract. Sixth hfeeting o i the International Societ) of Haematolog, European and African Section. 1981. .Athens. Greece. IO. Anderson R L . Bagb! GC Jr. The prognosuc talue of chromotome irudies in patienti \rith the preleukemic cyndrome (Hematopoietic dysplasia). Leuk Res 1982; 6: 175-81 Correspondence: G. H. Borgstrom. Department of 5ledical Generic5 Haa:rmaninkatu 3, SF-W290 Helsinki. Finland 1 e, Vo ob l e u k e r n 17 60 I9 II 20 6.) 3J 9 41 Iox 22 IO 35 3 43 U 26