Leukemia Research Vol. 16, No. 1, pp. 43~.6, 1992. Printed in Great Britain.
0145--2126/92 $5.00 + .00 Pergamon Press plc
CYTOGENETIC FINDINGS IN PRIMARY A N D S E C O N D A R Y MDS SVERRE H E l M
Department of Clinical Genetics, University Hospital, Lund, Sweden, and Department of Medical Genetics, Odense University, Odense, Denmark Abstract--More than 1300 MDS cases with clonal cytogenetic abnormalities, 200 of them secondary MDS, have been reported. The most common aberrations in primary MDS are del(5q) (27%), trisomy 8 (19%), monosomy 7 (15%), der(llq) (7%), -5, der(12p) and - Y (5%), del(7q) (4%), and t(1;7), der(3q), del(13q), i(17q) and del(20q) in 2% or less. The 5q- is mostly, but not always, a del(5)(q13q33); it is the cytogenetic hall-mark of the "5q- syndrome" and is frequently found as the sole abnormality. The frequency of the aberrations varies among MDS subgroups: 5q- is most frequent in RA, -5, -7, and der(12p) are more common in CMML and especially in RAEB, and +8 and der(llq) are more often found in RARS. The most common aberrations in secondary MDS are - 7 (41%), del(5q) (28%), - 5 (11%), der(21q) (9%), 7q-, +8 and der(12p) (8%), t(1;7) and -12 (7%), der(17p) (6%), der(3p) and der(6p) (5%), and der(3q), der(llq), -17, -18 and der(19q) (4%). The average number of abnormalities per case is 5.3, compared with 2.9 in unspecified MDS. The frequency of cytogenetically unrelated clones is 5.7% in secondary and 4.3% in primary MDS. When the literature data are broken down by type of genotoxic exposure, it turns out that -5, -7, and der(17p) are over-represented in patients who have received chemotherapy, whereas 5q- is associated with no exposure or preceding radiotherapy only. The karyotypic profile is prognostically important: patients with - 7 or complex karyotypes have a higher risk of progression to acute leukemia and shorter survival. Key words: Chromosomes, cytogenetics, myelodysplasia.
karyotypic features are useful diagnostic and prognostic markers [3-6]. The following brief review by no means attempts to be exhaustive; only some of the more salient features of MDS cytogenetics will be focused on. The literature cited will mostly be large and recent review articles; more extensive referencing to original data may be found elsewhere [1, 6-11].
INTRODUCTION CHROMOSOME abnormalities have been reported in more than 1300 patients [1~] with myelodysplastic syndromes (MDS), and the very finding of these clonal genetic changes is one of the strongest arguments that MDS are neoplastic disorders. In roughly 200 cases MDS developed secondarily to another neoplasm (sMDS). Most of these patients have also been exposed to genotoxic therapeutic regimens. Similar sMDS or the related secondary acute nonlymphocytic leukemia (sANLL) may develop after occupational exposure to genotoxins, indirectly supporting the view that it is the environmental factors, not any inherently heightened tendency to develop malignant diseases, that is the main cause for the high frequency of sMDS/sANLL in successfully treated cancer patients [2]. The comparison between primary and secondary MDS may therefore shed light on both etiologic and pathogenetic factors in myelodysplasia and leukemia. In addition to this basic research aspect of MDS cytogenetics, chromosome analyses may also be of direct clinical value in as much as the
CHARACTERISTIC C H R O M O S O M A L ABNORMALITIES IN MDS All the MDS-associated cytogenetic abnormalities are also common in ANLL. The opposite is not necessarily true: some of the most specific rearrangements in ANLL--Iike t(8;21) in M2, t(15;17) in M3, and inv(16) in M4 [4--6]--are rarely or never seen in MDS. The most frequent clonal chromosome aberrations encountered in MDS are the following: t(1 ;7), der(3p), der(3q), 5 q - , - 5 , der(6p), - 7 , 7 q - , +8, der(llq), der(12p), del(13q), -17, i(17q), -18, der(19q), del(20q), - Y . These abnormalities have all been extensively reviewed (in, e.g. [6-11]), and only a few pertinent aspects concerning some of them will be discussed here.
Correspondence to: Dr S. Heim, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. 43
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t(1;7)(p11;p11) The MDS in patients with t(1;7) regularly progresses to ANLL, mostly to M4 [12]. In situ hybridization studies using centromere-specific probes have revealed that the breakpoints are in the middle of the centromeres and not proximally in the short arms, and consequently a new description, t(1 ;7)(cen;cen), has been proposed [13].
child originally appears to have a Ph-negative, juvenile-type chronic myeloid leukemia, but the clinical course is characterized by repeated infectious episodes and the disease rapidly progresses to ANLL. +8 This trisomy is the single most common abnormality in ANLL and is the second (after 5 q - ) most common change in primary MDS.
der(3q) The rearrangements t(1;3)(p36;q21) and inv(3) (q21q26), as well as variant 3q changes, have been associated with MDS progressing to ANLL. The hematologically most distinguishing feature has been prominent dysmegakaryocytopoiesis, but also the other lineages show morphologic signs of being involved in the neoplastic process.
der(12p) These abnormalities, mostly deletions or unbalanced translocations, have been associated with secondary disease [16]. As is the case elsewhere when a rearrangement results in loss of genetic material, this leads to speculation that loss of a tumor suppressor gene or antioncogene is the pathogenetically important consequence.
5qThe most characteristic MDS-associated abnormality is a deletion of the long arm of chromosome 5 [14]. It occurs in roughly 30% of MDS patients. The typical patients with the 5 q - syndrome are elderly women with therapy-resistant macrocytic anemia. The platelets are normal or elevated, the number of megakaryocytes in the bone marrow is increased, many are micromegakaryocytes, and their nuclei are hypolobulated. The clinical course is typically mild; progression to ANLL is rare, at least when 5 q - is the sole abnormality. Although it seems clear that the amount of lost chromatin material varies, the most common deletion appears to be del(5)(13q33), and a higher than expected breakpoint consistency has been reported [15]. The pathogenetic consequences of the del(5q) are unknown.
der(6p) The most consistent among aberrations involving 6p has been a t(6;9)(p23;q34), repeatedly described in MDS with fairly rapid progression to ANLL. The breakpoint in 9q34 is proximal to the breakpoint in the same band in the t(9;22) of chronic myeloid leukemia, and so the pathogenetic consequences of the two translocations appear to be unrelated. Patients with t(6;9) are often young and may exhibit bone marrow basophilia. -7 This is the most common aberration in secondary MDS and ANLL (see below), but it is also found in idiopathic disease. In addition to its frequent occurrence in sMDS/sANLL, monosomy 7 may also be found as the sole karyotypic anomaly in a characteristic myeloproliferative syndrome of childhood. The
del(13q) This deletion is more common in idiopathic myelofibrosis/agnogenic myeloid metaplasia than in MDS.
del(2Oq) This deletion is the most common aberration in polycythemia vera, but it is also seen in other myeloproliferative disorders and in myelodysplasia. -y Loss of a sex chromosome (more often - Y in men than - X in women) is fairly common in bone marrow cells, but the interpretation is far from straightforward. In spite of being an acquired clonal abnormality, it can occur as a non-neoplastic, age-associated change. However, on other occasions - Y is unquestionably neoplasia-related, disappearing in remission and recurring in relapse, and sometimes it may be the only detectable abnormality [17]. CLONAL EVOLUTION D U R I N G DISEASE PROGRESSION Karyotypic complexity varies among the MDS subtypes [11], from 1.7 aberrations per case in refractory anemia (RA), via 2.9 in unselected MDS, to 3.2 in the more malignant refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t). The general tendency is obviously that the more leukemia-like the MDS, the more complex is, on average, the karyotype. A perhaps more puzzling aspect of the clonal evolution in MDS regards the frequently simultaneous detection in the same case of two of the most common aberrations, 5 q - and trisomy 8. Both these changes are also often found as sole anomalies and
Cytogenetics of MDS
are hence presumably of primary pathogenetic importance. One evidently has to conclude that although 5 q - and +8 may in some cases act as primary aberrations, at other times their function is secondary. This view is also consonant with the occasional emergence of del(5q) only late in the disease course [18]. One should also bear in mind that there is nothing principally wrong with a scenario in which submicroscopic genetic changes precede both 5 q and +8, also when the chromosomal abnormalities appear to be the only genetic change. If this is so, at least in some instances, then this could also partly explain the finding of cytogenetically unrelated clones in 4.3% of all MDS cases [19]. It is presently uncertain whether these unrelated clones really reflect true biological polyclonality. CYTOGENETIC DIFFERENCES BETWEEN MDS SUBGROUPS The increasing karyotypic complexity as the MDS becomes more leukemia-like has been alluded to above. But also additional group differences exist [9, 11]. The quantitatively dominating aberrations in RA are 5 q - , trisomy 8, and monosomy 7. It is particularly noteworthy that changes like - 5 and 7 q - , both often cited as common changes in MDS, do not occur more frequently than chance may allow. In refractory anemia with ringed sideroblasts (RARS) the average karyotypic complexity is on a par with that of RA (1.8 aberrations per case). The picture of aberrations is dominated by four anomalies: +8 is found in one quarter of all abnormal cases, 5 q - is found at about the same frequency, structural changes of l l q are seen in 15%, and del(20q) is found in another 10%. In particular, the high frequency of llq changes, mostly deletions, sets this subgroup apart from other MDS subtypes. In chronic myelomonocytic leukemia (CMML) four aberrations are encountered in more than 5% of the cases, namely - 7 (15%), +8 (15%), der(12p) (10%), and - Y (10%). It is remarkable that 5 q - , the overall most common aberration in primary MDS, is seen in less than 1% of all cases. Finally, in primary RAEB and RAEB-t, where the average number of aberrations reaches 3.2, the changes that are seen in more than 10% are 5 q - (25%), monosomy 7 (15%), and trisomy 8 (15%). CYTOGENETIC DIFFERENCES BETWEEN PRIMARY AND SECONDARY MDS These differences are quantitative, not qualitative [8-11]. First of all, sMDS cases generally have more complex karyotypes (5.3 aberrations per case) and cytogenetically unrelated clones are found in 5.7%,
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i.e. somewhat more often than in primary disease [8]. The most common aberrations in sMDS are, in descending order of frequency, as follows (percentages derived from [1] and [8]): - 7 (41%), 5 q (28%), - 5 (11%), 7 q - (8%), +8 (8%), der(12p) (8%), t(1;7) (7%), and der(llq) (4%). This means that whereas some abnormalities, in particular - 7 , - 5 , 7 q - , der(12p), and t(1;7), are more common in sMDS, others, especially +8, der(llq), and - Y , are relatively more frequent in primary disease. For 5 q there is no frequency difference between de n o v o and secondary disease. The total reported data base on the cytogenetics of sMDS has recently [8] been broken down by type of treatment for the previous neoplasms, leaving four categories (no genotoxic therapy, radiotherapy, chemotherapy, and combined radio- and chemotherapy) with enough cases to permit reasonably reliable, quantitative assessment of potential associations. 5 q - was much more common in the no therapy and radiotherapy-only groups. It thus seems that the high overall frequency of 5 q - in sMDS is due to admixture of patients with the 5 q - syndrome, which is not related to genotoxic exposure [14]. The most dominant correlation was between monosomy 7 and chemotherapy: the frequency of - 7 rose from 25% in the radiotherapy-only group to 43% in patients who had received both radio- and chemotherapy. Other cytogenetic aberrations which in the total material were found to be more frequent in patients who had received cytostatic drugs were - 5 and der(17p). The other previously suggested correlations (full referencing in [8])--between t(1 ;7), 7 q - , der(11 q), der(12p), -18 and der(19q) and chemotherapy and between der(3p), der(6p) and - 1 7 and radiotherapy ----could be confirmed only partially or not at all. CLINICAL IMPLICATIONS OF CYTOGENETIC FINDINGS Most studies have found that the karyotype is a prognostic factor in MDS. The Second International Workshop on Chromosomes in Leukemia (1979) [20] found that patients with an abnormal clone, whether AA or AN, ran a greater risk of developing ANLL than NN patients. The follow-up study undertaken by the Sixth International Workshop [3] confirmed that a clonal cytogenetic anomaly was associated with shorter survival and a higher progression rate to leukemia, and essentially similar results have also been reached in other studies [21-26]. Patients with - 7 or complex karyotypes have generally been found to have the worst prognosis, including the greatest risk of progression to ANLL. All these comparisons have been based on karyo-
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S. HEIr,!
typic data obtained at diagnosis. Additional clinically important information may be derived from repeated cytogenetic bone marrow analyses [27, 28]: when transformation to more aggressive MDS stages occurs or when the MDS evolves into acute leukemia, this is often accompanied (caused?) by the emergence of secondary clonal chromosomal aberrations. Bone marrow chromosome analysis can therefore help diagnose such transformations.
13.
14. 15.
Acknowledgements---Supported by grants from the Danish and Swedish Cancer Societies and from the Children's Cancer Fund of Sweden.
16.
17. REFERENCES 1. Mitelman F. Catalog of Chromosome Aberrations in Cancer, 4th edn. Wiley-Liss, New York. (In press.) 2. Fourth International Workshop on Chromosomes in Leukemia 1982 (1984) A prospective study of acute nonlymphocytic leukemia. Cancer Genet. Cytogenet. 11, 249-360. 3. Pierre R. V., Catovsky D., Mufti G. J., et al. (1989) Clinical-cytogenetic correlations in myelodysplasia (preleukemia). Cancer Genet. Cytogenet. 40, 149-161. 4. Heim S. & Mitelman F. (1987) Cancer Cytogenetics. Alan R. Liss, New York. 5. Heim S. (1990) Cytogenetics in the investigation of haematological disorders. Baillidre's Clin. Haemat. 3, 921-948. 6. Sandberg A. A. (1990) The Chromosomes in Human Cancer and Leukemia. Elsevier, New York. 7. Mitelman F., Kaneko Y. & Trent J. M. (1990) Report of the Committee on Chromosome Changes in Neoplasia, Human Gene Mapping 10.5 (1990): Update to the Tenth International Workshop on Human Gene Mapping. Cytogenet. Cell Genet. 55, 358-386. 8. Johansson B., Mertens F., Heim S., et al. (1991) Cytogenetics of secondary myelodysplasia (sMDS) and acute nonlymphocytic leukemia (sANLL). Eur. J. Haemat. 47, 17-27. 9. Heim S. & Mitelman F. Chromosomal abnormalities in primary myelodysplastic syndromes. In The Myelodysplastic Syndromes (Mufti G. J. & Galton D. A. G., Eds). Churchill Livingstone, London. (In press.) 10. Berger R. & Flandrin G. Chromosomal abnormalities in secondary acute nonlymphocytie leukemia and the myelodysplastic syndromes. In The Myelodysplastic Syndromes (Mufti G. J. & Galton D. A. G., Eds). Churchill Livingstone, London. (In press.) 11. Heim S. & Mitelman F. (1986) Chromosome abnormalities in the myelodysplastic syndromes. Clin. Haemat. 15, 1003-1021. 12. Seheres J. M. J. C., Hustinx T. W. J., Geraedts J. P. M., Leeksma C. H. W. & Meltzer P. S. (1985) Translocation 1;7 in hematologic disorders: a brief
18. 19. 20. 21. 22.
23. 24.
25.
26. 27.
28.
review of 22 cases. Cancer Genet. Cytogenet. 18, 207213. Alitalo T., Willard H. F. & de la Chapelle A. (1989) Determination of the breakpoints of 1;7 translocations in myelodysplastic syndrome by in situ hybridization using chromosome-specific alpha satellite DNA from human chromosomes 1 and 7. Cytogenet. Cell Genet. 50, 49-53. van den Berghe H., Vermaelen K., Mecucci C., Barbieri D. & Tricot G. (1985) The 5 q - anomaly. Cancer Genet. Cytogenet. 17, 189-255. Mitelman F., Manolova Y., Manolov G., et al. (1986) High resolution analysis of the 5 q - marker chromosome in refractory anemia. Hereditas 105, 49-54. Berger R., Bernheim A., Le Coniat M., et al. (1986) Abnormalities of the short arm of chromosome 12 in acute nonlymphocytic leukemia and dysmyelopoietic syndrome. Cancer Genet. Cytogenet. 19, 281-289. Holmes R. I., Keating M. J., Cork A., et al. (1985) Loss of the Y chromosome in acut~ myelogenous leukemia: a report of 13 patients: Cancer Genet. Cytogenet. 17, 269-278. Heim S., Billstr6m R., Kristoffersson U., et al. (1987) Late appearing 5 q - marker in refractory anemia. Cancer Genet. Cytogenet. 24, 159-162. Heim S. & Mitelman F. (1989) Cytogenetically unrelated clones in hematological neoplasms. Leukemia 3, 6-8. Second International Workshop on Chromosomes in Leukemia 1979 (1980) Chromosomes in preleukemia. Cancer Genet. Cytogenet. 2, 108-113. Coiffier B., Adeleine P., Viala J. J., et al. (1983) Dysmyelopoietic syndromes. A search for prognostic factors in 193 patients. Cancer 52, 83-90. Jacobs R. H., Cornbleet M. A., Vardiman J. W., et al. (1986) Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67, 1765-1772. Groupe Frangais de Cytog6n6tique H6matologique (1986) Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet. Cytogenet. 21, 11-30. Nowell P. C., Besa E. C., Stelmach T. & Finan J. (1986) Chromosome studies in preleukemic states. V. Prognostic significance of single versus multiple abnormalities. Cancer 58, 2571-2575. Yunis J. J., Lobell M., Arnesen M. A., et al. (1988) Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogeneous leukaemia. Br. J. Haemat. 68, 189-194. Billstr6m R., Thiede T., Hansen S., et al. (1988) Bone marrow karyotype and prognosis in primary myelodysplastic syndromes. Eur. J. Haemat. 41, 341-346. Benitez J., Carbonell F., Sanchez Fayos J. & Heimpel H. (1985) Karyotypic evolution in patients with myelodysplastic syndromes. Cancer Genet. Cytogenet. 16, 157-167. Horiike S., Taniwaki M., Misawa S. & Abe T. (1988) Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis. Cancer 62, 1129-1138.
0145--2126/92 $5.00 + .00 Pergamon Press plc
CYTOGENETIC FINDINGS IN PRIMARY A N D S E C O N D A R Y MDS SVERRE H E l M
Department of Clinical Genetics, University Hospital, Lund, Sweden, and Department of Medical Genetics, Odense University, Odense, Denmark Abstract--More than 1300 MDS cases with clonal cytogenetic abnormalities, 200 of them secondary MDS, have been reported. The most common aberrations in primary MDS are del(5q) (27%), trisomy 8 (19%), monosomy 7 (15%), der(llq) (7%), -5, der(12p) and - Y (5%), del(7q) (4%), and t(1;7), der(3q), del(13q), i(17q) and del(20q) in 2% or less. The 5q- is mostly, but not always, a del(5)(q13q33); it is the cytogenetic hall-mark of the "5q- syndrome" and is frequently found as the sole abnormality. The frequency of the aberrations varies among MDS subgroups: 5q- is most frequent in RA, -5, -7, and der(12p) are more common in CMML and especially in RAEB, and +8 and der(llq) are more often found in RARS. The most common aberrations in secondary MDS are - 7 (41%), del(5q) (28%), - 5 (11%), der(21q) (9%), 7q-, +8 and der(12p) (8%), t(1;7) and -12 (7%), der(17p) (6%), der(3p) and der(6p) (5%), and der(3q), der(llq), -17, -18 and der(19q) (4%). The average number of abnormalities per case is 5.3, compared with 2.9 in unspecified MDS. The frequency of cytogenetically unrelated clones is 5.7% in secondary and 4.3% in primary MDS. When the literature data are broken down by type of genotoxic exposure, it turns out that -5, -7, and der(17p) are over-represented in patients who have received chemotherapy, whereas 5q- is associated with no exposure or preceding radiotherapy only. The karyotypic profile is prognostically important: patients with - 7 or complex karyotypes have a higher risk of progression to acute leukemia and shorter survival. Key words: Chromosomes, cytogenetics, myelodysplasia.
karyotypic features are useful diagnostic and prognostic markers [3-6]. The following brief review by no means attempts to be exhaustive; only some of the more salient features of MDS cytogenetics will be focused on. The literature cited will mostly be large and recent review articles; more extensive referencing to original data may be found elsewhere [1, 6-11].
INTRODUCTION CHROMOSOME abnormalities have been reported in more than 1300 patients [1~] with myelodysplastic syndromes (MDS), and the very finding of these clonal genetic changes is one of the strongest arguments that MDS are neoplastic disorders. In roughly 200 cases MDS developed secondarily to another neoplasm (sMDS). Most of these patients have also been exposed to genotoxic therapeutic regimens. Similar sMDS or the related secondary acute nonlymphocytic leukemia (sANLL) may develop after occupational exposure to genotoxins, indirectly supporting the view that it is the environmental factors, not any inherently heightened tendency to develop malignant diseases, that is the main cause for the high frequency of sMDS/sANLL in successfully treated cancer patients [2]. The comparison between primary and secondary MDS may therefore shed light on both etiologic and pathogenetic factors in myelodysplasia and leukemia. In addition to this basic research aspect of MDS cytogenetics, chromosome analyses may also be of direct clinical value in as much as the
CHARACTERISTIC C H R O M O S O M A L ABNORMALITIES IN MDS All the MDS-associated cytogenetic abnormalities are also common in ANLL. The opposite is not necessarily true: some of the most specific rearrangements in ANLL--Iike t(8;21) in M2, t(15;17) in M3, and inv(16) in M4 [4--6]--are rarely or never seen in MDS. The most frequent clonal chromosome aberrations encountered in MDS are the following: t(1 ;7), der(3p), der(3q), 5 q - , - 5 , der(6p), - 7 , 7 q - , +8, der(llq), der(12p), del(13q), -17, i(17q), -18, der(19q), del(20q), - Y . These abnormalities have all been extensively reviewed (in, e.g. [6-11]), and only a few pertinent aspects concerning some of them will be discussed here.
Correspondence to: Dr S. Heim, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. 43
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t(1;7)(p11;p11) The MDS in patients with t(1;7) regularly progresses to ANLL, mostly to M4 [12]. In situ hybridization studies using centromere-specific probes have revealed that the breakpoints are in the middle of the centromeres and not proximally in the short arms, and consequently a new description, t(1 ;7)(cen;cen), has been proposed [13].
child originally appears to have a Ph-negative, juvenile-type chronic myeloid leukemia, but the clinical course is characterized by repeated infectious episodes and the disease rapidly progresses to ANLL. +8 This trisomy is the single most common abnormality in ANLL and is the second (after 5 q - ) most common change in primary MDS.
der(3q) The rearrangements t(1;3)(p36;q21) and inv(3) (q21q26), as well as variant 3q changes, have been associated with MDS progressing to ANLL. The hematologically most distinguishing feature has been prominent dysmegakaryocytopoiesis, but also the other lineages show morphologic signs of being involved in the neoplastic process.
der(12p) These abnormalities, mostly deletions or unbalanced translocations, have been associated with secondary disease [16]. As is the case elsewhere when a rearrangement results in loss of genetic material, this leads to speculation that loss of a tumor suppressor gene or antioncogene is the pathogenetically important consequence.
5qThe most characteristic MDS-associated abnormality is a deletion of the long arm of chromosome 5 [14]. It occurs in roughly 30% of MDS patients. The typical patients with the 5 q - syndrome are elderly women with therapy-resistant macrocytic anemia. The platelets are normal or elevated, the number of megakaryocytes in the bone marrow is increased, many are micromegakaryocytes, and their nuclei are hypolobulated. The clinical course is typically mild; progression to ANLL is rare, at least when 5 q - is the sole abnormality. Although it seems clear that the amount of lost chromatin material varies, the most common deletion appears to be del(5)(13q33), and a higher than expected breakpoint consistency has been reported [15]. The pathogenetic consequences of the del(5q) are unknown.
der(6p) The most consistent among aberrations involving 6p has been a t(6;9)(p23;q34), repeatedly described in MDS with fairly rapid progression to ANLL. The breakpoint in 9q34 is proximal to the breakpoint in the same band in the t(9;22) of chronic myeloid leukemia, and so the pathogenetic consequences of the two translocations appear to be unrelated. Patients with t(6;9) are often young and may exhibit bone marrow basophilia. -7 This is the most common aberration in secondary MDS and ANLL (see below), but it is also found in idiopathic disease. In addition to its frequent occurrence in sMDS/sANLL, monosomy 7 may also be found as the sole karyotypic anomaly in a characteristic myeloproliferative syndrome of childhood. The
del(13q) This deletion is more common in idiopathic myelofibrosis/agnogenic myeloid metaplasia than in MDS.
del(2Oq) This deletion is the most common aberration in polycythemia vera, but it is also seen in other myeloproliferative disorders and in myelodysplasia. -y Loss of a sex chromosome (more often - Y in men than - X in women) is fairly common in bone marrow cells, but the interpretation is far from straightforward. In spite of being an acquired clonal abnormality, it can occur as a non-neoplastic, age-associated change. However, on other occasions - Y is unquestionably neoplasia-related, disappearing in remission and recurring in relapse, and sometimes it may be the only detectable abnormality [17]. CLONAL EVOLUTION D U R I N G DISEASE PROGRESSION Karyotypic complexity varies among the MDS subtypes [11], from 1.7 aberrations per case in refractory anemia (RA), via 2.9 in unselected MDS, to 3.2 in the more malignant refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t). The general tendency is obviously that the more leukemia-like the MDS, the more complex is, on average, the karyotype. A perhaps more puzzling aspect of the clonal evolution in MDS regards the frequently simultaneous detection in the same case of two of the most common aberrations, 5 q - and trisomy 8. Both these changes are also often found as sole anomalies and
Cytogenetics of MDS
are hence presumably of primary pathogenetic importance. One evidently has to conclude that although 5 q - and +8 may in some cases act as primary aberrations, at other times their function is secondary. This view is also consonant with the occasional emergence of del(5q) only late in the disease course [18]. One should also bear in mind that there is nothing principally wrong with a scenario in which submicroscopic genetic changes precede both 5 q and +8, also when the chromosomal abnormalities appear to be the only genetic change. If this is so, at least in some instances, then this could also partly explain the finding of cytogenetically unrelated clones in 4.3% of all MDS cases [19]. It is presently uncertain whether these unrelated clones really reflect true biological polyclonality. CYTOGENETIC DIFFERENCES BETWEEN MDS SUBGROUPS The increasing karyotypic complexity as the MDS becomes more leukemia-like has been alluded to above. But also additional group differences exist [9, 11]. The quantitatively dominating aberrations in RA are 5 q - , trisomy 8, and monosomy 7. It is particularly noteworthy that changes like - 5 and 7 q - , both often cited as common changes in MDS, do not occur more frequently than chance may allow. In refractory anemia with ringed sideroblasts (RARS) the average karyotypic complexity is on a par with that of RA (1.8 aberrations per case). The picture of aberrations is dominated by four anomalies: +8 is found in one quarter of all abnormal cases, 5 q - is found at about the same frequency, structural changes of l l q are seen in 15%, and del(20q) is found in another 10%. In particular, the high frequency of llq changes, mostly deletions, sets this subgroup apart from other MDS subtypes. In chronic myelomonocytic leukemia (CMML) four aberrations are encountered in more than 5% of the cases, namely - 7 (15%), +8 (15%), der(12p) (10%), and - Y (10%). It is remarkable that 5 q - , the overall most common aberration in primary MDS, is seen in less than 1% of all cases. Finally, in primary RAEB and RAEB-t, where the average number of aberrations reaches 3.2, the changes that are seen in more than 10% are 5 q - (25%), monosomy 7 (15%), and trisomy 8 (15%). CYTOGENETIC DIFFERENCES BETWEEN PRIMARY AND SECONDARY MDS These differences are quantitative, not qualitative [8-11]. First of all, sMDS cases generally have more complex karyotypes (5.3 aberrations per case) and cytogenetically unrelated clones are found in 5.7%,
45
i.e. somewhat more often than in primary disease [8]. The most common aberrations in sMDS are, in descending order of frequency, as follows (percentages derived from [1] and [8]): - 7 (41%), 5 q (28%), - 5 (11%), 7 q - (8%), +8 (8%), der(12p) (8%), t(1;7) (7%), and der(llq) (4%). This means that whereas some abnormalities, in particular - 7 , - 5 , 7 q - , der(12p), and t(1;7), are more common in sMDS, others, especially +8, der(llq), and - Y , are relatively more frequent in primary disease. For 5 q there is no frequency difference between de n o v o and secondary disease. The total reported data base on the cytogenetics of sMDS has recently [8] been broken down by type of treatment for the previous neoplasms, leaving four categories (no genotoxic therapy, radiotherapy, chemotherapy, and combined radio- and chemotherapy) with enough cases to permit reasonably reliable, quantitative assessment of potential associations. 5 q - was much more common in the no therapy and radiotherapy-only groups. It thus seems that the high overall frequency of 5 q - in sMDS is due to admixture of patients with the 5 q - syndrome, which is not related to genotoxic exposure [14]. The most dominant correlation was between monosomy 7 and chemotherapy: the frequency of - 7 rose from 25% in the radiotherapy-only group to 43% in patients who had received both radio- and chemotherapy. Other cytogenetic aberrations which in the total material were found to be more frequent in patients who had received cytostatic drugs were - 5 and der(17p). The other previously suggested correlations (full referencing in [8])--between t(1 ;7), 7 q - , der(11 q), der(12p), -18 and der(19q) and chemotherapy and between der(3p), der(6p) and - 1 7 and radiotherapy ----could be confirmed only partially or not at all. CLINICAL IMPLICATIONS OF CYTOGENETIC FINDINGS Most studies have found that the karyotype is a prognostic factor in MDS. The Second International Workshop on Chromosomes in Leukemia (1979) [20] found that patients with an abnormal clone, whether AA or AN, ran a greater risk of developing ANLL than NN patients. The follow-up study undertaken by the Sixth International Workshop [3] confirmed that a clonal cytogenetic anomaly was associated with shorter survival and a higher progression rate to leukemia, and essentially similar results have also been reached in other studies [21-26]. Patients with - 7 or complex karyotypes have generally been found to have the worst prognosis, including the greatest risk of progression to ANLL. All these comparisons have been based on karyo-
46
S. HEIr,!
typic data obtained at diagnosis. Additional clinically important information may be derived from repeated cytogenetic bone marrow analyses [27, 28]: when transformation to more aggressive MDS stages occurs or when the MDS evolves into acute leukemia, this is often accompanied (caused?) by the emergence of secondary clonal chromosomal aberrations. Bone marrow chromosome analysis can therefore help diagnose such transformations.
13.
14. 15.
Acknowledgements---Supported by grants from the Danish and Swedish Cancer Societies and from the Children's Cancer Fund of Sweden.
16.
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