GENES, CHROMOSOMES & CANCER 5:392-398 (1992)
Recurring Chromosome Abnormalities in Hodgkin’s Disease Hartmut Dohner, Clara D. Bloomfield, Glauco Frizzera, Joy Frestedt, and Diane C. Arthur Departments of Laboratory Medicine/Pathology (H.D., D.C.A.). Pediatrics (D.C.A.), and Medicine (H.D., J.F.). University of Minnesota. Minneapolis, Minnesota, Department of Medicine, Roswell Park Cancer Institute, Buffalo, N e w York (C.D.B.), and Department of Hematopathology, Armed Forces Institute of Pathology, Washington, D C (G.F.)
Cytogenetic analysis was performed on lymph nodes or other tumor masses from 33 patients with Hodgkin’s disease. Metaphase cells were obtained in 25 of the 33 cases. Analyzable abnormal clones were found in nine cases. Characteristic abnormalities included polyploidy and complex structural rearrangements nonrandomly involving certain chromosomal regions. Chromosomes most commonly gained were 2,9, I I, 19, and 20, and those most often lost were 10, 13. I S , I6,2 I, and Y. Translocation breakpoints clustered in bands I p I I- I p 13, Ip36, 4q35, 14q I I, and I5p I I. In five patients, breakpoints were in bands t o which T-cell receptor genes have been mapped. No specific, recurring translocation was identified. There was. however, recurring loss of chromosomal material from I q. 4q, 6q, and I7p. Loss o r deletions of chromosomes 4 and 6 were found in five and six patients, respectively. Deletions overlapped; the smallest overlapping segments included bands 4q25-4q27 and 6q2 I-6q23. The data suggest that loss of specific chromosomal regions may be important in the pathogenesis of Hodgkin’s disease. With respect t o tumor specificity, deletions of 4q are of particular interest because these have not been previously reported t o occur nonrandomly in other human malignancies. Genes Chrom Cancer 9392-398 ( I 992). 0 1992 Wiley-Liss. Inc.
INTRODUCTION
Data on chromosome abnormalities in hematologic malignancies have been accumulating rapidly in recent years, and in a majority of these malignancies, recurring chromosome aberrations have been found. A number of specific abnormalities have been identified that are associated with distinct morphologic and immunologic subtypes of leukemia and lymphoma (Mitelman et al., 1990).The cloning of genes located at some of these chromosomal breakpoints has provided insight into the molecular mechanisms involved in cellular malignant transformation (Showe and Croce, 1987). In contrast to other hematologic malignancies, only scant cytogenetic data are currently available in Hodgkin’s disease (HI)) (Reeves, 1973; Hossfeld and Schmidt, 1978; Reeves and Pickup, 1980 Fonatsch et al., 1986; Kristoffersson et a]., 1987; Cabanillas et al., 1988;Schouten et al., 1989;Banks et al., 1991;Ladanyi et al., 1991; Tilly et al., 1991). A review of 40 cases reported in the literature shows that there are nonrandom structural rearrangements of certain chromosome regions (Thangavelu and LeBeau, 1989). Rearrangements most frequently involve lp, lq, 2q, 6q, l l p , l l q , 14q, and Xq; however, no specific, recurring chromosomal abnormality has yet been identified. The paucity of available information on genetic alterations in HD underlines the importance of providing accurate cytogenetic data that are based on completely defined karyotypes. By analogy with the cytogenetic findings in most other hematologic malignan0 t992 WILEY-LISS, INC.
cies, it is expected that HD will also be characterized by specific chromosomal abnormalities once a sufficient number of cases has been studied. We report the results of cytogenetic analyses of lymph nodes or other tumor masses from 33 patients with HD. Abnormal clones were detected in 13 cases; the clones could be defined in nine. High quality metaphase spreads revealed recurring chromosome abnormalities that have not previously been reported in HD. MATERIALS A N D METHODS Patients and Tumor Specimens
Cytogenetic analysis was performed on involved lymph nodes or other tumor masses from 33 consecutive patients with HD biopsied at the University of Minnesota Hospital between January 1, 1984, and December 31, 1988.The 18 male patients and 15 female patients ranged in age from 5 to 62 years (median 28 years). Involved tissues included lymph nodes in 31, a pleural mass in one, and a soft tissue flank mass in one patient. Twenty-one patients were studied at diagnosis, and 12 were evaluated at relapse. Histologic classification was done according to the criteria established by Lukes and Butler (1966). The distribution of cases among the different subgroups Reccivcd February 12, 1992; accepted May 14, 1992. Address reprint requests to I k IIartmut Diihner. who is now a t Medizinischc Klinik and l’oliklinik V, University of Ileidelherg, Ilospitalstr. 3 , 6900 Ilcidelberg, Germany. The opinions cxprcssed in this article arc the personal views of the authors and are not to be construed as representing the views of the Department of the Army or the Department of Defense.
393
CHROMOSOME ABNORMALITIES IN HODGKINS DISEASE
TABLE I. Clonal Chromosome Abnormalities in Nine Patients with Hodgkin’s Disease Pt. No.
Agea (Yr)
Stage
Priorb Therapy
Karyotype‘ ~
~~
Nodular Sclerosis 18 22 IIA
CT/RT
20
21
IIA
-
21
I2
IllA
-
22
28
IllB
-
+
+
62.XY. - 4, t 5, + 6, - 7, + 10, - 12, + 13. - 14, 16, + 18, 20, 22, t del( l)(q32q42),2xde1(6) (q I ?5q2?3), t(4;?)(q35;?), t(7;?)(p22;?), t ( I2;?)(q24;?),+ t( I7;?)(pI3;?), 9mar[4]/46, XY1161 46,XX, +X, 5, - I I, - 14, - 14, - 15, 16, 17, 19, 2 I.de1(3)(q2 Iq27), + del(6) (qI?3q2?5),i(17q),+der(l)t(l;?I4)(p13;?qI I),+ins(l I;?)(q13;?),+t(15;?)(pI l;?),+t(l9;?) (q l3;?), mar[3y46,XX[77] 75,XX, - Y, - 3, - 6, - 8,- 10, I I,- 13, - 13, 15, - 15, - 18, + 19, - 22,2xde1(4)(q25q27). Zxi(9p). del( I2)(q I5q24),i( I7q). t(3;?)(q2?3;?), t(3;?)(pl I;?),+ t(6;?)(q25;?), +der(8)t(8;13)(q24;qlZ),+der( I5)t( 15;15)(pl l;qIS),+der( 18)t( 14;18)(ql I;pl I), der(22)t( I ;22)(q I I;p I I),+ 2xxder(22)t(2 I ;22)(q I I ;p I I), + der(?)t(?;7)(?;pI ?I), + 2mar[71/46,XX[99] 67,XXY.p l,-2,-2,-4,-4,-6,+9,10.- 1 1 , - 12,- 13,- 17,- 17,+ 19.+20,+20,-21, 22, - 22,del( l)(q32942),2xde1(3)(q? I3),de1(6)(q?2Iq?23). 2xt(2;?)(q37;?),+ t(4;?)(q2?7;?), t t(6;?)(q I ?5;?),t 2xder(22)t(?I7;22)(?q2I;q I I), + mar I, f 2mar2[2] 66,XY, - 1.-2, -2,-5,-6,+9, - I I,- 12.- 13,- 15, - 17,+ 19, t 20,-21,-22,-22,del(X) (q I3q26),del( l)(q32q42),2xdel(3)(q? I3).de1(6)(q?2Iq?23). 2xt(2;?)(q37;?).+ t(6;?)(q I ?5;?), + der(22)t(?I7;22)(?q2I;q I I), 3mar[31/46,XY [2 I] 76,XX,-X, I, - I,- 2, +3, -4, +5,+7,-8,-8,-9,lo.+ I I, t 12,- 14,- 15,- 15,- 15, 17, - 19, 2 I, 2 I, 22.inv( l)(q23q32),del( I)(pl3p22),de1(4)(q2 Ior23q27),2xde1(5) (43 Iq33),3xde1(7)(q3?lq3?4),de1(20)(q I I.2q 13. I),+ t( I;?)(p36;?), der( I) Ip I 3 + Iq32: : ?), t(4;?)(q35;?), der(7)t( I ;7)(q25;pl5), der(9)t(?;9;?) (?::9p2?4+9q32: :?),+der( 14)t(8;14)(ql I;pl l),+t(IS;?)(pl I;?),+der(l5)t(2;15)(pI l;q22). der( I9)t(9; I9)(q I3;p 13). t( I9?)(p I3;?), + 6mar[4]/46,XX[22]
+
+
+
+
+
+ +
-
-
+
+
+
29
IVB
-
-
+
+
+
+
-
+
-
-
+
+
+
Mixed Cellularity 29
29
IllA
RT
30
30
IVB
-
-
+
+
-
+
-
+ +
32
60
IVB
-
+
-
-
+
IllB
+
77,XXY, I, +2, 5, +6, 9, - 10, - 10, - 10, + I I, + 12, - 13, - 16, + 22,+22,2xde1(6) (q I ?3q2?5), dic( I; l)(p36;p I I), + 3xt( IO;?)(q24;?),+ t( I3;?)(pl I ;?),t 3mar[4]/46,XY[6] 87,XXY,-Y,- I,- l,-4,-4,-7,-7,+9,15,- 16,- 18,-22,?del(l1)(q14or2Iq23),de1(16) (q22), + t( 14q 14q),t( 14qISq), + t( I5q I Sq), t( I ;?)(p36;?),+ der( I)t( I;7)(p I I;p I I), t(4;?) (q35;?), der(7)t(7;? I5)(q32?qI5)[4] 86,XXY, -Y, I , I, -4, -4, -4, - 7, - 7, +9, - 10, - I I , - 15, 16, 18, - 22,2xde1(6) (q?2lq23),del( I6)(q22), + t( 14q 14q),t( 14q ISq), + t( I5q I5q). + t( I ;?)(p36;?),+ der( I)t( I;7) (p I I ;PII), t(4;?)(q35;?), der(4)t(4;? I2)(p I6;?q13). der(7)t(7;?I5)(q32;?qIS), mar[5]/46, XY[47] 52,X,-X,+2,-3,-4,-4,-7,-8,10.- 10,- 12,- 13.- 14,- 14, - 15,- 15,- 16,- 17, + 19,+20,- 21, -2l.del(6)(q?I5q?23),?de1(7)(q22q32),del(12)(pl Ip13),+der(3)t(3;14) (92 I;q I Io r 13). + t(4;?)(q?27;?), t(4;?)(q3 I ;?), + t(6;?)(q2?I;?),+ t(8;?)(pI I ;?), t( I I ;?)(pIS;?), t( l4;?)(pI I ;?), t ( I5;?)(pI I;?), t( I7;?)(p I3;?), 2xt(2 I ;?)(pI I ;?),t der(?)t(?;X)(?;q 13). der(?)t(?;S)(?;qI I), 2mar I, 6mar[21/46XX[23] 47,X,+X,-Y,-l,+2,+9,lO,-ll,+l4,-l5,16,t20,-2l.del(4)(q2?3q3l),+der(l) (?:lp13+1q41 :),+t(l l;?)(q14or2I;?),+der(2l)t(1;2l)(p22;q22)[6~46,XY[SS] -
3I
+
+
+
+
31
+
-
-
24
-
+
+
+
-
+
+ + +
+
+
+
aAge at diagnosis. bTreatment prior to time of cytogenetic analysis: RT = Radiotherapy; CT = Chemotherapy. ‘Numerical changes in relation to 2n (pt. nos. 18. 20. 3 I, and 32); t o 3n (pt. nos. 21. 22, 24, and 29); and t o 4n (pt. no. 30).
was as follows: lymphocyte predominance (LP) = 1, nodular sclerosis (NS) = 24, mixed cellularity (MC) = 7, and unclassified (Uncl) = 1. Cytogenetic Methods
A portion of the specimen that was used for histologic diagnosis was also processed for cytogenetic analysis. The tissue was finely minced with surgical blades. Cells were harvested from direct preparations (25/33); unstimulated 24 hr (32/33), 48 hr (2/33), and
72 hr (2/33) cultures; and from 24-hr methotrexatesynchronized (18/33) cultures using previously described methods (Rloomfield et al., 1983). Wright’s G-banding (Sanchez et al., 1973)was done in all cases. Karyotypes were designated according to the ISCN (1985). Chromosome abnormalities were defined as clonal if two or more metaphase cells had identical structural abnormalities or extra chromosomes, or if three or more metaphase cells had identical missing chromosomes.
394
D6IHNER ET AL.
RESULTS
Metaphase cells were obtained from 25 of the 33 specimens (76%). Eight cases (24%) had no analyzable mitotic cells (NS = 7, Uncl = 1). In 12 of the 25 evaluable cases (48%) only karyotypically normal or nonclonal abnormal metaphase cells were found (LP = 1,NS = 8, MC = 3); the number of metaphase cells analyzed per case in this group ranged from 7 to 130 (median 24). Thirteen of the evaluable cases (52%) had abnormal clones (NS = 9, MC = 4); the number of metaphase cells analyzed per case ranged from 6 to 106 (median 25). The karyotypes of the abnormal clones could be defined in nine of these 13 cases. In four patients abnormal metaphase cells were technically inadequate for complete evaluation; the abnormal cells were near triploid in three, and near tetraploid in one of these cases. Thus cytogenetic analysis was possible in 17 of 24 patients (71%) with NS, all seven patients with MC, and the one patient with LP HD. Nine of the 17 cases (53%) with the NS subtype, and four of the seven cases (57%) with the MC subtype that were evaluable had abnormal clones. In nine of the 13 cases, the abnormal clones had polyploid modal chromosome numbers; in seven cases the clones were near triploid, and in two the clones were near tetraploid. One case had a pseudodiploid abnormal clone, and three had hyperdiploid clones. Seven of the nine analyzable cases had one abnormal clone, and two cases had two related abnormal clones. Loss of chromosomes 10, 13, 15, 16, 21, and Y, and gain of chromosomes 2, 9, 11, 19, and 20 were each found in three or more cases. All nine analyzable cases exhibited complex karyotypic abnormalities. These are enumerated in Table 1. Structural aberrations were nonrandom. Chromosomes most commonly involved, in order of decreasing frequency, were numbers 1, 6, 4, 7, 15, and 14. Specific chromosomal regions were preferentially rearranged by breaks generating either translocations or deletions (Fig. 1).Clusters of three or more breaks resulting in translocations were found in bands l p l l lp13,lp36,4q35,14qll, and 15~11. As a consequence of unbalanced rearrangements of chromosome 1,there was an extra copy of part or all of l q in four cases (nos. 20, 21, 24, and 29). In five patients (nos. 20, 21, 24, 30, and 31) breaks occurred in bands to which T-cell receptor genes have been localized; i.e., 7p15, 7q35, and 14ql1. No specific, recurring translocation was identified. Breaks giving rise to loss of chromosomal material also clustered in specific chromosomal regions including lq, 4q, 6q, and 17p. Three patients (nos. 21, 24, and 32) had interstitial deletions of 4q (Figs. 2, 3A). These deletions overlapped, the region
common to all being 4q25-4q27. Three other patients also had loss of chromosomal material from this region. Patient 22 had an unbalanced translocation involving 4q2?7 (resulting in loss of 4q2?7-4qter) and also loss of one chromosome 4. Patient 31 had an unbalanced translocation involving 4q?27, with loss of 4q?27-4qter,and patient 30 had loss of one chromosome 4. Six patients had deletions of 6q (Fig. 3B). Although breakpoints were more difficult to ascertain than on 4q, there also appeared to be a commonly deleted segment 6q21-6q23. In patient 30 the deletion of 6q represented clonal evolution. There was loss of chromosomal material from 17p in five cases. In two of them (patients 20 and 21) this loss resulted from formation of an isochromosome 17q (Fig. 2), whereas unbalanced translocations led to loss of 17q21-17pter in one (no. 22) and of 17~13-17pterin two other cases (nos. 18 and 31). Three patients (nos. 18, 22, and 32) had terminal or interstitial deletions of the distal long arm of chromosome 1. Finally, three to nine unidentifiable marker chromosomes were found in five of the nine cases. DISCUSSION
Our cytogenetic analyses of lymph nodes or other tumor masses from patients diagnosed with HD revealed a distinct pattern of chromosome abnormalities including a predominance of polyploidy and highly complex structural rearrangements. Nine of 13 kary otypically abnormal cases had modal chromosome numbers in the triploid or tetraploid range. This finding is in accord with previous cytogenetic studies performed on fresh tumor specimens in HD (Reeves, 1973;Kristoffersson et al., 1987;Cabanillas et al., 1988; Tilly et al., 1991). Among the nonrandom numerical chromosome changes observed in our study, loss of chromosomes 10, 13, 21, and Y, and gain of chromosomes 2, 9, and 11 are findings that are consistent with data compiled from the literature (Thangavelu and LeBeau, 1989; Tilly et al., 1991). The most frequent previously reported aneuploidies, i.e., gain of chromosome 5 and loss of chromosome 22, were not among the most common numerical changes in our series. All of our abnormal cases exhibited complex structural chromosome rearrangements. Chromosomes most frequently involved in structural rearrangements were 1, 4, 6, 7, 14, and 15. Breaks involved in translocations clustered in bands lpll-1p13, lp36, 4q35, 14ql1, and 15pll; however, no specific, recurring translocation was identified. In contrast, there was recurring loss of chromosomal material resulting from simple deletions or other unbalanced rearrangements that was notably confined to specific chrorno-
1
2
6
7
13
14
9
i
4
5
10
11
12
16
17
18
22
Y
l
n
19
20
X
b 0
21
Figure I. Schematic illustration of clonal structural chromosome abnormalities in nine analyzable patients with Hodgkin’s disease: Dots involved in translocations. plain lines = deletions, asterisks = inversion breakpoints, arrows = isochromosomes.
2
breaks
396
DdHNfR ET AL.
Figure 2. Representative G-banded karyotype from patient 2 I. Note the recurring chromosome abnormalities: small interstitial deletions of two chromosomes 4, unbalanced translocation involving one chromosome I 8 and one chromosome I 4 with a break in band 14q I I, isochromosome I7q, and unbalanced translocation involving one chromosome 22 and an extra copy of the long arm of chromosome I resulting in tetrasomy of Iq. All chromosome abnormalities are designated by arrowheads (for complete karyotype see Table I).
soma1 regions. Five patients had interstitial deletions of 4q or loss of chromosome 4, and six patients had deletions of 6q. Five patients had loss of chromosomal material from 17p, and three patients had deletions of lq. Frequent rearrangements of chromosome 1 and deletions of 6q and 17p have been reported in previous studies of HD (Schouten et al., 1989; Thangavelu and LeBeau, 1989; Tilly et al., 1991). Recurring involvement of 4q has been reported in two studies (Schouten et al., 1989;Ladanyi et al., 1991);however, the types of rearrangement and assignment of breakpoints do not coincide with our findings. We did not observe the frequent involvement of regions 2q, l l p , l l q , 12p, 13p, or Xq previously reported (Thangavelu and LeBeau, 1989; Tilly et al., 1991).In accord with the study by Tilly et al. (1991),3q was rearranged in more than three cases. The lack of specific, recurring translocations and the frequent loss of genetic material in our series raise intriguing questions as regards the pathogenesis of HD. In the past, molecular research in hematologic malignancies has focused on the analysis of specific translocations that result in aberrant juxtaposition of genes and in activation of cellular protooncogenes by various mechanisms (Showe and Croce, 1987).Loss of genetic material, resulting in the loss of function of putative tumor suppressor genes, has been proposed as an alternative model of tumorigenesis (Marshall,
1991; Weinberg, 1991). The existence of such tumor suppressor genes has been suggested by the frequent microscopic detection of chromosomal deletions and by the molecular demonstration of allelic loss in a variety of human malignancies. With regard to tumor specificity, deletions of 4q are of particular interest in our study. To date, deletions of this chromosomal region have not been reported to recur in any other malignancy (Mitelman et al., 1990). High-resolution metaphases revealed the commonly deleted segment to be 4q25-4q27. It is unlikely that genes mapped to this region, such as the genes encoding the epidernial growth factor, the fibroblast growth factor, and interleukin-2 (Cox et a]., 1989),play a role in the pathogenesis of these cases. In contrast, there is evidence from somatic cell hybridization studies that human chromosome 4 might harbor a tumor suppressor gene (Renedict et al., 1984). The other recurring deletions found in our series, including lq, 6q, and 17p, are findings common to many hematologic and nonhematologic malignancies (Mitelman et al., 1990). The TP53 gene, a novel candidate tumor suppressor gene localized to 17p, has been shown to be structurally altered in a variety of malignancies, all of which are associated with cytogenetic abnormalities and/or allelic loss of 17p (Ahuja et al., 1989; Nigro et al., 1989). These molecular studies suggest that tumors of various histolo-
CHROMOSOME ABNOfiMALlTlES IN HODGUN’S DfSEASE
397
in up to two-thirds of cases (Agnarsson and Kadin, 1989; Casey et al., 1989). Our data suggest that, analogous to other hematologic malignancies, HD is characterized by recurring chromosome abnormalities. Correlation of karyotypic and molecular genetic findings with clinical characteristics will not be possible until a larger number of cases have been successfully studied. ACKNOWLEDGMENTS
The authors thank Molly Carey and Grace Peng for their help in data collection. This work was supported in part by the Coleman Leukemia Research Fund and the University of Minnesota Children’s Cancer Research Fund. H.D. was the recipient of a postdoctoral fellowship of the Mildred Scheel Stiftung der Deutschen Krebshilfe. REFERENCES
Figure 3. Partial G-banded karyotypes showing A. de1(4)(q2?3q3I) from patient 32 (left) and de1(4)(q21orq23q27) from patient 24 (right). B. del(b)(q?2Iq23) from patient 30 (left) and del(b)(q1?3q2?5) from patient 24 (right). C. Unbalanced translocation involving one chromosome 7 and one chromosome I with a break in band 7p15 and three de1(7)(q3?I q3?4) from patient 24 (left) and unbalanced translocation involving one chromosome I and one chromosome 14 with a break in 14ql I from patient 20 (right). The abnormal chromosomes are designated by arrowheads.
gies may gain a growth advantage by common genetic pathways. Our results raise an interesting possibility with regard to the histogenesis of the Reed-Stemberg cell. Based on cytogenetic data, the lymphoid origin of the Reed-Stemberg cell has been suggested by the frequent involvement of band 14q32 (Cabanillas et al., 1988) that is commonly rearranged in B lymphoid malignancies. No clonal rearrangement of band 14q32 was found in our series. However, in five of our patients chromosomal breaks involved bands containing the T-cell receptor genes that are frequently rearranged in leukemias and lymphomas of T-cell origin. These results suggest that the Reed-Sternberg cell may be of T-cell origin in at least some cases of HD. These cytogenetic findings are also in accord with recent immunophenotypic studies of HD that show expression of various T-cell antigens on Hodgkin and Reed-Stemberg cells
Agnarsson BA, Kadin ME (1989) The immunophenotype of Reed stern^ berg cells. Cancer 63:2083 2087. Ahuja H, Bar-Eli M, Advani SH, Henchimol S, Clinc MJ (1989) A l t a a tions in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia. Proc Natl Acad Sci USA 8667856787. Ranks RE, Cledhill S,Ross FM, Kralewski A, Dewar AE, Weir-Thompson EM (1991) Karyotypic abnormalities and immunoglobulin gene rearrangements in Hodgkin’s disease. Cancer (bet Cytngenet 51: 10>111. Fknedict WF, Weissman RE, Mark C, Stanbridge EJ (1984) Tumorigenicity of human HT 1080 fibrosarcoma x normal fibroblast hybrids: Chromosome dosage dependency. Cancer Res 44: 3471 3479. Rlmmfield CD, Arthur DC,Frizzera G, Levine EG, Peterson BA, Gajl. Peczalska KJ (1983)Non-random chromosome abnormalities in lymphoma. Cancer Res 43:29752984. Cabanillas F, Pathak S,Trujillo J, Grant G. Cork A, Hagenieister FB, Velasquez WS, M d a g h l i n P, Redman J, Katz R, Butler JJ, Frcireich EJ (1988)Cytogenetic features of Hodgkin’s disease suggest possible origin from a lymphccytc. Hlood 71:361F1617. Casey TT, Olson SJ, CousarJB, Collins RD (1989)Immunophenotypes of Reed-Sternberg cells: A study of 19 cases of Hdgkin’s disease in plastic-embedded sections. Blood 74:2624,2628, 1989. Cox DR, Murray JC, Buetow KH (1989) Report of the committee on the genetic constitution of chromosome 4. Human Gene Mapping 10 (1989): Tenth International Workshop on Human Gene Mapping. Cytogenet Cell Genet 51:121--136. Fonatsch C, Diehl V, Schaadt M, Burrichter H, Kirchner HH (1986) Cytogenetic investigations in Hcdgkin’s disease: I. Involvement of specific chromosomes in marker formation. Cancer Genet Cytogenet 203S52. Hossfeld DK, Schmidt CG (1978)Chromosome findings in effusions from patients with Hodgkin’s discasc. Int J Cancer 21:147 156. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harnden 1)G and Klingcr HP (cds), published in collaburation with Cytogcnct Cell Gcnct (Karger. Basel 1985); also in Birth Defects: Original Article Series, Vol 21, No 1 (March of Dimes Birth Defects Foundation, New York 1985). Kristoffersson U, Heim S, Mandahl N, Olsson H, Akerman M. Mitelman F (1987) Cytogenetic studies in Hodgkin’s disease. Acta Path Microbiol Immunol Scand A 95:289 295. Ladanyi M, Parsa NZ, Offit K, Wachtel MS, Filippa DA, Jhanwar SC (1991)Clonal cytogenetic abnormalities in Hodgkin’sdisease. Genes Chrom Cancer 3:294-299. Lukes RJ, Butler JJ (1966)The pathology and nomenclature of Hodgkin’s disease. Cancer Res 261063-1081. Marshall CJ (1991) Tumor suppressor genes. Cell 64313-326. Mitelman F, Kaneko Y, Trent JM (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 551358-386.
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Nigro JM, Baker SJ,Preisinger AC, Milhurn Jcssup J, Hostettcr R, Cleary K, Bigncr SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B (1989)Mutations in the p53 gene occur in diverse human tumour types. Nature 342705708. Reeves BR (1973)Cytogenetics of malignant lymphomas. Hurnangenetik 20:231-250.
Reeves BR and Pickup VL (1980) The chromosome changes in nonBurkitt lymphomas. Hum Genet 53349 355. Sanchez 0, Fscohar JJ, Yunis JJ (1973) A simple G-banding technique [letter]. Iancet 2269. Schouten HC, Sanger WG, Duggan M, Weisenburger DD, MacLennan
KA, Armitage JO (1989) Chromosomal abnormalities in Hodgkin's disease. Blood 73:214%2154. Showe LC and Croce CM (1987)The role of chromosomal translocations in R- and T-cell neoplasia. Ann Rev lrnrnunol 525S277. Thangavelu M and LeBeau MM (1989) Chromosomal abnormalities in Hodgkin's disease. Hematology/Oncology Clinics of North America 3221-236. Tilly H, Bastard C, Delastre T, Duval C. Bizet M, Lenormand B, D a u d JP,Monconduit M, Piguet H (1931) Cytogenetic studies in untreated Hodgkin's disease. Blmd 77:1298-1304. Weinberg RA (1991) Tumor suppressor genes. Science 254:113b 1146.
Recurring Chromosome Abnormalities in Hodgkin’s Disease Hartmut Dohner, Clara D. Bloomfield, Glauco Frizzera, Joy Frestedt, and Diane C. Arthur Departments of Laboratory Medicine/Pathology (H.D., D.C.A.). Pediatrics (D.C.A.), and Medicine (H.D., J.F.). University of Minnesota. Minneapolis, Minnesota, Department of Medicine, Roswell Park Cancer Institute, Buffalo, N e w York (C.D.B.), and Department of Hematopathology, Armed Forces Institute of Pathology, Washington, D C (G.F.)
Cytogenetic analysis was performed on lymph nodes or other tumor masses from 33 patients with Hodgkin’s disease. Metaphase cells were obtained in 25 of the 33 cases. Analyzable abnormal clones were found in nine cases. Characteristic abnormalities included polyploidy and complex structural rearrangements nonrandomly involving certain chromosomal regions. Chromosomes most commonly gained were 2,9, I I, 19, and 20, and those most often lost were 10, 13. I S , I6,2 I, and Y. Translocation breakpoints clustered in bands I p I I- I p 13, Ip36, 4q35, 14q I I, and I5p I I. In five patients, breakpoints were in bands t o which T-cell receptor genes have been mapped. No specific, recurring translocation was identified. There was. however, recurring loss of chromosomal material from I q. 4q, 6q, and I7p. Loss o r deletions of chromosomes 4 and 6 were found in five and six patients, respectively. Deletions overlapped; the smallest overlapping segments included bands 4q25-4q27 and 6q2 I-6q23. The data suggest that loss of specific chromosomal regions may be important in the pathogenesis of Hodgkin’s disease. With respect t o tumor specificity, deletions of 4q are of particular interest because these have not been previously reported t o occur nonrandomly in other human malignancies. Genes Chrom Cancer 9392-398 ( I 992). 0 1992 Wiley-Liss. Inc.
INTRODUCTION
Data on chromosome abnormalities in hematologic malignancies have been accumulating rapidly in recent years, and in a majority of these malignancies, recurring chromosome aberrations have been found. A number of specific abnormalities have been identified that are associated with distinct morphologic and immunologic subtypes of leukemia and lymphoma (Mitelman et al., 1990).The cloning of genes located at some of these chromosomal breakpoints has provided insight into the molecular mechanisms involved in cellular malignant transformation (Showe and Croce, 1987). In contrast to other hematologic malignancies, only scant cytogenetic data are currently available in Hodgkin’s disease (HI)) (Reeves, 1973; Hossfeld and Schmidt, 1978; Reeves and Pickup, 1980 Fonatsch et al., 1986; Kristoffersson et a]., 1987; Cabanillas et al., 1988;Schouten et al., 1989;Banks et al., 1991;Ladanyi et al., 1991; Tilly et al., 1991). A review of 40 cases reported in the literature shows that there are nonrandom structural rearrangements of certain chromosome regions (Thangavelu and LeBeau, 1989). Rearrangements most frequently involve lp, lq, 2q, 6q, l l p , l l q , 14q, and Xq; however, no specific, recurring chromosomal abnormality has yet been identified. The paucity of available information on genetic alterations in HD underlines the importance of providing accurate cytogenetic data that are based on completely defined karyotypes. By analogy with the cytogenetic findings in most other hematologic malignan0 t992 WILEY-LISS, INC.
cies, it is expected that HD will also be characterized by specific chromosomal abnormalities once a sufficient number of cases has been studied. We report the results of cytogenetic analyses of lymph nodes or other tumor masses from 33 patients with HD. Abnormal clones were detected in 13 cases; the clones could be defined in nine. High quality metaphase spreads revealed recurring chromosome abnormalities that have not previously been reported in HD. MATERIALS A N D METHODS Patients and Tumor Specimens
Cytogenetic analysis was performed on involved lymph nodes or other tumor masses from 33 consecutive patients with HD biopsied at the University of Minnesota Hospital between January 1, 1984, and December 31, 1988.The 18 male patients and 15 female patients ranged in age from 5 to 62 years (median 28 years). Involved tissues included lymph nodes in 31, a pleural mass in one, and a soft tissue flank mass in one patient. Twenty-one patients were studied at diagnosis, and 12 were evaluated at relapse. Histologic classification was done according to the criteria established by Lukes and Butler (1966). The distribution of cases among the different subgroups Reccivcd February 12, 1992; accepted May 14, 1992. Address reprint requests to I k IIartmut Diihner. who is now a t Medizinischc Klinik and l’oliklinik V, University of Ileidelherg, Ilospitalstr. 3 , 6900 Ilcidelberg, Germany. The opinions cxprcssed in this article arc the personal views of the authors and are not to be construed as representing the views of the Department of the Army or the Department of Defense.
393
CHROMOSOME ABNORMALITIES IN HODGKINS DISEASE
TABLE I. Clonal Chromosome Abnormalities in Nine Patients with Hodgkin’s Disease Pt. No.
Agea (Yr)
Stage
Priorb Therapy
Karyotype‘ ~
~~
Nodular Sclerosis 18 22 IIA
CT/RT
20
21
IIA
-
21
I2
IllA
-
22
28
IllB
-
+
+
62.XY. - 4, t 5, + 6, - 7, + 10, - 12, + 13. - 14, 16, + 18, 20, 22, t del( l)(q32q42),2xde1(6) (q I ?5q2?3), t(4;?)(q35;?), t(7;?)(p22;?), t ( I2;?)(q24;?),+ t( I7;?)(pI3;?), 9mar[4]/46, XY1161 46,XX, +X, 5, - I I, - 14, - 14, - 15, 16, 17, 19, 2 I.de1(3)(q2 Iq27), + del(6) (qI?3q2?5),i(17q),+der(l)t(l;?I4)(p13;?qI I),+ins(l I;?)(q13;?),+t(15;?)(pI l;?),+t(l9;?) (q l3;?), mar[3y46,XX[77] 75,XX, - Y, - 3, - 6, - 8,- 10, I I,- 13, - 13, 15, - 15, - 18, + 19, - 22,2xde1(4)(q25q27). Zxi(9p). del( I2)(q I5q24),i( I7q). t(3;?)(q2?3;?), t(3;?)(pl I;?),+ t(6;?)(q25;?), +der(8)t(8;13)(q24;qlZ),+der( I5)t( 15;15)(pl l;qIS),+der( 18)t( 14;18)(ql I;pl I), der(22)t( I ;22)(q I I;p I I),+ 2xxder(22)t(2 I ;22)(q I I ;p I I), + der(?)t(?;7)(?;pI ?I), + 2mar[71/46,XX[99] 67,XXY.p l,-2,-2,-4,-4,-6,+9,10.- 1 1 , - 12,- 13,- 17,- 17,+ 19.+20,+20,-21, 22, - 22,del( l)(q32942),2xde1(3)(q? I3),de1(6)(q?2Iq?23). 2xt(2;?)(q37;?),+ t(4;?)(q2?7;?), t t(6;?)(q I ?5;?),t 2xder(22)t(?I7;22)(?q2I;q I I), + mar I, f 2mar2[2] 66,XY, - 1.-2, -2,-5,-6,+9, - I I,- 12.- 13,- 15, - 17,+ 19, t 20,-21,-22,-22,del(X) (q I3q26),del( l)(q32q42),2xdel(3)(q? I3).de1(6)(q?2Iq?23). 2xt(2;?)(q37;?).+ t(6;?)(q I ?5;?), + der(22)t(?I7;22)(?q2I;q I I), 3mar[31/46,XY [2 I] 76,XX,-X, I, - I,- 2, +3, -4, +5,+7,-8,-8,-9,lo.+ I I, t 12,- 14,- 15,- 15,- 15, 17, - 19, 2 I, 2 I, 22.inv( l)(q23q32),del( I)(pl3p22),de1(4)(q2 Ior23q27),2xde1(5) (43 Iq33),3xde1(7)(q3?lq3?4),de1(20)(q I I.2q 13. I),+ t( I;?)(p36;?), der( I) Ip I 3 + Iq32: : ?), t(4;?)(q35;?), der(7)t( I ;7)(q25;pl5), der(9)t(?;9;?) (?::9p2?4+9q32: :?),+der( 14)t(8;14)(ql I;pl l),+t(IS;?)(pl I;?),+der(l5)t(2;15)(pI l;q22). der( I9)t(9; I9)(q I3;p 13). t( I9?)(p I3;?), + 6mar[4]/46,XX[22]
+
+
+
+
+
+ +
-
-
+
+
+
29
IVB
-
-
+
+
+
+
-
+
-
-
+
+
+
Mixed Cellularity 29
29
IllA
RT
30
30
IVB
-
-
+
+
-
+
-
+ +
32
60
IVB
-
+
-
-
+
IllB
+
77,XXY, I, +2, 5, +6, 9, - 10, - 10, - 10, + I I, + 12, - 13, - 16, + 22,+22,2xde1(6) (q I ?3q2?5), dic( I; l)(p36;p I I), + 3xt( IO;?)(q24;?),+ t( I3;?)(pl I ;?),t 3mar[4]/46,XY[6] 87,XXY,-Y,- I,- l,-4,-4,-7,-7,+9,15,- 16,- 18,-22,?del(l1)(q14or2Iq23),de1(16) (q22), + t( 14q 14q),t( 14qISq), + t( I5q I Sq), t( I ;?)(p36;?),+ der( I)t( I;7)(p I I;p I I), t(4;?) (q35;?), der(7)t(7;? I5)(q32?qI5)[4] 86,XXY, -Y, I , I, -4, -4, -4, - 7, - 7, +9, - 10, - I I , - 15, 16, 18, - 22,2xde1(6) (q?2lq23),del( I6)(q22), + t( 14q 14q),t( 14q ISq), + t( I5q I5q). + t( I ;?)(p36;?),+ der( I)t( I;7) (p I I ;PII), t(4;?)(q35;?), der(4)t(4;? I2)(p I6;?q13). der(7)t(7;?I5)(q32;?qIS), mar[5]/46, XY[47] 52,X,-X,+2,-3,-4,-4,-7,-8,10.- 10,- 12,- 13.- 14,- 14, - 15,- 15,- 16,- 17, + 19,+20,- 21, -2l.del(6)(q?I5q?23),?de1(7)(q22q32),del(12)(pl Ip13),+der(3)t(3;14) (92 I;q I Io r 13). + t(4;?)(q?27;?), t(4;?)(q3 I ;?), + t(6;?)(q2?I;?),+ t(8;?)(pI I ;?), t( I I ;?)(pIS;?), t( l4;?)(pI I ;?), t ( I5;?)(pI I;?), t( I7;?)(p I3;?), 2xt(2 I ;?)(pI I ;?),t der(?)t(?;X)(?;q 13). der(?)t(?;S)(?;qI I), 2mar I, 6mar[21/46XX[23] 47,X,+X,-Y,-l,+2,+9,lO,-ll,+l4,-l5,16,t20,-2l.del(4)(q2?3q3l),+der(l) (?:lp13+1q41 :),+t(l l;?)(q14or2I;?),+der(2l)t(1;2l)(p22;q22)[6~46,XY[SS] -
3I
+
+
+
+
31
+
-
-
24
-
+
+
+
-
+
+ + +
+
+
+
aAge at diagnosis. bTreatment prior to time of cytogenetic analysis: RT = Radiotherapy; CT = Chemotherapy. ‘Numerical changes in relation to 2n (pt. nos. 18. 20. 3 I, and 32); t o 3n (pt. nos. 21. 22, 24, and 29); and t o 4n (pt. no. 30).
was as follows: lymphocyte predominance (LP) = 1, nodular sclerosis (NS) = 24, mixed cellularity (MC) = 7, and unclassified (Uncl) = 1. Cytogenetic Methods
A portion of the specimen that was used for histologic diagnosis was also processed for cytogenetic analysis. The tissue was finely minced with surgical blades. Cells were harvested from direct preparations (25/33); unstimulated 24 hr (32/33), 48 hr (2/33), and
72 hr (2/33) cultures; and from 24-hr methotrexatesynchronized (18/33) cultures using previously described methods (Rloomfield et al., 1983). Wright’s G-banding (Sanchez et al., 1973)was done in all cases. Karyotypes were designated according to the ISCN (1985). Chromosome abnormalities were defined as clonal if two or more metaphase cells had identical structural abnormalities or extra chromosomes, or if three or more metaphase cells had identical missing chromosomes.
394
D6IHNER ET AL.
RESULTS
Metaphase cells were obtained from 25 of the 33 specimens (76%). Eight cases (24%) had no analyzable mitotic cells (NS = 7, Uncl = 1). In 12 of the 25 evaluable cases (48%) only karyotypically normal or nonclonal abnormal metaphase cells were found (LP = 1,NS = 8, MC = 3); the number of metaphase cells analyzed per case in this group ranged from 7 to 130 (median 24). Thirteen of the evaluable cases (52%) had abnormal clones (NS = 9, MC = 4); the number of metaphase cells analyzed per case ranged from 6 to 106 (median 25). The karyotypes of the abnormal clones could be defined in nine of these 13 cases. In four patients abnormal metaphase cells were technically inadequate for complete evaluation; the abnormal cells were near triploid in three, and near tetraploid in one of these cases. Thus cytogenetic analysis was possible in 17 of 24 patients (71%) with NS, all seven patients with MC, and the one patient with LP HD. Nine of the 17 cases (53%) with the NS subtype, and four of the seven cases (57%) with the MC subtype that were evaluable had abnormal clones. In nine of the 13 cases, the abnormal clones had polyploid modal chromosome numbers; in seven cases the clones were near triploid, and in two the clones were near tetraploid. One case had a pseudodiploid abnormal clone, and three had hyperdiploid clones. Seven of the nine analyzable cases had one abnormal clone, and two cases had two related abnormal clones. Loss of chromosomes 10, 13, 15, 16, 21, and Y, and gain of chromosomes 2, 9, 11, 19, and 20 were each found in three or more cases. All nine analyzable cases exhibited complex karyotypic abnormalities. These are enumerated in Table 1. Structural aberrations were nonrandom. Chromosomes most commonly involved, in order of decreasing frequency, were numbers 1, 6, 4, 7, 15, and 14. Specific chromosomal regions were preferentially rearranged by breaks generating either translocations or deletions (Fig. 1).Clusters of three or more breaks resulting in translocations were found in bands l p l l lp13,lp36,4q35,14qll, and 15~11. As a consequence of unbalanced rearrangements of chromosome 1,there was an extra copy of part or all of l q in four cases (nos. 20, 21, 24, and 29). In five patients (nos. 20, 21, 24, 30, and 31) breaks occurred in bands to which T-cell receptor genes have been localized; i.e., 7p15, 7q35, and 14ql1. No specific, recurring translocation was identified. Breaks giving rise to loss of chromosomal material also clustered in specific chromosomal regions including lq, 4q, 6q, and 17p. Three patients (nos. 21, 24, and 32) had interstitial deletions of 4q (Figs. 2, 3A). These deletions overlapped, the region
common to all being 4q25-4q27. Three other patients also had loss of chromosomal material from this region. Patient 22 had an unbalanced translocation involving 4q2?7 (resulting in loss of 4q2?7-4qter) and also loss of one chromosome 4. Patient 31 had an unbalanced translocation involving 4q?27, with loss of 4q?27-4qter,and patient 30 had loss of one chromosome 4. Six patients had deletions of 6q (Fig. 3B). Although breakpoints were more difficult to ascertain than on 4q, there also appeared to be a commonly deleted segment 6q21-6q23. In patient 30 the deletion of 6q represented clonal evolution. There was loss of chromosomal material from 17p in five cases. In two of them (patients 20 and 21) this loss resulted from formation of an isochromosome 17q (Fig. 2), whereas unbalanced translocations led to loss of 17q21-17pter in one (no. 22) and of 17~13-17pterin two other cases (nos. 18 and 31). Three patients (nos. 18, 22, and 32) had terminal or interstitial deletions of the distal long arm of chromosome 1. Finally, three to nine unidentifiable marker chromosomes were found in five of the nine cases. DISCUSSION
Our cytogenetic analyses of lymph nodes or other tumor masses from patients diagnosed with HD revealed a distinct pattern of chromosome abnormalities including a predominance of polyploidy and highly complex structural rearrangements. Nine of 13 kary otypically abnormal cases had modal chromosome numbers in the triploid or tetraploid range. This finding is in accord with previous cytogenetic studies performed on fresh tumor specimens in HD (Reeves, 1973;Kristoffersson et al., 1987;Cabanillas et al., 1988; Tilly et al., 1991). Among the nonrandom numerical chromosome changes observed in our study, loss of chromosomes 10, 13, 21, and Y, and gain of chromosomes 2, 9, and 11 are findings that are consistent with data compiled from the literature (Thangavelu and LeBeau, 1989; Tilly et al., 1991). The most frequent previously reported aneuploidies, i.e., gain of chromosome 5 and loss of chromosome 22, were not among the most common numerical changes in our series. All of our abnormal cases exhibited complex structural chromosome rearrangements. Chromosomes most frequently involved in structural rearrangements were 1, 4, 6, 7, 14, and 15. Breaks involved in translocations clustered in bands lpll-1p13, lp36, 4q35, 14ql1, and 15pll; however, no specific, recurring translocation was identified. In contrast, there was recurring loss of chromosomal material resulting from simple deletions or other unbalanced rearrangements that was notably confined to specific chrorno-
1
2
6
7
13
14
9
i
4
5
10
11
12
16
17
18
22
Y
l
n
19
20
X
b 0
21
Figure I. Schematic illustration of clonal structural chromosome abnormalities in nine analyzable patients with Hodgkin’s disease: Dots involved in translocations. plain lines = deletions, asterisks = inversion breakpoints, arrows = isochromosomes.
2
breaks
396
DdHNfR ET AL.
Figure 2. Representative G-banded karyotype from patient 2 I. Note the recurring chromosome abnormalities: small interstitial deletions of two chromosomes 4, unbalanced translocation involving one chromosome I 8 and one chromosome I 4 with a break in band 14q I I, isochromosome I7q, and unbalanced translocation involving one chromosome 22 and an extra copy of the long arm of chromosome I resulting in tetrasomy of Iq. All chromosome abnormalities are designated by arrowheads (for complete karyotype see Table I).
soma1 regions. Five patients had interstitial deletions of 4q or loss of chromosome 4, and six patients had deletions of 6q. Five patients had loss of chromosomal material from 17p, and three patients had deletions of lq. Frequent rearrangements of chromosome 1 and deletions of 6q and 17p have been reported in previous studies of HD (Schouten et al., 1989; Thangavelu and LeBeau, 1989; Tilly et al., 1991). Recurring involvement of 4q has been reported in two studies (Schouten et al., 1989;Ladanyi et al., 1991);however, the types of rearrangement and assignment of breakpoints do not coincide with our findings. We did not observe the frequent involvement of regions 2q, l l p , l l q , 12p, 13p, or Xq previously reported (Thangavelu and LeBeau, 1989; Tilly et al., 1991).In accord with the study by Tilly et al. (1991),3q was rearranged in more than three cases. The lack of specific, recurring translocations and the frequent loss of genetic material in our series raise intriguing questions as regards the pathogenesis of HD. In the past, molecular research in hematologic malignancies has focused on the analysis of specific translocations that result in aberrant juxtaposition of genes and in activation of cellular protooncogenes by various mechanisms (Showe and Croce, 1987).Loss of genetic material, resulting in the loss of function of putative tumor suppressor genes, has been proposed as an alternative model of tumorigenesis (Marshall,
1991; Weinberg, 1991). The existence of such tumor suppressor genes has been suggested by the frequent microscopic detection of chromosomal deletions and by the molecular demonstration of allelic loss in a variety of human malignancies. With regard to tumor specificity, deletions of 4q are of particular interest in our study. To date, deletions of this chromosomal region have not been reported to recur in any other malignancy (Mitelman et al., 1990). High-resolution metaphases revealed the commonly deleted segment to be 4q25-4q27. It is unlikely that genes mapped to this region, such as the genes encoding the epidernial growth factor, the fibroblast growth factor, and interleukin-2 (Cox et a]., 1989),play a role in the pathogenesis of these cases. In contrast, there is evidence from somatic cell hybridization studies that human chromosome 4 might harbor a tumor suppressor gene (Renedict et al., 1984). The other recurring deletions found in our series, including lq, 6q, and 17p, are findings common to many hematologic and nonhematologic malignancies (Mitelman et al., 1990). The TP53 gene, a novel candidate tumor suppressor gene localized to 17p, has been shown to be structurally altered in a variety of malignancies, all of which are associated with cytogenetic abnormalities and/or allelic loss of 17p (Ahuja et al., 1989; Nigro et al., 1989). These molecular studies suggest that tumors of various histolo-
CHROMOSOME ABNOfiMALlTlES IN HODGUN’S DfSEASE
397
in up to two-thirds of cases (Agnarsson and Kadin, 1989; Casey et al., 1989). Our data suggest that, analogous to other hematologic malignancies, HD is characterized by recurring chromosome abnormalities. Correlation of karyotypic and molecular genetic findings with clinical characteristics will not be possible until a larger number of cases have been successfully studied. ACKNOWLEDGMENTS
The authors thank Molly Carey and Grace Peng for their help in data collection. This work was supported in part by the Coleman Leukemia Research Fund and the University of Minnesota Children’s Cancer Research Fund. H.D. was the recipient of a postdoctoral fellowship of the Mildred Scheel Stiftung der Deutschen Krebshilfe. REFERENCES
Figure 3. Partial G-banded karyotypes showing A. de1(4)(q2?3q3I) from patient 32 (left) and de1(4)(q21orq23q27) from patient 24 (right). B. del(b)(q?2Iq23) from patient 30 (left) and del(b)(q1?3q2?5) from patient 24 (right). C. Unbalanced translocation involving one chromosome 7 and one chromosome I with a break in band 7p15 and three de1(7)(q3?I q3?4) from patient 24 (left) and unbalanced translocation involving one chromosome I and one chromosome 14 with a break in 14ql I from patient 20 (right). The abnormal chromosomes are designated by arrowheads.
gies may gain a growth advantage by common genetic pathways. Our results raise an interesting possibility with regard to the histogenesis of the Reed-Stemberg cell. Based on cytogenetic data, the lymphoid origin of the Reed-Stemberg cell has been suggested by the frequent involvement of band 14q32 (Cabanillas et al., 1988) that is commonly rearranged in B lymphoid malignancies. No clonal rearrangement of band 14q32 was found in our series. However, in five of our patients chromosomal breaks involved bands containing the T-cell receptor genes that are frequently rearranged in leukemias and lymphomas of T-cell origin. These results suggest that the Reed-Sternberg cell may be of T-cell origin in at least some cases of HD. These cytogenetic findings are also in accord with recent immunophenotypic studies of HD that show expression of various T-cell antigens on Hodgkin and Reed-Stemberg cells
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KA, Armitage JO (1989) Chromosomal abnormalities in Hodgkin's disease. Blood 73:214%2154. Showe LC and Croce CM (1987)The role of chromosomal translocations in R- and T-cell neoplasia. Ann Rev lrnrnunol 525S277. Thangavelu M and LeBeau MM (1989) Chromosomal abnormalities in Hodgkin's disease. Hematology/Oncology Clinics of North America 3221-236. Tilly H, Bastard C, Delastre T, Duval C. Bizet M, Lenormand B, D a u d JP,Monconduit M, Piguet H (1931) Cytogenetic studies in untreated Hodgkin's disease. Blmd 77:1298-1304. Weinberg RA (1991) Tumor suppressor genes. Science 254:113b 1146.
