Chromosome Abnormalities in Malignant Lymphoma in Patients from Saitama1

[CANCER RESEARCH 47, 6767-6775, December 15, 1987) Chromosome Abnormalities in Malignant Lymphoma in Patients from Saitama1

Nobuo Msiseki, ' Yasuhiko Kaneko, Masaharu Sakurai, Masato Kurihara, Kazumi Sampi, Kayako Shimamura, and Shojiro Takayama Hemalology Clinic [N. M., K. Sa.J and Departments of Laboratory Medicine (Y. K., M. K.J, Cancer Chemotherapy [M. S.J, and Pathology [K. Sh., S. T.], Saitama Cancer Center, 818 Komuro, Ina, Saitama 362, Japan

ABSTRACT may be less patients with t(14;18) in Japan than in the United States. Clonal chromosome abnormalities were found in 89 (97%) of 92 patients with non-Hodgkin's malignant lymphoma including immunologically determined 34 B- and 25 T-lymphomas; only 3 of 19 T-lymphoma MATERIALS AND METHODS patients examined had serum adult T-cell leukemia/lymphoma-associated antigen antibody. Association of 8q24 translocations with small non- Patients. Chromosome studies of lymphoma cells were successful in cleaved cell (/' < 0.01) and that of t(14;18) (q32;q21) with follicular 92 patients (61 males and 31 females, ages 3 to 92 years; median, 57) histology (/' = 0.03) were significant. Several other abnormalities were diagnosed as having non-Hodgkin's ML at the Saitama Cancer Center also found to be correlated with histolÃ³gica!or immunological pheno- Hospital except for one patient who was diagnosed at another hospital types: irisimiy 5 with diffuse, mixed cell lymphoma (P = 0.03); a break and whose lymph node material for chromosome studies was trans at 3q21 with diffuse, large cell lymphoma (/' = 0.04); gain of chromosome ferred to the Saitama Cancer Center Hospital. Of the 92 patients, 61 18 or X and rearrangements of 13q with immunoblastic lymphoma (P â€” were among the 79 studied between January 1982 and December 1986, 0.02,0.03, and 0.03, respectively); and rearrangements of 7q with diffuse and 31 were among the 90 studied during the earlier period after large cell histology (P = 0.02) and T-cell phenotype (P = 0.02). Multiple December 1975; many patients were excluded from the latter group clones were more frequently seen in T-cell lymphoma than in B-cell because of the unavailability of banding studies. Of 35 patients whose lymphoma (P = 0.01 ). Structural changes of the long arm of chromosome serum was tested for ATLA antibodies, only 3 had a positive reaction. 4 or 15 and a break in 6p21 were also associated with T-lymphoma (/' = Twenty-six patients who had been reported mostly with a diagnosis by 0.03, respectively). Since the frequency of T-lymphoma is significantly an older classification system in our earlier studies (6, 20-25), were higher and that of t(14;18) is significantly lower in the adult T-cell included in this study. Cytogenetic and clinical data on 32 patients in leukemia/lymphoma nonendemic area of Saitama in Japan than in Min this report were submitted to the Fifth International Workshop on nesota in the United States (/' < 0.01), factors affecting the lymphoma- Chromosomes in Leukemia-Lymphoma (3), and those on 14 patients genesis may be different or operating in different intensities in different with T-cell lymphoma to the ATL Karyotype Review Committeeâ€” areas. 1985." Diagnosis and Histological Classification. ML was diagnosed accord INTRODUCTION ing to the Working Formulation (1) based on the histology of lymph nodes or tumor tissue biopsied from each of the 92 patients before Malignant lymphoma is a disease characterized by histolÃ³g therapy. Biopsy was repeated mainly at relapse in 18 patients. ica!, immunological, and cytogenetic heterogeneity (1-3). Geo Cytogenetic Studies. Of the 71 untreated patients, the sample was graphic differences in the distribution of the histolÃ³gica! and obtained from a lymph node in 54 patients (bone marrow cells were immunological phenotypes are also known to exist (4). Chro also used for one patient), from a tonsil in 11 patients, from other mosome abnormalities have been found in most patients with tumor tissue in 5 patients, and from pleura! effusion in 1 patient. ML' (5-9), and certain abnormalities have been correlated with Samples were also taken after therapy for 7 of the 71 patients. Of the histological and immunological characteristics (3, 7-14). The 21 treated patients, such a sample was obtained from a lymph node in 12 patients, from a tonsil in 1 patient, from bone marrow in 5 patients, great majority of chromosome studies on large series of patients from other tumor tissue in 1 patient, and from ascites in 2 patients. with ML have been carried out in the United States where Lymph nodes or other tissue were finely minced with surgical blades, follicular lymphomas are common and T-cell lymphomas are and cells were suspended in RPMI 1640 supplemented with 20% fetal scarce in contrast with the situation in Japan (4, 15, 16). calf serum. Both direct (6) and short term (for 12 to 48 h) culture Although chromosomal data on ATL, the most common type techniques, with or without methotrexate-synchronization (7) or ethid- of ML in southwestern Japan, have been reported (17-19), ium bromide treatment (26), were used to obtain sufficient metaphases. those on other T- and B-cell lymphomas in Japan are limited. Chromosomes were analyzed with G- and/or Q-banding methods (6). We studied correlations of karyotypic abnormalities with his Karyotypes were described according to ISCN (1985) (27) standards tological and immunological phenotypes of non-Hodgkin's ML with some modifications for the designation of some complex rear rangements (6). Clonality was defined using the criteria of the First in a sizable group of patients admitted to a cancer hospital International Workshop on Chromosomes in Leukemia (1977) (28). located in an area nonendemic for ATL (4, 16) in the northern When two or more abnormal clones were observed, a clone with the suburbs of Tokyo and found correlations of several specific simplest abnormality was considered to be the primary one. Karyotypes chromosome abnormalities with certain histological and/or of 26 patients reported previously were meticulously rereviewed by the immunological phenotypes of ML. In addition, we suspect there three cytogeneticists (N. M., Y. K., and M. S.), and the interpretations were partly changed in 14 patients (Table 2, Footnote/). Immunophenotyping. Immunophenotypes of lymphoma cells were Received 5/13/87: revised 8/20/87; accepted 9/9/87. evaluated in 71 patients. Cells obtained from the same tumor tissue The costs of publication of this article were defrayed in part by the payment that was used for chromosome studies were tested by a direct immu- of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. nofluorescence method for surface immunoglobulins and by rosette 1This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for Comprehensive 10-Year Strategy for Cancer Control, Japan, and by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan. 4 N. Kamada, M. Sakurai, M. Shimoyama, S. Abe, T. Abe, N. Sadamori, Y. ! To whom requests for reprints should be addressed. Kaneko, S. Fukuhara, K. Miyamoto, I. Sanada, and Y. Shiraishi. Chromosome 3The abbreviations used are: ML, malignant lymphoma: ATL, adult T-cell aberrations of adult T-cell leukemia in Japan: a report of the ATL Karyotype leukemia/lymphoma: ATLA, ATL-associated antigen. Review Committeeâ€”1985. manuscript in preparation. 6767

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1987 American Association for Cancer Research. CHROMOSOMES OF LYMPHOMA IN SAITAMA formation for sheep erythrocyte receptor. Cell surface antigens were formation of lymphoma was noted at relapse in 3 patients; the also examined in 60 patients by an indirect immunofluorescence histology changed from Group C to Group F in Patient N2, method using several monoclonal antibodies: Bl, B2, and B4 (Coulter from Group E to Group H in Patient N13, and from Group F Immunology, Hialeah, FL) for B-cell markers; T3, T6, Til (Coulter), to Group H in Patient N19. Four patients (Patients N11-N13 OKT4, and OKT8 (Ortho Laboratories, Raritan, NJ) for T-cell mark and N15) in Group E and one (Patient N55) in Group H were ers; 12 (Coulter) for HLA-DR; and J5 (Coulter) for common acute also classified as diffuse, medium-sized cell type and diffuse, lymphoblastic leukemia antigen. Tissue sections were stained immu ne>histochern Â¡callyby a peroxidase-antiperoxidase method for 16 pa pleomorphic type, respectively, by the Japanese Lymphoma tients. Only tissue sections were used for immunophenotyping in one Study Group classification (15). These 5 patients were proved other patient. to have T-cell lymphoma by immunophenotyping (see below). Statistical Analyses. Correlation was sought for chromosome abnor Patients 21 and 22 were reported as having immunoblastic malities found in 3 or more patients with histolÃ³gica!and immunolog- lymphadenopathy in Ref. 6. Subsequent biopsies revealed the ical phenotypes. Trisomies or monosomies (gain or loss of a whole development of non-Hodgkin's ML in these patients. chromosome without structural abnormalities) were considered to be Chromosome Abnormalities. Among the 71 patients studied numerical changes for statistical analyses when the modal chromosome before treatment, 3 (4%) (Patients N16, N19, and N61) had no number of the lymphoma cells was in the diploid range. Statistical significance was tested by the x2 or Fisher's exact test. clonal chromosome abnormalities in their lymphoma cells (Ta ble 1). In Patient N19,2 of 17 cells studied at diagnosis showed nonclonal single cell abnormalities, and 27 of 32 cells at relapse showed clonal chromosome abnormalities. Twenty of the 21 RESULTS patients whose chromosomes were studied only after treatment had clonal chromosome abnormalities. Thus, all but 3 (97%) Histological Classification. Only 10% of the 92 patients had of the total 92 patients with non-Hodgkin's ML had clonal ML of follicular type, i.e.: Group B, ML, follicular, predomi chromosome abnormalities at diagnosis or at relapse (Table 2). nantly small cleaved cell; Group C, ML, follicular, mixed, small Among the 68 patients with clonal chromosome abnormali cleaved and large cell; or Group D, ML, follicular, predomi ties studied before therapy, 11 had multiple clones; 7 had 2, 2 nantly large cell (Table 1). The most common type was Group had 3, and 2 had 4 abnormal clones. Four patients (Patients G, ML, diffuse, large cell and was seen in 35%. Group F, ML, 23, 26, 27, and N19) with a diploid-only karyotype or a single diffuse, mixed, small cleaved and large cell, and Group H, ML, abnormal clone before therapy showed multiple clones after large cell, immunoblastic, were next in frequency and were seen therapy. Four other patients studied only after treatment also in 16% each. ML was classified in the miscellaneous group in had multiple clones. Thus, a total of 19 patients showed mul 2 patients. One (Patient 18) of these patients had a composite tiple clones sometime in the course of their diseases; 4 of them lymphoma with follicular and diffuse areas; a total of 10 pa had unrelated clones within each patient. tients, therefore, showed a follicular pattern. Histological trans The modal chromosome number of the primary clone found

Table 1 Immunophenotype, ATLA antibody, number of abnormal clones, and modal chromosome number by histolÃ³gica!group in 92 patients with malignant lymphoma HistologicalTotal Formulation0E82634141311FIS103219113627291G3223811483161319186H1514I5118213141I53231123111J63124116SMis2112112Total9264217342566213235735711according to Working no.Chromosomes 151

atDiagnosisAfterstudied 411 therapyBoth timesImmunophenotypeBTNon-T,

3111 non-BNot interpretableNot testedATLA antibody*NegativePositiveNot 141 testedNo. clones'012of abnormal

31D3312213group or moreABC0

Modaltheprimary chromosome no. of clonecHypodiploidPseudodiploidHyperdiploidPolyploid11abnormal 14 122212714106414 11011 1826277

* Malignant lymphoma was diagnosed before therapy for each patient. A, ML, small lymphocytic; B, ML, follicular, predominantly small cleaved cell; C, ML, follicular, mixed, small cleaved and large cell; D, ML, follicular, predominantly large cell; E, ML, diffuse, small cleaved cell; F, ML, diffuse, mixed, small and large cell; G, ML, diffuse, large cell; H, ML, large cell, immunoblastic; I, ML, lymphoblastic; J, ML, small noncleaved cell; Mis, miscellaneous. 0 Negative, 1:5 dilution or less; positive, more than 1:5 dilution. ' Data from cases studied before therapy were summarized.

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Table 2 Clinical, histological, immunological, and karyotypic characteristics of 92 patients with malignant lymphoma ATLA Prior No. of cells banded Age, anti Immnno- treat Patient' Sex body* phenotype' Source1' ment' Total Normal Abnormal Karyotype of abnormal clonefs/

Group B: ML, foliicular, predominantly small cleaved cell NI SI F LN 15 0 15 46,XX,t(14;18)(q32;q21) Group C: ML, foliicular, mixed small cleaved and large cell 1 70 F LN - 16 0 16 â€¢46,XX,-6,+der(6)t(I;6)(qll;q25) N2 45 M IV LN + 10 10 0 Normal N3 58 M Bfu LN - 12 0 12 49,XY,-l,-3,+7,-19,t(14;18)(q32;q21),+der(l8)t(14;18),+der(l)t (l;?Xp32;?),+3mar N4 47F n.i. LN - 15 9 4 45,X,-X 2 46,XX,del(6)(ql5q21) NS 59F LN - 16 0 16 48,XX,+5,+12,t(2;2)(pl3;p21),del(4Xpl2pl6) Group D: ML, foliicular, predominantly large cell N6 57 M Tonsil - 10 0 10 46,XY,-6,-ll,+der(H)t(ll;?)(pl3;?),+mar N7 59 M LN - 15 1 14 46,XY,-7,t(6;9)(p23;pl3), del(6)(ql5q21),+mar N8 43 M LN - 15 8 6 92,XX,[4nÂ±]-Y,-Y,-3,del(7)(pl3),dirdup(ll)(ql3->q25),dir dup(l Iq),+der(3)t(3;?)(q2l;?),+2mar (karyotypic instability) 1 SCA Group E: ML, diffuse, small cleaved cell (or medium-sized cell) 13 35F LN +12 0 12 Â»47,X,-X,+19,i(7q),i(17q),+mar N9 48 M LN - 11 0 11 47,Y,-X,-7,-14,+der(X)t(X;?Xp22;?),+der<7)t(7;?Xq22;?), +der( 18)t( 18;?)(q23;?),+mar N10 82 M By* LN -1-19 3 16 47,XY,+X Nil 61F T BM + 30 0 30 46,XX,-16,t(9;22)(q34;qll),+mar N12 30 M T Tumor + 15 0 15 47,XY,t(l;12)(p32;pl3),t(2;13)(pl2;q22),del(l)(pl3), +der(l)t(l;?Xq21;?) N13 42 M T (h/i) LN -I- 37 0 30 48,XY,-15,del(5)(ql3q22),+del(7)(pll),+der(15)t(l;15Xq23or q25;q24),+mar 3 49,XY,- 15,5q-,+7p-,+der( 15)t( 1;15),+2mar 4 47,XY,- 15,-22,5q-,+7p-,+der( 15)t( 1;15),+mar N14 54F LN + 15 6 9 49,XX,+3,+ 12,+ 18,del(9)(ql3q22) N15 73 M LN - 15 0 2 47,XY,-l,-3,del(4)(pl4),+der(l)t(l;?)(q32;?),+der(3)t(3;?)(ql2;?), +der(5)t(5;?)(q31;?) 2 48,XY,+22,lq+,3q+,4p-,+5q+ 6 49,X Y,- 17,+2 1,+22, 1q+,3q+,4p-,+5q+, +der( 17)t( 17;?)(q25;?) 4 49,X Y,- 1,- 17,- 18,+22,3q+,4p-,del(6)(q 13q23),del( 15)(q22), +der( 1)t(?; 1)(1;?)(?;p36q32;?),+der( 17)t( 17;?)(p 13;?),+der( 18)t (18;?)(q23;?),+2mar 1 SCA = related karyotype Group F: ML, diffuse, mixed small and large cell 11 68 M LN - 13 0 12 '51,XY,+X,-2,+5,-l-ll,-12,+21,del(6)(ql5q23), fder(2)t(2;?)(q35;?),+der( 12)t( 12;?)(pl 1;?),+mar 1 SCA = related karyotpe 16 32 M LN - 21 0 14 Â»50,XY,+ll,-H2,-15,+del(3)(qll),+del(3)(qll), +der(X)l(X;l)(p22;ql2) 7 SCA = related karyotypes 21 57 M T LN +70 7 46,XY,t(5;7)(q33;q32).del(4)(q33),del(6)(q23) 22 65 F T LN - 10 2 6 49,XX,+5,+ 19,+22 2 SCA LN - 5 1 4 49,XX,+5,+ 19,+22 27 69 M T (h/i) LN - 20 17 2 46,XY,del(6)(p21p23) 1 SCA BM + 27 1 12 46,XY,del(6)(p21p23),dirdup(ll)(qIl-Ki23),t(14;?16Xq32;pl3) 2 46,-X,Y,6p-,dir dup(l lq),t(14;?16),+mar 2 46,-X,Y,- 12,- 13,6p-,t( 14;? 16),+der( 12)t( 11;12)(q 11;q24),+mar 10 SCA = related karyotypes N16 56 M LN - 7 6 1 SCA N17 64 M Non-T, non-B LN - 8 0 8 47,XY,-3,+5,-14,-19,-20,-22,del(ll)(pll),+der(3)t(3;?)(q29;?), +der( 14)t( 14;?)(q32;?),+3mar N18 61 M Tonsil - 12 0 12 47,X,-Y,-l,-4,-8,-19,del(9)(p21),+del(9)(p22),i(17q),+der(l) t(l;?)(pl3 or 21;?),+der(8)t(8;?)(p22;?),+der(19)t(19;?)(pl3;?), +2mar N19 71 M LN - 17 15 2 SCA LN + 32 5 8 47,XY,+5,del(6)(ql5q23) 13 47,X Y,+3,- 15,+der( 15)t( 14; 15)(q 11;q24),del( 16)(q22) 4 48,XY,+3,+ 12,15q+,16q- 2 47,XY,+3,-13,15q+,16q-, +der(13)t(13;?)(q32;?) N20 64 M T (h/i) LN - 40 24 3 47,XY,+mar 3 50,XY,+3,+4,+7,+ 15 3 50,XY,+4,+7,+ 15,+20 6 50,XY,+3,+4,+7,+ 15,del(6)(q 15q23?) 1 SCA N21 47 M - T (h/i) LN - 15 7 7 72,XX,[4nÂ±]-Y,-Y,-l,-3,-3,-3,-4,+5,-6,-8,-8,-8,-8,-9,

(pl3;ql 1), del(7)(q22),dup(9)(pterâ€” q34::ql l-K)34::q21-. qter),dup(9) (ql l-Ki34),i(13q),del(16)(pl3),i(21q), +der(9)t(9;?)(pl l;?),+der(18)t(18;?)(q23;?),+ 13marwith cell to cell variation SCA

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Table 2â€”Continued ATLA Prior No, of cells banded Age, anti- Inumino treat- Patient" Sex body* phenotype' Source' ment' Total Normal Abnormal Karyotype of abnormal clone(s/ N22 47 M - T(h/i) LN + 21 9 5 46,XY,-2,-3,-12,del(5)(q22q31),+der(12)t(l;12)(q21;q24), +der(2)t(2;?)(q35;?),+der(3)t(3;?)(p25;?)(karyotypic instability) 7 SCA (with related karyotypes) N23 32 M - T LN 14 0 14 46,XY,del(10)(q24q26) N24 57 M - BuÂ« LN - 15 3 12 50,XY,-(-3,del(6)(ql3q23), and other abnormalities N25 43 M T(h/i) LN + 16 1 15 46,XY,-l,-6,-14,del(13)(ql2q22),+der(l)tp23::p21-Ki23:), +der( l )t( l ;?)(p36;?),+der( 14)t( 14;?)(q32;?) BM + 9 0 6 47,XY,inv(lp),lp+,+5,6p-q-,14q+ 3 47,XY,inv( l p), l p+,+5,6p-q-,-13,14q+,+mar N26 86 M n.i. LN - 18 6 12 46,XY,-2,-14,i(lq),+der(2)t(2;?)(q37;?),+der(14)t(14;?)(q32;?) N27 59 F BM LN - 13 0 6 47,XX,+ 13,-14,-16,+der(14)t(14;?)(q32;?),+mar 4 47,XX,14q+,-16,+21,+mar 3 48,XX,+ 13,14q+,-16,+2mar N28 39 F LN 11 4 7 47,XX,+mar N29 62 F Non-T, non-B LN - 11 0 11 45,X,-X,-2,-4,-6,-7,-8,-9, -ll,-14,-17,-18,-19,del (22Xq11 ),+der(4)t(4;?Xq35;?), +der(7)t(7;?)(p 15;?),+der(8)t(8;?) (q24;?),+der(9)t(9;?)(p24;?), +der(l l)t(l I;?)(q25;?),+der(14) t(14;?Xpl3;?), +der(18)t(18;?) (q23;?),+der(19)t(19;?)(ql3;?), +3mar N30 53 F - T LN - 41 12 15 46,X,-X,-l,-4,-5,+7,-8,-13,-13,-14,-14,-17,+ 18,-19,-21, -22,del( l Xp34),del(3)(p21 ),del(5Xp 13p 15),dup(6)(p2 lâ€”p21), del( 12)(q22),+der( l )t( l ;?)(p36;?)dir dup( l )(q21-*|32),+der(3) t(3;?Xq29;?),+der(4)t(4;?Xq33;?), +der( 13)t( l3;?Xp 13;?), +derU3)t(13;?XpH;?),+der(14) t(14;?Xq32;?),+der(14)t(14;?), +der( 17)t( 17;?Xpl l ;?),+der( 19)t( 19;?)(q 13;?),+2mar 6 45,X,-X,-5,-5,+7,-8,+18,-21 ,-22,lp-, l p+q+,3p-,+3q+,4q+, +der(5)t(5;?)(p 15;?),6p+, 12q-, 13p+, 13p-t-,14q+, 14q+, 17p+, 19q-Â»-,-l-mar 8 46,X-X,-5,+7,-8,+18,-21 ,-22, l p-, l p+q+,3p-,+3q+,4q+, 5p+,6p+, 12q-, 13p-l-,13p+, 14q-t-,14q+, 17p+, 19q-f,+2mar N31 65 M - T LN - 20 2 18 78,XXY,[4nÂ±]-Y,-l,-l,-l,-3,-4, -6,-7,-7,-8,-8,-8,-9,-10, -10,-11,-12,-13,-14,-14,-15,-17,-18,-20,-20,-22,t(2; 16) (p 11;p 13),t(2; 16),+der( l )t( l ;?)(p31 ;?),+der( l )t( l ;?)(p31 ;?), +der( l )t( l ;?)(q42;?),+der(7)t(7;?Xq22;?),-(-der(7)t(7;?), +der(8)t(8;?X?P U ;?),+7mar N32 82 F - T LN - 15 0 15 49,XX,+3,+ 10,+ 18,t(l;20)(pl3;pl3) N33 46 F - T (h/i) LN - 24 3 21 46,XX,t(3;6)(6;5;8)(q21;p25q21;qll;q24),t(6;7)(p23;q32) N34 47 M BaÂ« Ascites + 17 0 17 47,XY,-6,-7,+ 12,dirdup(l)(q21-Ki32),+2mar N35 76 M BpirX LN â€” 11 0 11 Hyperdiploid/tetraploid with complex abnormalities BM 12 l 11 50,XY,7q-, 12p+,i( 17q), and other abnormalities N36 40 M Non-T, non-B Tumor â€” 5 0 5 Hypotetraploid with 7qâ€”and other abnormalities N37 52 M BMA LN + 10 0 10 47,X,-Y,-l,-l,-2,-4,-8,-9,-10,-15,-17,-17,-(-18,-H8,-22, +inv(3)(p24q24),del(8)(q 13),del(9)(q22),+der( l )t( l ;?)(p36;?), +der( 10)t( 10;?)(p?;?),+der( 11)t( 11;?)(q?;?),+ins( 14;?)(q?;?), +der( 17)t( 17;?)(q?;?),-H5mar N38 83 M - B^X LN - 28 2 26 45,X,-Y,-2,-8,-12,-14,-18,del(l)(q42),invdup(3)(q23-H|21), del(5)(q31q33),del(6)(ql5),+der(2)t(2;?)(p23 or 25;?),-t-der(12) t( 12;?Xp 13;?),+der< 14)t( 14;?)(q32;?),+der( 18)t( 18;?)(q21 ;?), +mar N39 63 M - B-YÂ« Tumor - 10 0 10 46,XY,del(16)(q22) N40 92 M BMÂ« Tumor 15 l 14 47,X,-Y,-2,+7,-14,del(l)(q21q25),del(6)(ql5q23),del(21)(q21), +der(?14)t(14;?)(pl3;?),+2mar

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Table 2â€”Continued bandedtreat- No. of cells Inumimi body*Source"*- phenotypec ment'Total16141315-t- Patient"N41N42N43N44N45N46N47N48N49Age,Sex71 clone(s)^45,X,-Y,-2,-3,-7,-8,- of abnormal

M48 BMÂ«LNBjiA 3),del(6)(q2 12,- 13,- 13,del(2)(p 11P1 1q25),+der(2)t(2;?Xq37;?),+der(3)t(3;?)(q27;?),+der(7)t(7;?)(p22;?),+3mar46,XX,-

F61 LNNon-T, ;?)(p22;?),+der(l)t(l;?)(q44;?)46,XX,-l,-5,-HO,-15,+16,-l 7,t(3;6)(p2 1;p23),+der( 1)t( 1

F61 Tonsil- non-B 4;?)(q32;?)46,XX,del(3Xq214,del( 13Xq 12q 14),+der( 14)t( 1 4q+Hypotetraploid1), 13q-, 1 M60 BMALNT complexabnormalities47,XY,-9,-with 3q-t-, 6pâ€”,6q+, 12q+, and other

M52 LNâ€” (h/i) 56II151515Normal1123431219Abnormal151374125359111286231Karyotype),+der(7)t(7;?)(q22;?),+der(9)t(9;?)(q22;?),16,del(4)(q3 1 +der(16)t(16;?Xq24;?)47,XY,+3, variationSCA46,XY,t(8;14)(q24;q32)SCA46,X,i(Yq),+12,-13SCA44,Xand another structural change with cell to cell

M51 Tumorâ€”BMA

M46 Tonsil-BjryA

M53 TTumorBM 3),+der(Y,-5,- 10,- 11,- 13,- 15,- 17,+der(5)t(5;?8)(p 13;?q 1 7)t(I7;?)(cen;?)44,XY,-5,-11)t( 10; 11)(q11;q23),+der( 15)t(7; 15)(q 11;q24),+der( 1 ),+der( 10,- 10,- 11,- 13,- 17,+der(5)t(5;?8),+der( 11)t( 10; 11 7;?)46,X10)t( 10;?)(cen;?),+der( 17)t( 1 MATLAanti- LNPrior ;?)(p34;?).+der(3)t(3;?)(q21;?),+der(3)t(3;?)(q27Y,- 1,-3,-3,-8,-9,del(2)(q3 1q37),+der( 1)t( 1 29;?),+der(9)t(9;?)(q34;?),+r45,X,-Y,-8, or 3q27),9q+,+rSCAGroup 1p+,2q-,3q-,3q+,del(6)(q 1

immunoblastic34791217N50N51N52N53N54N55N56N57N5869 H: ML, large cell, F33F71 9)(pi 11,+ 18,- 19,del(7Xp 13p 15),i( 17q),+der( 19)1(4;1 ;?)(q25;?),+mar*47,XX,-2,-6,+l;q!3),+der(l l)t(l 1 4)(q22;q32),del( 16,- 19,t(? 1;14)(p 11;q 11), t(8; 1 25),+der(6)t(2;6)del(6)(ql5q21),+der(19)t(19;?)(ql3;?)*50,XX,+3,+3,-4,-6,-9,+11)(q23),+der(2)t(2;6)(q2 1;p

F40 8,+4mar47,X,+X,- 11,- 17,+ l M68 4)t(14;?)(q32;?)â€¢48,XY-Y,+ 12,- 14,del( 11)(q2 1q23),del( 16)(q22),+der( 1

M42 ;?),+3marâ€¢50,XY,+X,+5,+7,+15,- 16,- 18,+ 19,+der( 18)t( 18;?)(q2 1 M48F64 4),+der( 12,- 14,- 17,dup( 1)(q2 lâ€”q32),del(13)(q 12q 1 4;?)(q32;?)46,XX,+X,-17)t( 1;17)(q2 1;q25),+der( 14)t( 1 LNTonsilBMÂ« 9,del(2Xq24),-l-i(6p)1-l-der(1,-8,- 10,- 10,+ 11,- 12,- 1 2)52,X,-X,+7,-1)t( 1;?)(p32;?)del( 1)(q32q42),+der( 10)t( 10;?)(p 15;?),+der( 1

F68F71 3;q24),-t-der(3)t(3;?)(p12,+ 13,- 14,+ 18,+der( 12)t(9; 12)(q 1 4;?)(q32;?),+2mar49.XX,-13;?),+der(3)t(3;?),+der (14)t( 1 LNLNH,,\ 3;?),+der(11,- 13,- 18,+del(3)(q25),+der( 11)t( 11;?)(pl ;?),+2mar49,XY,+3,-13)t( 13;?)(q34;?),+der( 18)t( 18;?)(p 11 M63 8,+2mar46,del(X)(q24),-14,+ 1 M61 LNT 8,del(6)(q25),-t-der(8)t(8;?)(p23;?),+der(Y,-8,- 11,- 13,- 17,- 1 7)t( 11)t( 11;?)(q25;?),+der( 13)t( 13;?)(q34;?),-t-der( 1 ;?)48,X17;?)(p 13;?),+der( 18)t( 18;?)(q23;?),+der(?)t< 1;?)(q 11 M55 LNâ€” ;?),+der(4)t(4;?)(q27;?),+mar92,XXY,- 1,+der( 1)t( 1;?)(pl 1 2q+46,XY,+7,-YY,2p-, 11p-t-,1 M68 n.i.TonsilBMÂ« 4),+mar48,X 11,- 14,del(4)(p 1 M81 LNTestisBMÂ« 4)(q24;q32),+der(14)t(8;14)SameY,- 14,del(6)(q2 1),+del(6)(q2 1),+i(7p),t(8; 1

15100100013055611301Group asabove87,XXXX,[4nÂ±)-2,-3,-4,-5,-8,+9,- FLNLNLNLNTonsilLNBMÂ« TonsilU1817121010971318182248+ 7,- 14,- 14,- 15,- 15,- 1 q25),+der(17,- 19,del( 1)(pl 1),del( 1p),+del( 1)(q25),del(6)(q2 1 4;?)(q32;?)lymphoblaslic131533913440Â«46,XY,-4,del(6)(p214)t( 14;?)(q32;?),+der( 14)t( 1 ML,1825N59N60N6117M14 I: 13+ p23),del(9)(p22),-l-mar47,XY,-4,6p-,9p-,-l-2mar48,XY-4,6p-,9p-,+3mar46,XY,t(ll;19)(q23;pl3)45.X.-X,-1 2141-1-

M3F75 (pre-T)LNT (pre-T)BMNon-T, 138190320019111717121096781312111035159â€¢46,X,-X,-4,-2;?)(ql3;?),+2mar45,X12,- 16,- 17,del( 1)(q32),del(9)(p22),-t-der(?)t( 1

M48 LNT non-B 13;?)45,XY,- 12,- 18,del(6)(q2 1),+der( 12)t( 12;?)(p 13;?)NormalGroup Y,- 12,- 18,del(6)(q23),+der( 12)t( 12;?)(p MLNBMT (h/i) LN+ cell823N62N6381 J: ML, small noncleaved F45F12M25FTonsilBM ;?),+mar45,X,-X,t(2;8)(pl11,- 18,+der( 11)t( 11;?)(q25;?),-t-der( 18)t( 18;?)(q2 1

LNPEBMTA I;q24)Same 11+ asaboveÂ«45,X,-X,-2,t(2;8),+der(2)t(2;8)(2pter-.2p 3-Â»2qter)48,X 11::8q24â€”8q2 1::2p 1

BMB-yÂ« 8160000013274816*46,X,-X,- 5),+der(7)t(7;?)46.XXÃŒ-ÃŒY,- 16,+2 1,t(8; 14)(q24;q32),del(6)(q 1 LN132+ l,+der(l l)t(5;l I)(ql5;q25)

6771

Table 2â€”Continued bandedSource''BM No. of cells ImmunÂ» Patient"N64Sex5M4M29body* phenotypecNon-T, Total+ '46.XX,- of abnormal clÂ»nc(s) 8 3 11,del( 1Xq2 1),+der( 11)t(5; 11) non-B LNTonsilLN 12 0 12 46,X Y,-2,t(8; 14)(q24;q32),-l-mar N6519N66Age, BpXBpx 2011+ 317ML, 46,XY,-3,t(8;14)(q24;q32),+der(3)t(3;?)(ql2;?)46,XX,t( miscellaneous F 0 11 14; 18)(q32;q2 1),)del(20Xq 11) LNLNment' 2214NormalAbnormal56161 46,XX,t(14;18),inv dup(lXq21â€”q25),dir dup(12Xql 1â€”q24), ins(17;?Xq21;?) 63 MATLAanti- BÂ«Prior 13Karyotype45,X6,- Y,- 1,-2,-2,-3,-4,-5,-6,-8,- 10,- 11,- 12,- 12,- 14,- 1 17,- 19,-20,del(6Xq 13q25),-t-der( 1)t( 1;?)(q32;?),+der(2)t(2;?) (q37;?),+der(5)t(5;?)(pl5;?),+der(l l)t(l I;?)(pl5;?),+der(12) t( 12;?)(p 13;?),+der(?)t( 10;?)(q 11;?),+ 1Omar * Patients 1-14 and 16-22 are Patients 1-14 and 16-22 in Ref. 6. Patients 23-25 are Case 2, and Cases 2 and 7 in Refs. 22 and 23, respectively. Patients 18, 26, and 27 were reported in Ref. 25 as Patients 1, 2, and 3, respectively. N1-N66 are new cases. Partial kam Â»typesofPatients 23 and N62 were reported in Ref. 21 as those of Patients 5 and 3, respectively. Partial karyotypes of Patients 18 and N59 were reported in Ref. 24 as those of Cases 5 and 6, respectively. Patients 1, 3-5, 7- 9, 11, 12, 17, 19, 22, 23, 26, 27, N9, N15-N18, N26-N28, N50-N55, N60, N63, and N64 were submitted to the Fifth International Workshop on Chromosomes in Leukemia-Lymphoma (3). Patients 22, 25-27, N19-N21, N29-N33, N55, and N61 were submitted to ATL Karyotype Review Committeeâ€”1985.4 * â€”,1:5dilution or less; +, more than 1:5 dilution. ' n.i., not interpretable; h/i, helper/inducer subtype. 'UN, lymph node; BM, bone marrow; Tumor, tumors of paranasal sinus (Patient N12), epipharynx (Patients N36 and N40), stomach (Patient N39), or skin (Patients N46 and N48), respectively; PE, pleural effusion. ' â€”,studied before treatment; +, studied after treatment. ' Revised karyotypes of previously reported patients were asterisked. (The interpretation of the karyotype was partly changed from the one reported in Refs. 6 and 20.) Karyotype designations of second or subsequent clones were simplified. SCA, single cell abnormality. before therapy was 46 (pseudodiploid) in 26 patients, 44 or 45 lymphoma cells formed no sheep erythrocyte rosettes and had (hypodiploid) in 8, 47 to 52 (hyperdiploid) in 27, 72 to 78 no detectable surface immunoglobulin, and for whom no further (near-triploid) in 3, and 87 to 92 (near-tetraploid) in 4. helpful information was available, into the non-T, non-B type Among 89 patients with clonal chromosome abnormalities 3 and the other 6 patients as having not interprÃ©tablephenotypes. patients had only numerical abnormalities, 10 had only struc All 3 patients (Patients 21, 22, and N13) whose serum tural changes, and the other 76 had both numerical and struc contained ATLA antibody had T-lymphoma. tural abnormalities. All chromosomes were involved in numer Chromosome Abnormalities and Histology. The relationship ical and structural abnormalities. of the type of the chromosome abnormality to the histology of In pseudo- or near-diploid tumors, chromosomes 5, 7, 12, the tumor was examined in the 71 untreated patients (Table 3). and 18 were most repeatedly found as a supernumerary chro Three of 5 patients with trisomy 5 in their tumor cells had mosome (8 patients each), and X chromosome was most fre Group F, ML, diffuse, mixed, small and large cell (P = 0.03). quently lost (10 patients). A near-triploid tumor with pentasomy 5 had the same histology, Forty types of translocations and 4 types of inversions were while none of the triploid or tetraploid tumors without penta observed in 36 patients. The only types that recurred were somy 5 had the Group F histology. In one patient (Patient t(8;14)(q24;q32) (5 patients) and t(14;18)(q32;q21) (3 patients). N19), two cells with different single cell abnormalities, both Sixty-two types of deletions were found in 52 patients, 21 types without trisomy 5, were seen before therapy in the lymph node as interstitial and 41 as terminal. The long arm of chromosome on which ML of Group F was diagnosed, and a clone with 6 was deleted most frequently (20 patients). trisomy 5 was found in the tumor after relapse when the A total of 146 bands were involved in the various structural histology had transformed to Group H. chromosome changes, 79 of them in 2 or more patients. The Four of 6 lymphomas with trisomy 18, and 3 of 4 with band most frequently involved was 14q32 (24 patients). trisomy X belonged to Group H, ML, large cell immunoblastic Immunophenotype.Of the 71 patients whose lymphoma cells (P = 0.02 and 0.03, respectively). Five of 7 lymphomas with were immunophenotyped, 34 were thought to have B-cell lym- loss of a chromosome 8, and all 3 lymphomas with loss of a phomas (Tables 1 and 2). Among these patients, only immu- chromosome 13 belonged to Group G, ML, diffuse, large cell noglobulin heavy chains or light chains were studied in 3 (P = 0.03, respectively). (Patients N2, N27, and N49) and 2 (Patients 5 and N66) Some translocations were also correlated with specific his patients, respectively, and only a heavy chain, but no light tologies. Two of 4 patient with t(8;14)(q24;q32) had a lym chain, was detected in one patient (Patient 23). Lymphoma phoma of Group J, small noncleaved cell. In addition, one cells of one patient (Patient N49) had only cytoplasmic but no patient (Patient 23) with t(2;8)(pl I;q24) was classified as hav surface immunoglobulin, and thought to be pre-B. Twenty-five ing the same histology. Thus, 3 of 5 Group J, ML, small patients were determined to have T-cell lymphomas. Lym noncleaved cell had an 8q24 translocation (P < 0.01), and vice phoma cells of 9 patients (Patients 27, N13, N20-N22, N25, versa. N33, N45, and N61) were positive for OKT4 but negative for Two of the 3 tumors with t(14;18)(q32;q21) were classified OKT8, and thought to be helper/inducer. Lymphoma cells of as having follicular lymphomas (P = 0.03). The other tumor two patients (Patients 25 and N57) showed positive reactions (Patient 19) with t(14;18) had composite, follicular, and diffuse to several T-cell-specific monoclonal antibodies but formed no histologies. Therefore, all 3 lymphomas with t(14;18) had a sheep erythrocyte rosettes and were thought to be pre-T. In 12 follicular pattern. patients, we could not define the phenotype as either of B- or Four of 5 lymphomas with a break in 3q21 belonged to T-cell lineage because of insufficient information due to scanty Group G, diffuse, large cell (P = 0.04). In two other instances, material or lack in possibly helpful immunohistochemical ex structural chromosome abnormalities were correlated with spe aminations. Thus, we tentatively classified 6 patients whose cific histologies: 6 of 8 lymphomas with a break in 7q were 6772

Table 3 Correlation of chromosome abnormality with histology in 71 untreated malignant lymphomas group"Chromosome No. of patients with each abnormality by histolÃ³gica!

E F G I(n Mis abnormalityNumerical (n =24)1 8) (n = 2) (n =12) (n = =15)3)114313J (n = (n = 5) (n = 2)Total51 abnormalities*+5-8-13+ 35321321 73643

18+XStructural

abnormalities8q24 translocationst(14;18)(q32;q21)7q r\" 3845P0.030.030.030.020.03<0.010.030.020.030.04 rearrangements1 611 1 3qrearrangementsBreak at 3q21Follicular 4H "Classified according to the Working Formulation. E, ML, diffuse, small cleaved cell; F, ML, diffuse, mixed small and large cell; G, ML, diffuse, large cell; H, ML, large cell, immunoblastic; I, ML, lymphoblastic; J, ML, small noncleaved cell; Mis, miscellaneous. * Seven cases with a polyploid tumor, i.e., one with follicular lymphoma, one in Group F, 4 in Group G, and one in Group H, were excluded. c Includes four patients with t(8;14)(q24;q32), one with t(2;8)(pl I;q24), one with t(3;6)(6;5;8)(q2I;p25q21;ql I;q24), and one with t(8;?)(q24;?). '' Composite lymphoma with follicular and diffuse areas.

Table 4 Correlation of recurrent chromosome abnormalities with the t(14;18)(q32;q21) were of B-cell type. Two lymphomas had a immunophenotype T-cell phenotype and a translocation with a break in 14qll. ImmunophenotypeChromosome The association was not statistically significant in any of these 3 instances. There were no clear correlations between chromo abnormalityMultiple =34)4 =25)IO some abnormalities and heavy- or light-chain expressions of clones immunoglobulin. -Y 6 04 6*4 0.02 4q rearrangements 0 0.03 7q rearrangements 2 7 94 0.02 15q rearrangements 0 4 0.03 DISCUSSION Break at 6p21B(Â« 0T(n 4Total"14 4P0.01 0.03 " Cases with non-T, non-B or not interprÃ©tablephenotype were excluded, We studied karyotypes of tumor cells from 92 patients with "of 22 B- and 17 'I-lymphomas among 39 male patients with a modal ML and found clonal chromosome abnormalities in 97% of chromosome number in the diploid range. them (Tables 1 and 2). Our patients were sequentially studied and seemed to represent an average sample of lymphoma in an classified in Group G, diffuse, large cell (P = 0.02); and 3 of 4 area nonendemic for ATL in the northern suburbs of Tokyo, lymphomas with a break in 13q were classified in Group H, Japan. There was only one typical ATL patient (Patient N55) large cell, immunoblastic (P = 0.03). among 25 T-lymphoma patients in this series, and only 3 of Chromosome Abnormalities and Immunophenotype. The kar- the 19 patients of T-lymphoma tested for ATLA antibodies had yotypes of the 34 patients with immunologically determined B- a positive reaction. lymphoma were compared with those of the 25 patients with Several chromosome abnormalities seemed to be specifically T-lymphoma determined in the same manner (Table 4). associated with certain histolÃ³gica! or immunological pheno- Among the 59 patients (39 males and 20 females) whose types (Tables 3 and 4). Translocations with a break in band lymphoma cells were immunophenotyped as either B- or T- 8q24 and t(14;18)(q32;q21) were significantly associated with cell, 10 of 14 lymphomas with multiple clones were T-cell (P Group J, ML, small noncleaved cell (P< 0.01) and the follicular = 0.01). Multiple clones were detected in 9 untreated patients lymphoma (P = 0.03), respectively (3, 7-10). (3 with B- and 6 with T-lymphoma) and in 5 treated patients Trisomy 5 was associated with Group F, ML, diffuse, mixed (one with B- and 4 with T-lymphoma). Three (Patients N19, small and large cell (P = 0.03). Two studies (29, 30) reported N45, and N55) of the 10 T-lymphomas, but none of the 4 B- the association of trisomy 5 with angioimmunoblastic lymph- lymphomas with multiple clones had unrelated clones. adenopathy, a probable subgroup of peripheral T-cell lym Although various numerical abnormalities were present in phoma (31). Unfortunately, immunological data of our three pseudo- or near-diploid tumors, only the correlation of loss of ML cases of the Group F histology and trisomy 5 were incom a Y chromosome with B-cell phenotype in male patients was plete; only one of them was demonstrated to have T-cell phe statistically significant (P = 0.02); loss of a Y chromosome was notype. On the other hand, Koduru et al. (14) reported signifi observed in 6 of 22 males with B-lymphoma and in none of 17 cant association between trisomy 5 and large cell immunoblastic males with T-lymphoma. histology. A case of lymphoma having trisomy 5 in our series Structural abnormalities in some chromosome arms were (Patient N19) and a reported case (29) showed histolÃ³gica! correlated with T-lymphoma; i.e., all 4 lymphomas with 4q transformation from diffuse, mixed cell lymphoma or angioim rearrangements, 7 of the 9 with 7q rearrangements, and all 4 munoblastic lymphadenopathy to immunoblastic lymphoma with 15q rearrangements had a T-cell phenotype (P - 0.03, during the course of their diseases. Trisomy 5 may be correlated 0.02, and 0.03, respectively). The breakpoints in the same arms with both of diffuse, mixed cell histology (or also angioimmu were not necessarily identical, but they often clustered in chro noblastic lymphadenopathy) and immunoblastic histology. mosome bands such as 4q27-q33 (4 patients), 7q32 (3 patients), Lymphomas with a break at 3q21 were associated with Group and 15q24 (3 patients). All 4 lymphomas with a break in 6p21 G, ML, diffuse, large cell (P = 0.04). Kaneko el al. (10) also were of T-cell phenotype (P = 0.03). reported the association of a 3q+ chromosome and diffuse large Of the 7 lymphomas with the 8q24 translocation, 5 were B, cell lymphoma although their interpretations of the breakpoints 1 was T, and 1 was non-T, non-B. All 3 lymphomas with in the 3q were different from ours. 6773

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1987 American Association for Cancer Research. CHROMOSOMES OF LYMPHOMA IN SAITAMA Six other chromosome abnormalities were also correlated cai phenotypes of non-Hodgkin's ML in Saitama, an area with specific histolÃ³gica!groups of the Working Formulation nonendemic for ATL in Japan, and clarified that one of the (Table 3). Among these, the significance of the loss of chro common translocations, t(14;18), may not occur in Japan as mosome 8 or 13 may not be real because these abnormalities frequently as in the United States. We also found for the first were usually accompanied by totally unknown marker chro time association of several chromosome abnormalities with mosomes. certain histological and immunological phenotypes of ML. The Rearrangements in the long arms of chromosomes 4, 7, and roles of some chromosome translocations in the lymphoma- 15 seemed to be associated with T-cell phenotype in this study genesis have been recognized by molecular approaches (43). (Table 4). Interestingly, the genes for epidermal growth factor, However, little is known about how most of the chromosome T-cell growth factor, and T-cell receptor /3-chain,and protoon- abnormalities described in this report act in the genetic steps cogenefes have been localized to the vicinities of the breakpoint toward the development of lymphoma. We hope that our data clustering regions in these rearrangements (32-35); in our will help to clarify the molecular mechanism of lymphoma- patients, the breakpoints clustered in 4q27-q33, 7q32, and genesis and the nature of the heterogeneity of the disease. 15q24. The association of 7q rearrangements with malignant T-cell diseases has been emphasized (36, 37). T-lymphoma/ ACKNOWLEDGMENTS leukemia cases with rearrangements of 4q and 1Sq were also reported (8-10, 12, 17, 18, 37), although the association be The authors thank Dr. T. Uchiyama, Saitama Medical College, for tween the chromosome abnormalities and the phenotype was providing a sample for chromosome study from Patient N25. We also thank Drs. R. Abe and Y. Hayashi for their cooperation in the chro not mentioned. mosome analysis of some of our earlier cases; Y. Nomoto, K. Fuku- Association of breaks in 6p and T-lymphoma has been re shima, and N. Itami for their expert technical assistance; Dr. S. Naka- ported by Mecucci et al. (38) and us (25). The data presented zawa, Keio University School of Medicine, for immunophenotyping of in this report confirmed the correlation and specified the break lymphoma cells from some patients; and Professor M. Kojima, Tokyo point in 6p21. Band 6p21 contains the major histocompatibility Women's Medical College, and Professor K. Nanba, Hiroshima Uni complex gene cluster (39) and the putative oncogene pirn (40). versity, for reviewing some pathology slides. Future molecular studies will clarify whether or not these genes are involved in the genesis of T-lymphoma with the 6p21 REFERENCES abnormalities. 1. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National T-lymphoma with a break in 14ql 1was found in only 2 cases Cancer Institute sponsored study of classifications of non-Hodgkin's lym- of this series, and we could not evaluate the association of the phomas: summary and description of a working formulation for clinical translocation or inversion involving 14qll with T-cell pheno usage. Cancer (Phila.), 49: 2112-2135, 1982. type (3, 19). Since the great majority of our T-lymphomas had 2. Bloomfield. C. D., Gajl-Peczalska, K. J., FrizzerÃ , G., Kersey, J. H., and Goldman, A. I. 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6775

Nobuo Maseki, Yasuhiko Kaneko, Masaharu Sakurai, et al.

Cancer Res 1987;47:6767-6775.

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