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NEOPLASIA
From the Cell Biology Program and the Departments of
Medicine, Pathology, and Epidemiology and Biostatistics, Memorial
Sloan-Kettering Cancer Center, New York, NY.
Diffuse large B-cell lymphoma (DLBCL), a histologically
well-defined subset of non-Hodgkin lymphoma, is clinically and
genetically heterogenous. By G-banding, most cases showed complex
hyperdiploid karyotypes and diverse cytogenetic abnormalities that
included recurring and nonrecurring translocations, deletions,
duplications, and marker chromosomes. While G-banding provided valuable
leads to identification of specific rearrangements that enabled gene discovery and clinical correlations, many aberrations remained uncharacterized because of their complexity. The molecular cytogenetic technique spectral karyotyping (SKY), on the other hand, enables complete characterization of all aberrations in a tumor cell karyotype and, hence, precise quantitation of chromosome instability. We report
here, for the first time, SKY analysis of a panel of 46 DLBCL cases
previously analyzed by G-banding, ascertained at the Memorial
Sloan-Kettering Cancer Center. This analysis provided a cytogenetic
profile of DLBCL that was characterized by a higher level of
instability, qualitatively as well as quantitatively, compared with
G-banding. Thus, 551 breakpoints were detected by SKY, in contrast to
the 295 by G-banding. Several new recurring breakpoints,
translocations, and regions of gain and loss were identified, which
included 13 breakpoints not previously identified by G-banding,
10 breakpoints that were underrepresented by G-banding, and 4 previously unrecognized translocations: der(14)t(3;14)(q21;q32), t(1;13)(p32;q14), t(1;7)(q21;q22), and der(6)t(6;8)(q11;q11). We
identified new clinical associations involving recurring breakpoints detected by SKY. These studies emphasize the value of SKY analysis for
redefinition of chromosomal instability in DLBCL to enhance gene
discovery as well as clinical correlation analysis.
(Blood. 2002;99:2554-2561) Diffuse large B-cell lymphoma (DLBCL) is the most
common form of non-Hodgkin lymphoma (NHL), representing 40% of all
adult cases, and comprises several entities characterized by genetic, morphologic, and clinical features. This heterogeneity has been suggested to derive from the developmental stage of the B cell at which
it is transformed The cytogenetic features of DLBCL have been partly defined by G-banding
analysis.4 Approximately 50% of cases exhibit chromosomal translocations involving one of the IG gene sites, which
lead to deregulated expression of a variety of genes. The remaining cases display diverse types of chromosomal rearrangements that include
translocations, deletions, and undefined aberrations such as additions
and marker chromosomes.4 The recent introduction of
spectral karyotyping (SKY) has made possible the identification of each
of the human chromosomes by a different color, facilitating precise
identification of all rearrangements in a tumor
karyotype.5 A limited number of hematopoietic tumors such
as multiple myeloma6,7 and acute leukemia8-11
have been studied by SKY. These studies showed that SKY detected a
several-fold increase in random as well as nonrandom chromosomal
aberrations compared with G-banding. So far, there have been no
attempts to examine clinical correlations based on SKY data in
hematopoietic or other neoplasms. There have also been no SKY-based
studies of NHL. Here we report SKY analysis of a panel of 46 DLBCLs
ascertained at the Memorial Sloan-Kettering Cancer Center. We
identified 13 new recurring breakpoints; 4 new recurring
translocations; a number of cryptic, balanced, and unbalanced translocations; and regions of gain and loss. We identified new clinical associations involving recurring breakpoints detected by SKY.
Tumor ascertainment
Cytogenetic and SKY analysis
Fluorescence in situ hybridization analysis Fluorescence in situ hybridization (FISH) with whole chromosome painting probes for chromosomes 1, 3, and 14 (Vysis, Downers Grove, IL) was performed according to manufacturer-supplied protocols. To confirm 14q32 rearrangements, the PAC clone 120H10, derived from the region immediately telomeric to IGHV, was used in FISH analysis.16 For each case, 5 to 13 metaphases were analyzed using the Quips Pathvision (Applied Imaging, Santa Clara, CA).Statistical analysis of data Differences in percentage of variables were tested for significance using the 2-tailed Fischer exact test. Survival times were estimated by Kaplan-Meier analysis and compared by log-rank test. Cytogenetic variables included 32 recurring break sites. Clinical variables included age, sex, performance status, stage, B symptoms, bulky disease, lactate dehydrogenase, extranodal disease, number of extranodal sites, international prognostic index,17 and response. Time to treatment failure was measured from time of initiation of treatment until disease progression. Overall survival was measured from initiation of treatment (45 cases) or the date of diagnosis, if the patient was observed (1 case), until the date last seen.
Clinical and histologic features of patients The clinical and histologic features of the 46 cases with reconfirmed DLBCL at diagnosis are summarized in Table 1. Morphologic variants included 28 centroblastic, 5 plasmablastic, 4 immunoblastic, 3 pleomorphic, and 5 T-cell-rich/histiocyte-rich lymphomas. The 1 case with primary effusion lymphoma (2612) could not be subtyped. Of the 46 cases, 3 (2293, 2473, 1800) were primary mediastinal large B-cell lymphomas. The male:female ratio was 1:1.19 (21 males, 25 females). The age range was 21 to 85 years (median, 57.5). Eight patients had stage I disease, 11 had stage II disease, 10 had stage III disease, and 16 had stage IV disease. Of the 46 patients, 28 were at low or low-intermediate risk, whereas 14 were at high or high-intermediate risk. Clinical data were not available for 1 patient (980), and 3 patients (980, 2358, 2433) were lost to follow-up. All patients, with the exception of cases 2202 and 2627, received anthracycline-containing combination chemotherapy as part of their initial treatment.
Chromosome involvement and breakpoints identified by SKY analysis versus G-banding Figure 1 shows the percentage involvement of each chromosome. With the exception of chromosome 1, all chromosomes were affected more frequently in the SKY analysis than in the G-banding analysis; however, the difference in involvement only of chromosomes 2, 5, 22, and X was significant (P .05).
Figure 2 shows the distribution of
breakpoints, and a representative SKY karyotype with multiple and
cryptic rearrangements is shown in Figure
3A. A total of 551 breakpoints were
identified by SKY, compared with 295 by G-banding. SKY analysis
confirmed 234 (80%) breakpoints identified by G-banding and revised 53 (20%). Most of the revisions comprised breakpoints that were
classified by G-banding as terminal, which were identified by SKY to be
interstitial. Breakpoints on chromosomes 1, 2, 3, 6, and 8 were
misidentified most frequently. In addition, SKY analysis identified 264 new breakpoints, including 60 that could not be precisely assigned to a
band. The 551 breakpoints identified by SKY analysis were located at
171 bands and, of these, 125 (73%) were recurring (
To identify new recurring breakpoints, all breakpoints identified in
SKY and G-banding analyses were compared. Thirteen new recurring
breakpoints were identified by SKY, with 16q11-13 (13%), 12p11, and
11p11 (9% each) as the most frequent (Table
2). Because the number of cases in the
present cohort was small, the 551 breakpoints identified by SKY also
were compared with the 1021 breakpoints identified by G-banding in our
previously reported cohort of 363 consecutively ascertained
DLBCLs.4 All the new recurring sites identified in the
present study by SKY were either nonrecurring or were undetected by
G-banding in this larger cohort.
To determine the effect of therapy on the incidence of breakpoints,
data from treated and untreated cases were compared. The mean number of
breaks per case was higher in treated cases (16) than untreated cases
(9). Most (24 of 32) of the recurring breakpoints were noted to be
affected more frequently in the treated cases; however, the difference
was significant only for breaks at 17q11-21 (P Chromosome structural aberrations identified by SKY analysis versus G-banding Multiple complex structural aberrations (translocations, deletions, duplications, isochromosomes, inversions, insertions, additions, and markers) were present in 85% of the cases in this study. Of the 46 cases with clonal chromosome abnormalities, the G-banded karyotype of only 4 cases remained unchanged after SKY analysis. In the remaining 42 cases, SKY provided additional cytogenetic information. G-banding analysis detected a total of 240 aberrations, of which 98 were undefined (73 additions, 24 markers, and 1 ring chromosome). All the undefined aberrations were resolved by SKY. Of the 240 aberrations, SKY confirmed 74 and revised 166. Of the marker and addition chromosomes detected by G-banding, 75% represented translocations. In addition, SKY identified 79 new aberrations. A total of 211 translocations were identified by SKY. Of these, 64 were new, including 30 that were cryptic. Several of the latter were confirmed by FISH using whole chromosome painting or locus-specific probes (Figure 3B,C).While rearrangements affecting one of the IG gene sites were
the most common aberrations detected by both the techniques, they were
detected at a slightly higher rate by SKY (66%) than by G-banding
(61%) (Table 3). Of the 25 cases with
translocations affecting 14q32 detected by SKY, 6 had t(3;14)(q27;q32),
5 had t(14;18)(q32;21), 4 had t(9;14)(p13;q32), and 1 each had
t(8;14)(q24;q32) and t(8;14;18)(q24;q32;q21), while 10 had other
14q32-associated translocations (Table
4). The incidence of translocations
affecting 14q32 detected by G-banding analysis was the same as that
detected by SKY (25 cases); however, 3 of the 14q32 breakpoints were
misidentified by G-banding. Translocations affecting 22q11 were noted
in 7 cases by SKY, compared with 2 by G-banding. Of the former 7 cases,
3 cases had t(3;22)(q27;q11) and 4 had other 22q11 translocations (Table 4). Translocations involving 2p11 were less frequent and were
detected in 2 cases by SKY alone (Table 4).
Translocations involving 3q27 were the next most frequent after those
affecting the IG gene sites. Eight cases exhibited
t(3;14)(q27;q32) or t(3;22)(q27;q11), and 5 involved other sites (Table
5). Only 9 of these translocations were
detected by G-banding. Translocations affecting 1q11-21 (15%), 1p32-36
(11%), and 1q42-44 (9%) were also common and noted equally in SKY and
G-banding analyses. Of note were 10 other non-IGH sites
identified by SKY that were promiscuously involved in balanced and
unbalanced translocations: 2q31, 12q11-13 (15%), 1p11-13, 2p13, 7q11,
16q11-13, 17q11-21 (13% each), 3p21, 7q22, and 15q13-15 (11% each).
These sites were either undetected or underrepresented in G-banding
analysis.
SKY is known for its ability to unambiguously characterize complex
chromosomal aberrations and thus facilitate identification of new or
hidden recurring translocations. Indeed, 4 new recurring translocations
were identified in 2 cases each (Table 6)
(Figure 3D). The translocations t(3;14)(q21;q32) and t(1;7)(q21;q22)
were also identified by G-banding; the former was nonrecurring.
Interestingly, 3 translocations, t(1;13)(p32;q14), t(1;7)(q21;q22), and
der(6)t(6;8)(q11;q11), were observed only in cases without t(3q27) or
t(14q32). In addition, 2 potentially new recurring translocations were
identified in 2 cases each: t(5;16)(?;q11-12) and t(19;22)(q13;q11-13).
A search in our database revealed another t(14;18)(q32;q21)-negative
follicular large cell lymphoma with a t(19;22)(q13;q13). The ability to
precisely delineate chromosomal abnormalities also facilitated the
correct identification of known specific recurring translocations.
Thus, in 2 cases, SKY revealed the presence of t(3;14)(q27;q32) and t(3;22)(q27;q11), respectively, that were overlooked by G-banding due
to poor morphology. In 3 other cases, t(9;14)(p13;q32) (2 cases)
and t(14;18)(q32;q21) (1 case), identified by G-banding, were revised by SKY and shown to be otherwise.
Gains and losses of chromosomes Resolution of all derived, addition, and marker chromosomes by SKY resulted not only in the detection of a 2-fold increase in the gains and losses but also in their correct identification. Fifty percent of deletions and 11% of translocations identified by G-banding were found to represent translocations and duplications, respectively, by SKY. Figure 4 shows the regions of partial- or whole-arm gains and losses identified by SKY. Gains (89%) were noted more frequently than losses (80%). While gains were noted equally in both treated and untreated groups (90% vs 88%), losses were more frequent in the treated group than the untreated (94% vs 72%). All the chromosomes were affected by gains. Chromosomes frequently involved in gains were 7 (39%), 1 (37%), 3 (35%), 12 (33%), 2 (30%), and 18 (28%). Region of common cytogenetic gain in these chromosomes comprised 7q11, 7q22, 1q11-23, 3q21-29, 12q13-15, 12q22-24, 2q21, 2p13-21, and 18q21-23. Most of the chromosomes also were affected by deletions, with del(6q) (35%) being the most frequent. Five regions of common cytogenetic deletions, in decreasing order of incidence, were observed: 6q23, 6q21, 6q25-27, 6q15, and 6q11-13. Other chromosomes involved in deletions were 2 (22%), 13q (17%), 1 (15%), and 17p (13%). The region commonly deleted on chromosome 13 was 13q22-32. Deletions affecting chromosomes 1 and 2 were highly heterogenous and involved both arms of each chromosome.
Correlation of the recurring breakpoints with clinical features A correlation analysis of recurring breakpoints identified by SKY with clinical features was performed. Of 32 such sites, 5 showed a significant association with one of the clinical features (P .05): 7q11 with female, 3p21 with male, 3q27 with
stage III-IV disease, 3q27 and 2q31 with more than 2 high or
high-intermediate risk, and 2q31 and 7q22 with poor response to
treatment (Table 7). Correlation with
time to treatment failure and overall survival were not performed
because the median follow-up was short.
DLBCL is a histologically well-defined entity that is clinically and genetically heterogeneous. Previous G-banding studies by us and others have shown that most cases are characterized by complex hyperdiploid karyotypes. The types of chromosomal rearrangements are diverse and include translocations, deletions, duplications, and several undefined aberrations such as additions and marker chromosomes.4,12,18-21 This study is the first reported to use SKY to fully characterize the chromosomal rearrangements in a panel of histologically reconfirmed DLBCL. In more than 90% of the cases, SKY provided additional cytogenetic information. Resolution of all the derived, addition, and marker chromosomes by SKY revealed several new recurring breakpoints, translocations, and regions of gains and losses. By SKY, 13 new recurring translocation breakpoints (Xp11, 4p11, 4p14, 5q11, 11p11, 12p11, 16p11, 16q11-13, 17q11, 17q23, 18p11, 18q11, 20q11-13) were detected that were noted as unique occurrences by G-banding (this study and Cigudosa et al4). The frequency of 10 other recurring translocation breakpoints (1p11-13, 2p13, 2q31, 3p21, 7q11, 7q22, 12q11-13, 15q13-15, 17q11-21, 22q11) was higher in SKY analysis compared with G-banding (11%-17% vs 1%-5%).4,12,18-20 Based on G-banding analysis, we have previously shown that translocations involving 14q32 and 3q27 were the most frequent and together affected 50% of cases. Among these, the partner chromosomes involved remained unidentified in 5% to 15% of the cases due to poor morphology or karyotype complexity. SKY unambiguously identified all the partner chromosomes involved in these translocations, and this in turn enabled the detection of a new recurring translocation, t(3;14)(q21;q32). We have previously observed t(3;12)(q27;q22) (case 862) as nonrecurring in our larger G-banded series.4 The identification of a t(3;12)(q27;q22), designated by G-banding as t(3;12;14)(q29;q22;q32) in the present cohort (2541), makes this a recurring translocation. The incidence of the known recurring translocations, t(3;14)(q32;q27), t(14;18)(q32;21), t(3;22)(q27;q11), and t(8;14)(q24;q32), was in keeping with the literature. The incidence of t(9;14)(p13;q32) was comparatively higher in the present cohort and may be due to case selection. Apart from detecting some of these recurring translocations with a higher frequency, SKY also enabled their correct identification. Rearrangements affecting bands 3q27 and/or 14q32 were absent in 39% of the cases. We have previously shown, by G-banding analysis, that this subset is characterized by deletions and numerous unidentified additions.4 SKY facilitated the complete cytogenetic characterization of this subset and identified 3 new recurring translocations, t(1;13)(p32;q14), t(1;7)(q21;q22), and der(6)t(6;8)(q11;q11). We also identified 2 potentially new recurring translocations in this group: t(5;16)(?;q11-12) and t(19;22)(q13;q11-13). A search of our database revealed another t(14;18)(q32; q21)-negative follicular large cell lymphoma with a t(19;22)(q13;q13). Recurring chromosomal changes that lead to gain and/or loss of genetic material constitute important events in both disease transformation and progression.1,22 In this study, SKY identified gains and losses in more than 80% of the cases, a higher frequency of detection than by G-banding. Delineation of all the unbalanced translocations, additions, and marker chromosomes by SKY allowed us to narrow the regions of gain and loss in several chromosomes, namely, gain of 2p13-22, 2q21, 3q27-29, 9p11-24, 13q22-34, 18q21, and 19q11-13 and loss of 6q11-13 and 18p11-13. Although these regions have previously not been identified by G-banding, they have been delineated more precisely by comparative genomic hybridization.22-25 Interestingly, all the cases without translocations of 14q32 or 3q27 showed gains. Gain of 3 (53%), 7q (65%), and 18q21 (41%) and loss of 6q11-13 (59%) were significantly more frequent, suggesting that gain and/or loss of genetic material may play a more proximal role in the development of this subset. Several studies have attempted to correlate cytogenetic findings with
clinical features and/or patient outcome, and the results have been
generally contradictory. Most studies failed to show an association
between the recurring translocations t(3q27)/BCL6, t(14;18)/BCL2, and t(8;14)/MYC and clinical
outcome.26-31 In some studies, changes such as trisomies
of chromosomes 2/2p, 3/3p, 5, 6, or 18, monosomy 7, del(6q),
abnormalities of 17 [ The SKY studies reported here and the previously reported comparative genomic hybridization studies by us and others22,23,25 present a picture of impressive genetic instability of DLBCL manifested at the cytogenetic level. Much of it remained undetected by conventional G-banding studies that most likely contributed to the conflicting reports in the literature, especially in the clinical correlation analyses. Therefore, the studies reported here emphasize the need for redefinition of chromosomal instability in DLBCL and other NHL subsets applying modern molecular cytogenetic techniques, together with conventional G-banding, for gene discovery as well as meaningful clinical correlations.
We thank Jane Houldsworth for careful reading of the manuscript and constructive criticism.
Submitted July 27, 2001; accepted November 29, 2001.
Supported by the National Cancer Institute grants CA34775, CA66999, and CA80814 (R.S.K.C.).
G.N. and P.H.R. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: R. S. K. Chaganti, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: chagantr{at}mskcc.org.
1. Chaganti RS, Nanjangud G, Schmidt H, Teruya-Feldstein J. Recurring chromosomal abnormalities in non-Hodgkin's lymphoma: biologic and clinical significance. Semin Hematol. 2000;37:396-411[CrossRef][Medline] [Order article via Infotrieve]. 2. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503-511[CrossRef][Medline] [Order article via Infotrieve].
3.
Lossos IS, Alizadeh AA, Eisen MB, et al.
Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas.
Proc Natl Acad Sci U S A.
2000;97:10209-10213 4. Cigudosa JC, Parsa NZ, Louie DC, et al. Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas. Genes Chromosomes Cancer. 1999;25:123-133[CrossRef][Medline] [Order article via Infotrieve]. 5. Schrock E, du Manoir S, Veldman T, et al. Multicolor spectral karyotyping of human chromosomes. Science. 1996;273:494-497[Abstract].
6.
Rao PH, Cigudosa JC, Ning Y, et al.
Multicolor spectral karyotyping identifies new recurring breakpoints and translocations in multiple myeloma.
Blood.
1998;92:1743-1748
7.
Sawyer JR, Lukacs JL, Munshi N, et al.
Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping.
Blood.
1998;92:4269-4278
8.
Rowley JD, Reshmi S, Carlson K, Roulston D.
Spectral karyotype analysis of T-cell acute leukemia.
Blood.
1999;93:2038-2042 9. Mohr B, Bornhauser M, Thiede C, et al. Comparison of spectral karyotyping and conventional cytogenetics in 39 patients with acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2000;14:1031-1038[CrossRef][Medline] [Order article via Infotrieve]. 10. Kerndrup GB, Kjeldsen E. Acute leukemia cytogenetics: an evaluation of combining G-band karyotyping with multi-color spectral karyotyping. Cancer Genet Cytogenet. 2001;124:7-11[CrossRef][Medline] [Order article via Infotrieve]. 11. Elghezal H, Le Guyader G, Radford-Weiss I, et al. Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis. Genes Chromosomes Cancer. 2001;30:383-392[CrossRef][Medline] [Order article via Infotrieve]. 12. Offit K, Jhanwar SC, Ladanyi M, Filippa DA, Chaganti RS. Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment. Genes Chromosomes Cancer. 1991;3:189-201[Medline] [Order article via Infotrieve].
13.
Offit K, Wong G, Filippa DA, Tao Y, Chaganti RS.
Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations.
Blood.
1991;77:1508-1515
14.
Harris NL, Jaffe ES, Diebold J, et al.
The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997.
Ann Oncol.
1999;10:1419-1432 15. Mitleman F, ed. ISCN: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1995. 16. Chen W, Palanisamy N, Schmidt H, et al. Deregualtion of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. Oncogene. 2001;20:7686-7693[CrossRef][Medline] [Order article via Infotrieve].
17.
The International Non-Hodgkin's Lymphoma Prognostic Factors Project.
A predictive model for aggressive non-Hodgkin's lymphoma.
N Engl J Med.
1993;329:987-994
18.
Levine EG, Arthur DC, Frizzera G, Peterson BA, Hurd DD, Bloomfield CD.
There are differences in cytogenetic abnormalities among histologic subtypes of the non-Hodgkin's lymphomas.
Blood.
1985;66:1414-1422 19. Juneja S, Lukeis R, Tan L, et al. Cytogenetic analysis of 147 cases of non-Hodgkin's lymphoma: non-random chromosomal abnormalities and histological correlations. Br J Haematol. 1990;76:231-237[Medline] [Order article via Infotrieve].
20.
Schouten HC, Sanger WG, Weisenburger DD, Anderson J, Armitage JO.
Chromosomal abnormalities in untreated patients with non-Hodgkin's lymphoma: associations with histology, clinical characteristics, and treatment outcome. The Nebraska Lymphoma Study Group.
Blood.
1990;75:1841-1847
21.
Johansson B, Mertens F, Mitelman F.
Cytogenetic evolution patterns in non-Hodgkin's lymphoma.
Blood.
1995;86:3905-3914
22.
Rao PH, Houldsworth J, Dyomina K, et al.
Chromosomal and gene amplification in diffuse large B-cell lymphoma.
Blood.
1998;92:234-240
23.
Monni O, Joensuu H, Franssila K, Knuutila S.
DNA copy number changes in diffuse large B-cell lymphoma
24.
Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S.
BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma.
Blood.
1997;90:1168-1174 25. Palanisamy N, Abou-Elella AA, Chaganti SR, et al. Similar patterns of genomic alterations characterize primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma. Genes Chromosomes Cancer. 2002;33:114-122[CrossRef][Medline] [Order article via Infotrieve].
26.
Romaguera JE, Pugh W, Luthra R, Goodacre A, Cabanillas F.
The clinical relevance of t(14;18)/BCL-2 rearrangement and DEL 6q in diffuse large cell lymphoma and immunoblastic lymphoma.
Ann Oncol.
1993;4:51-54 27. Gascoyne RD. Pathologic prognostic factors in diffuse aggressive non-Hodgkin's lymphoma. Hematol Oncol Clin North Am. 1997;11:847-862[CrossRef][Medline] [Order article via Infotrieve].
28.
Bastard C, Deweindt C, Kerckaert JP, et al.
LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients.
Blood.
1994;83:2423-2427 29. Tang SC, Visser L, Hepperle B, Hanson J, Poppema S. Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin's lymphoma: an analysis of 83 cases. J Clin Oncol. 1994;12:149-154[Abstract].
30.
Kramer MH, Hermans J, Wijburg E, et al.
Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.
Blood.
1998;92:3152-3162
31.
Vitolo U, Gaidano G, Botto B, et al.
Rearrangements of bcl-6, bcl-2, c-myc and 6q deletion in B-diffuse large-cell lymphoma: clinical relevance in 71 patients.
Ann Oncol.
1998;9:55-61 32. Levine EG, Arthur DC, Frizzera G, et al. Cytogenetic abnormalities predict clinical outcome in non-Hodgkin lymphoma. Ann Intern Med. 1988;108:14-20. 33. Yunis JJ, Mayer MG, Arnesen MA, Aeppli DP, Oken MM, Frizzera G. bcl-2 and other genomic alterations in the prognosis of large-cell lymphoma. N Engl J Med. 1989;320:1047-1054[Abstract]. 34. Cabanillas F, Pathak S, Grant G, et al. Refractoriness to chemotherapy and poor survival related to abnormalities of chromosomes 17 and 7 in lymphoma. Am J Med. 1989;87:167-172[Medline] [Order article via Infotrieve].
35.
Schlegelberger B, Zwingers T, Harder L, et al.
Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group.
Blood.
1999;94:3114-3120
36.
Whang-Peng J, Knutsen T, Jaffe ES, et al.
Sequential analysis of 43 patients with non-Hodgkin's lymphoma: clinical correlations with cytogenetic, histologic, immunophenotyping, and molecular studies.
Blood.
1995;85:203-216
© 2002 by The American Society of Hematology.
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  S. Bea, A. Zettl, G. Wright, I. Salaverria, P. Jehn, V. Moreno, C. Burek, G. Ott, X. Puig, L. Yang, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction Blood, November 1, 2005; 106(9): 3183 - 3190. [Abstract] [Full Text] [PDF]
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 S. Bea, L. Colomo, A. Lopez-Guillermo, I. Salaverria, X. Puig, M. Pinyol, S. Rives, E. Montserrat, and E. Campo Clinicopathologic Significance and Prognostic Value of Chromosomal Imbalances in Diffuse Large B-Cell Lymphomas J. Clin. Oncol., September 1, 2004; 22(17): 3498 - 3506. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
ie, germinal center or post-germinal center B
cell
2 cases). In
the case of G-banding, the 295 breakpoints were located at 144 bands
and, of these, 63 (44%) were recurring. While the number of recurring
sites noted in more than 10% of the cases was 32 in SKY analysis, it
was only 10 in G-banding. With the exception of 1q32, 6q23, 8q24,
14q32, and 19q13, all the recurring sites (27) were noted to be
involved more frequently in SKY analysis than in G-banding. Breaks at 2 sites, 16q11-13 and 17q11-21, were significantly more frequent in SKY
analysis (P 
represents 10 breakpoints; 
represents a single
breakpoint misidentified by G-banding; 
17, del(17p), i(17q)], and breaks or
duplications of 1q have been shown to correlate with advanced stage
disease and poor prognosis.