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6q Deletions Define Distinct Clinico-Pathologic Subsets
of Non-Hodgkin’s Lymphoma
By K. Offit, N.Z. Parsa, G. Gaidano, D.A. Filippa, D. Louie, D. Pan, S.C. Jhanwar, R. Dalla-Favera, and R.S.K. Chaganti
Commonly observed in lymphoid neoplasms, deletions of
6q have been correlated with histologic and clinical subsets of non-Hodgkin’s lymphoma (NHL). Our recent analysis of loss of heterozygosity of 6q loci in NHL showed t w o
regions of minimal molecular deletion (RMD), an RMDl at
6q25-27 and an RMDZ at 6q21-23. To establish correlations between these RMDs and regions of minimal cytogenetic deletions (RCDs) on 6q. and t o define associations
between RCDs and clinico-pathologic features, we have
analyzed chromosome 6 abnormalities in 459 consecutively ascertained, karyotypically abnormal cases of NHL.
Among these, 126 (27.5%)cases had structuralabnormalities of chromosome 6, of which 94 were deletions. Analysis of these deletions identified three RCDs. An RCDl encompassing 6q25-27 was seen in 45 intermediate-grade
NHL. An RCDP at 6q21 was observed in 11 high-grade
NHL, 9 of which were of the immunoblastic subtype. An
RCD3 at 6q23 was noted in 1 8 low-grade NHL lacking a
t(l4;18) translocation. Of these 1 8 cases, 1 2 were small
lymphocytic NHL and, in 2 of these, del(6q) was the sole
karyotypic abnormality. In 20 cases of low-grade NHLwith
t(14;18), the deletions spanned both RCDl and RCD3.
These data suggested the presence of at least 3 tumor
suppressor genes on 6q within RCDl , RCDP, and RCD3;
they also showed associations between RCDs in 6q and
subsets of NHL, including a specific association between a
group of well-differentiated lymphoid neoplasms and
RCDB. The apparent heterogeneity of breakpoints when all
NHLs are considered together explains the inability of previous studies to reliably establish correlations between recurring 6q deletions and histologic and clinical features of
NHL.
0 1993 by The American Society of Hematology.
0
clature (ISCN, 199 l ) . I 4 Of the 781 specimens, 480 specimens from
459 patients had clonal chromosomal abnormalities. Among the
same 459 specimens, 126 (27.5%)showed structural abnormalities
of chromosome 6, of which 94 were deletions. These 94 cases with
del(6q) comprised the dataset for the analysisreported here. A summary of cytogenetic abnormalities in 46 of these 94 cases have been
previously reported by US.'^"^"
For the purpose of this analysis, we defined deletions by the following criteria. Whenever 6q ended in a dark band without a recognizable pale end, the deletion was scored as terminal. In the case of
deletions affectingthe 6q24-27 region, when a pale band was recognized at the terminus, the deletion was scored as interstitial with the
terminal pale band representing 6q27 or part of it. In such cases,
loss of 6q24 and/or 6q26 could easily be recognized because of the
positive G-staining of these two bands. Representativeillustrations
of interstitial deletions are shown in Fig 1. Recumng deletions were
analyzed to identify the RCDs encountered in subsets of cases. As
mentioned previously, our molecular analysis identified the limit of
BSERVED IN up to a third of the cases, structural
abnormalities of chromosome 6 are among the most
common recurring karyotypic abnormalities in non-Hodgkin’s lymphoma (NHL).’ The frequently encountered 6q
deletions in these tumors have been inconsistently correlated with clinical features of the disease, as well as with
tumor
Recurring 6q deletions have also been
observed in other hematologic and solid tumors and have
suggested the existence of one or more tumor suppressor
genes (TSGs).*-’*Recently, based on an analysis of loss of
heterozygosity(LOH) using a panel of probes mapped to 6q,
we showed two regions of minimal molecular deletion
(RMD) in NHL: an RMDl at 6q25-27 and an RMDZ at
6q21-23.’’ Because of the limited sample sizes of all previous cytogenetic and molecular series, it was not possible to
establish associationsbetween specific 6 s deletions and subsets of NHL. In the current series of 126 consecutively
ascertained NHL with structural abnormalities of chromosome 6, we identified three regions of minimal cytogenetic
deletion (RCD) suggesting the involvement of at least three
TSGs and noted new correlations between RCDs and clinical, histologic, and immunophenotypic features of tumors.
Thus, a subset of low-grade NHL were associated with an
RCD at 6q23 (RCD3) and subsets of high-grade and intermediate-grade NHL were associated with two additional
RCDs, RCD 1 and RCD2, respectively. These observations
form the basis for further definition of RMDs, eventually
leading to isolation and characterization of TSGs and correlation of their loss with histologic and clinical features of
NHL.
MATERIALS AND METHODS
Between January 1984 and December 1991, 78 I consecutively
ascertained specimens of histologically confirmed NHL seen at Memorial Hospitalwere subjectedto cytogeneticanalysis.Biopsy material was divided for histopathologic, cytogenetic, and immunophenotypic/immunogenotypic analyses, which were performed as
previously described.13Karyotypes were defined and described according to the International System for Human Cytogenic NomenBlood, Vol82, No 7 (October 1), 1993: pp 2157-2 162
From the Cell Biology and Genetics Program, the Departments of
Medicine and Pathology, and the Cytogenetics Service, Memorial
Sloan-Kettering Cancer Center; and the Division of Oncology, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY.
Submitted April 15, 1993; accepted June I , 1993.
Supported by Grants No. CA-08748, CA-34775, CA-20194, CA44029, and CA-44029 from the National Institutes of Health, Bethesda, MD; the Matheson Foundation; and the Lymphoma Foundation. G.G. is supported by a Fellowship for AIDS Research from
Instituto Superiore di Sanith (Roma, Italy). K.O. is supported by a
Clinical Oncology Career Development Award from the American
Cancer Society.
Address reprint requests to K. Ofit, MD, MPH, Memorial SloanKettering Cancer Center, Box 192, 1275 York Ave, New York, NY
10021.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 I993 by The American Society of Hematology.
0006-4971/93/8207-0004$3.00/0
2157
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OFFIT ET AL
2158
C
the distal deletion in this region (6q25-27) to be 6q27 (RMDI).
Therefore, to define the molecular limit of deletion in cases for
which the distal limit of the deletion was scored as 6q25 by cytogenetic analysis, LOH was assayed using restriction fragment length
polymorphisms (RFLPs) mapped to 6q27. For this, Southern blot
hybridization analysis was performed on 5 p g of tumor DNA, as
previously described," using two highly polymorphic probes
(>90% heterozygosity in normal DNA) mapped to 6q27: D6S132
and D6S133 (gift of Dr G. Vergna~d).".~~
Cytogenetic, histologic,and clinical correlations were performed
on subsets of low-, intermediate-, and high-grade NHL as defined
by the International Working Form~lation.~~
The cases were further stratified according to presence or absence of f(14;18)
(q32;q21) because this translocation has been shown to be a frequent aberration in low-grade (>70%) and intermediate-/highgrade (>25%) NHL.' Comparisonsof histologicand clinical subsets
with 6q deletions were performed using the method of inferences
from proportions." Survival analysis, using the method of Kaplan
and Meier?' was performed only on the subset of cases of diffuse
lymphoma with a large cell component (DLLC),as describedpreviously.'S
RESULTS
Interstitial (45 cases) or terminal (40 cases) deletions of6q
were noted in 85 cases: in 9 cases, poor banding morphology
precluded precise identification of the deletion breakpoints.
Whereas there was no single region deleted in every case,
each of the 85 cases showed deletion of either band 6q2 1 or
6q25, or both. RCDs were defined by comparison of cases
stratified according to histologic grade and presence or absenceoft(14;18).
The largest histologic subset was comprised of 45 intermediate-grade NHL with and without the t( 14;18) translocation (Fig 2). This subset included 31 diffuse large cell
(DLC), 8 diffuse mixed cell (DMC), 5 follicular large cell
(FLC), and I diffuse small cleaved cell (DSC) NHL. B-cell
immunophenotype/genotype was shown in 42 of the tumors: 2 DLC were of T-cell lineage and 1 DMC was a nullcell NHL. The single chromosomal band most commonly
deleted in this subset was 6q25, here designated as RCDl
(Fig 2). The same RCD was also noted when 28 of these
intermediate-grade NHL cases, analyzed at the time ofdiagnosis, were compared with the remaining 17 cases analyzed
at the time of relapse (posttreatment).
In this ascertainment, evidence for transformation from a
lower grade was shown in 8 of 56 cases of intermediate-/
high-grade NHL with (nos. 159,3 16, and 501) and without
(nos. 66, 158,746,766, and 824) the t( 14;18) translocation.
The common deleted segment in these cases extended from
6q in NHL. (A) deI(6Nq23q25):
(B) de1(6)(q21q27); (C) del(6)
(ql5q27).
6q23 to 6q25. In contrast, among 1 I cases of high-grade
NHL, of which IO were immunoblastic (IMB) and I lymphoblastic (LYB), an RCD here designated as RCD2 was
identified at 6q21 (Fig 3). The LYB NHL and one of the
IMB tumors were of T-cell lineage: another IMB tumor was
null cell by immunophenotypic/genotypicanalysis. The remaining eight tumors in this subset were of Bcell lineage.
A del(6q) was observed in 18 cases of low-grade NHL
without a t(14;18) translocation. In this subset, an RCD
here designated as RCD3 was identified at 6q23 (Fig 4). This
group included a subset of 12 small lymphocytic (sm lym)
NHL, of which 7 were of chronic lymphocytic leukemia
(CLL) subtype, and 5 were of plasmacytoid (pl) subtype. In
2 of these cases (nos. 1000 and 1046), the del(6q) was the
only karyotypic abnormality; both cases were classified as
sm lym NHL of CLL type. In the remaining cases, del(6q)
was seen in association with additional chromosomal abnormalities.
A del(6q) was also observed in 20 low-grade NHL, with a
t(14;18) translocation. The RCD in 19 of these cases
spanned the region 6q23-27, which included the regions
RCDl and RCD3 (Fig 5). In case no. 732, the deletion did
not include RCD3, but included RCD2; this case was one of
a subset of t(3;22)(q27;ql1) NHL which were included in a
previous report.'6
The distal limits of RCDl determined here by cytogenetic
analysis (6q25) and RMD 1 previously determined by RFLP
analysis (6q27)'* unexpectedly were different. To establish
if this discrepancy was attributable to real differences in the
limits of the deletions or to a complex nature of the lesion
that resulted in inconsistent cytogenetic resolution of the
distal deletion break, we subjected cases with a distal cytogenetic break at 6q25 to RFLP analysis using the two highly
polymorphic probes, D65132 and D65133, which have
been mapped to 6q27. These comprised 8 cases of intermediate-grade NHL with or without t(14;18) (nos. 159, 430,
84 I , 843, I04 I , I 163, 1 172, and 1230) and 5 cases of lowgrade NHL with t(14;18) (nos. 826, 846, 975, 1024, and
1 125) (Figs 2 and 5). DNA for study was available from 5 of
the intermediate-grade tumors and 4 of the low-grade lesions. Southern blot analysis showed a loss in intensity of
one allele compared with the other, indicating deletion in
6q27 in 5 cases(nos. 826,843,1125, I172,and 1230; Fig6).
Alleles of intensity comparable with that in normal DNA,
indicating no loss, were seen in the remaining 4 cases (nos.
430,946,975, and 1 163). However, histologic and immunohistochemical analysis of these cases showed infiltrates of
large numbers (20% to 60%) of reactive T cells (nos. 430,
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6a DELETIONS IN NHL
P
21 59
22
21.3
1-
RCDl
._I
Fig 2. Deletion map of 45 cases of intermediate-grade NHL. An RCD (RCD1)was identified at 6q25 by cytogenetic analysis (indicated by
solid line in the bracket), and extended to 6q27 (indicated by broken line in the bracket) by RFLP analysis. *Cases showing t(14;18)
(q32:q21).
946, and 1163) in the setting of extensive necrosis, skeletal
muscle invasion (no. 430), or focal sclerosis(no. 946). Therefore, the failure of the RFLP analysis to detect LOH in these
4 cases is considered most likely to be attributable to contaminating non-neoplastic cells in the tissue biopsy. Thus,
where informative, the deletions in these cases extended to
6q27; therefore, we concluded that the distal limit of RCD 1
was 6q27, rather than 6q25, equating RCDl with RMD1.
The median survival of the 36 DLLC with cytogenetic
analysis at the time of diagnosis was not reached. The median survival was only 2 1 months for the subset of 7 DLLC
cases that showed only RCD 1, compared with median not
reached for 24 cases that showed both RCDl and RCD2 (P
= .008). These subsets did not differ in median age or LDH.
The clinical behavior of low-grade NHL with 6q deletion
was typical for this histology, with a median survival not yet
reached at the time of last follow-up. There was no adverse
prognostic impact of presence of the t( 14;18) translocation
in this subset.
DISCUSSION
P
Deletions of chromosome 6 have been observed in many
types of tumors, notably acute lymphoblastic leukemia
21.3
21.2
J
21 3
21 2
cen
I+
-
RCD2
11
12
13
14
15
16
21
q
22
1-C RCD3
23
24
25
26
twr
-27
b
Fig 3. Deletion map of 11 cases of high-grade NHL. An
RCD (RCDZ) was identified at 6q21. *Cases showing a
t(l4;18)(q32;q21).
Fig 4. Deletion map in 18 cases of low-grade NHL without
t(14;18)(q21;q32). An RCD (RCD3) was identified at 6q23.
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OFFIT ET AL
2160
6RCDlI RCD3
Fig 5. Deletion map in 20 cases of low-grade NHL with
t(14;18). The RCD spanned 6q23-6q25 (upper bracket) by cytogenetic analysis and 6q23-6q27 (lower bracket) by RFLP analysis
(RCD1 and RCD3). Some areas of the biopsy specimen of case
1 125 showed evidence of transformation to a diffuse large cell tumor. *Case 7 3 2 showed t(3;22)(q27;q21).
(ALL), malignant melanoma, renal cell carcinoma, and salivary gland adenocarcinoma.8-’I The frequency of del(6q)
ranged from 14% to 31% in six large series of NHL,’ and
these deletions have been associated with the t( 14; 18) transl~cation.~*’*~
The most frequently deleted segment of chromosome 6 noted in a prior large series included the region
6q2 1->ter, with no case of interstitial deletion identified.7
However, interstitial deletions of 6q, observed in half of our
cases, have been documented in other large series of
NHL23.24and have been reported to comprise the majority
of 6q deletions in ALL.* Del(6q) has previously been reported as the solitary karyotypic abnormality in four cases
of NHL.25-2*
The molecular and histologic correlations of the three
RCDs identified in this study are summarized in Table 1.
These data provide a framework for the interpretation of
previous attempts at histologic, clinical, and molecular
9.4 -
9.4 -
6.6 -
6.6
-
-
4.4 -
2.3 2.0 1.35 1.07 0.87 -
2.3 2.0 1.35 1.07 0.87 -
4.4
correlations of del(6q) in NHL and other lymphoid neoplasms. Thus, the association of RCDZ with immunoblastic
NHL observed by us may account for the association of
del(6q) with this histologic subtype reported in an earlier
series7; however, none of the nine cases of immunoblastic
NHL in this series with del(6q) exhibited interstitial deletions, thereby complicating the interpretation of the data.
An interstitial deletion encompassing RCDZ was observed
as the sole karyotypic abnormality in a single case of highgrade NHL previously reported.27
Interestingly, among the t( 14;18) carrying low-grade
NHL with del(6q), deletions encompassing both RCDl and
RCD3 were seen in this study, whereas intermediate-/highgrade lesions with evidence of histologic transformation
from a lower grade also showed these same regions of deletion. Therefore, the association of large 6q deletions with
t( 14; 18)-bearing low-grade and transformed NHL, if confirmed by further studies, may comprise a specific marker
for tumor progression, as was suggested previously.2 As
such, these deletions were distinct from the subset of highgrade lesions showing RCDZ (see above). The correlations
between RCDl and RCDZ deletions and intermediate- and
high-grade NHL, respectively, appeared to be independent
of B-cell or T-cell lineage.
In this series, we have identified a specific association
between RCD3 and low-grade NHL without the t( 14; 18)
translocation. The del(6q) in this group, presenting either as
the sole karyotypic abnormality or accompanied by other
aberrations, was associated with a subset of diffuse lowgrade lymphocytic tumors with or without plasmacytoid
features. Subsets of sm lym NHL have been associated with
t(9;14)(pI3;q32)l7 or trisomy 3,” although the majority of
cases of this histologic subtype have previously not been
associated with a recurring cytogenetic abnormality. The
observation of del(6q) as the sole karyotypic abnormality in
two sm lym tumors in this series and in another reported
case with RCD326suggests an important role for this abnormality in the pathogenesis of these low-grade tumors.
Fig 6. Analysis of LOH in the
6q27 region in selected cases
of NHL with RCDl and 6q25
distal break. Genomic DNAs
were digested with (A) Haelll or
(6) Pvull and subjected to
Southem blot analysis using
highly polymorphic probes (A)
D6S132 and (B) D6S133.
which mapped to 6q27. Cases
1230. 843. 1172, 1125. and
8 2 6 were scored as positive for
deletion, based on the identification of only one allelic band or
allelic bands of unequal intensities, the latter due to samples
containing contaminating normal cells. N, normal (nontumor)
DNA.
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2161
6q DELETIONS IN NHL
Table 1. Correlation of RCD and RMD in 6q With t(14;18)
Translocation and Histologic Subsets of NHL
RCD
RMD
Chromosomal
Location
RCDl
RCD2
RCD3
RCD1-3
RMDl
RMD2
RMD3’
RMD1-3
6q25-27
6q2 1
6q23
6q23-27
Correlation
With
Histologic
Subset
t(l4;18)
Intermediate grade
High grade
Low grade
Low grade
+/+/~
+
Postulated.
The histologic correlations of del(6q) in high grade NHL
presented here may also be considered in conjunction with
patterns of deletion reported in acute and chronic lymphoid
leukemias. All 45 cases of ALL with del(6q) in a large singleinstitution series showed a common deleted band at 6q2 1
suggesting a link between ALL and RCD2 observed by us in
high-grade NHL. In contrast, in CLL, five cases with del(6q)
as the only karyotypic abnormality have been reported, the
deleted regions in these cases were consistent with the
RCD3 observed here.29-32Although the most frequent cytogenetic abnormality in CLL is trisomy 12, 4% of CLL in
large series showed del(6q), albeit rarely as a solitary abnormality.33-35
The large number of cases in this cytogenetic series enabled identification of clinico-pathologicsubsets associated
with RCDs. Two of these RCDs corresponded to RMDs
previously identified by us by LOH analysis, namely, RCDl
(=RMDl) and RCD2 (=RMD2). A third, RCD3, found
exclusively in the subset of low-grade NHL without the
t( 14; 18) translocation, suggested an additional RMD3. Because of the overlap of RCDl and RCD3 in low-grade NHL
with t( 14; 18), the resolution of these two regions will require
further investigation using appropriate DNA markers. The
ultimate goal of mapping RCD-RMD lesions is to facilitate
isolation of candidate TSGs at these sites. Our studies of 6q
deletions in NHL have identified at least three such sites of
candidate TSGs. An understanding of the significance of
these TSGs in the normal and abnormal proliferation of
lymphoid, and possibly other, cell types awaits their isolation and characterization.
,’
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1993 82: 2157-2162
6q deletions define distinct clinico-pathologic subsets of nonHodgkin's lymphoma
K Offit, NZ Parsa, G Gaidano, DA Filippa, D Louie, D Pan, SC Jhanwar, R Dalla- Favera and RS
Chaganti
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