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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1773-1781
Frequent Methylation Silencing of p15INK4b
(MTS2) and p16INK4a (MTS1)
in B-Cell and T-Cell Lymphomas
By
Audrey S. Baur,
Phil Shaw,
Nathalie Burri,
Françoise Delacrétaz,
Fred T. Bosman, and
Pascal Chaubert
From Institut Universitaire de Pathologie, Lausanne, Switzerland.
 |
ABSTRACT |
The methylation status of p15INK4b
(MTS2), p16INK4a (MTS1) and
p14ARF (p16 ) was
analyzed in 56 lymphomas by restriction-enzyme related polymerase chain
reaction (PCR) (REP), methylation-specific PCR (MSP), and bisulfite
genomic sequencing (BGS). Methylation of the p15 and
p16 genes was detected, respectively, in 64% and 32% of the
B-cell lymphomas, in 44% and 22% of the T-cell lymphomas, and in none
of the 5 reactive lymph nodes analyzed. Both p15 and p16 genes were methylated more often in the high-grade (78%
and 50%, respectively) than in the low-grade B-cell lymphomas (55% and 21%, respectively). For 5 cases, mapping of the methylated CpGs of
the p16 promoter region confirmed the results of REP and MSP.
In addition, a large variation in the methylation patterns of
p16 exon 1 was observed, not only from one lymphoma to another, but also within a given tumor. Methylation of p15 and
p16 was associated with an absence of gene expression, as
assessed by reverse transcription-PCR. The p14 gene was
unmethylated and normally expressed in all 56 tumors. We found no
mutations of p15, p16, or p14 in any of the 56 lymphomas. Our results suggest a role for p15 and p16
gene methylation during lymphomagenesis and a possible association
between p15 and p16 inactivation and aggressive transformation in B-cell and T-cell lymphomas.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
UNCONTROLLED PROLIFERATION of tumor cells
in lymphoma, as in other malignancies, is thought to result from a
deregulation of 2 main pathways of cell-cycle control: the p53/p21 and
p16/Rb pathways. Wild-type p53 induces transcription of the
cyclin-dependent kinase (CDK) inhibitor
p21WAF1.1 The lack of
functional p53 protein, due to mutation or deletion of the gene,
results in reduced p21 protein levels, preventing the association of
p21 with cyclin-CDK complexes, which leads to cell-cycle activation.
The Mdm2 protein can bind to and inactivate the transcriptional
activity of p53, abrogating its antiproliferative effect.2
In addition, Mdm2 targets the p53 protein for rapid degradation.3 Therefore, Mdm2 overexpression may have the
same biological consequences that p53 mutations have on cell
proliferation.4,5 Mdm2, p53, and p21 gene
alterations are relatively rare in hematological malignancies,6-13 suggesting that deregulation of the
p53/p21 pathway does not play a central role in the genesis of these tumors.
Phosphorylation of pRb by cyclin D-CDK 4/6 complexes or Rb gene
mutations lead to dissociation of the Rb-E2F complex and subsequent entry of the cell into the S phase. The
p16INK4a (MTS1) tumor suppressor
gene product14,15 acts as a negative regulator of cellular
proliferation by interacting with CDK4 and inhibiting its kinase
activity.16 In the absence of functional p16 protein, CDK4
binds to cyclin D and phosphorylates pRb, which stimulates entry into
the S phase. The p16 gene is inactivated by mutations,
homozygous deletions, or gene methylation in many tumors of diverse
origin.17-19 The p16 locus encodes a second
protein, referred to as p14ARF, p19ARF (mice),
ORF2, or p16, resulting from a distinct exon 1 (exon 1) spliced
to the second shared exon of p16.20-22
The overexpression of p14 protein induces cell-cycle arrest in
mammalian fibroblasts.20 The recently characterized
p14 promoter23 is located within a CpG island and
has been found methylated in several colon cancer cell lines.
p16 and p14 (p19ARF) null
mice develop diverse types of cancer including, notably, lymphomas.15,24 Recently, it has been shown that p14
promotes the rapid degradation of Mdm2, leading to stabilization and
accumulation of p53.5,25 Thus, p14 gene
inactivation might be one way to deregulate cell-cycle control through
disruption of the p53/p21 pathway.
Another mechanism deregulating the cell cycle in neoplasia involves the
p15INK4b (MTS2) gene. p15
displays high homology to p16, maps to the same region of
chromosome 9, acts as inhibitor of CDK4 and 6,26 and has
been proposed to have a tumor suppressor role.27 It is
transcriptionally activated by transforming growth factor-
(TGF-). Homozygous deletions of the p15/p16 locus are found
in a high proportion of acute lymphoblastic
leukemias,6-7,28-35 adult T-cell
leukemias,36,37 and chronic myeloid
leukemias.38 Only a few studies have analyzed p15
and p16 gene alterations in lymphomas. Homozygous deletions involving p15 and/or p16 are found in a low proportion
(0% to 19%) of B-cell lymphomas,39-45 where they seem to
be associated with progression toward high-grade
lesions.46,47 Hemizygous allele loss (loss of
heterozygosity) of these 2 genes is somewhat more frequent than
complete loss,46,48 but mutations are rarely observed.29,39,41-43,47,48 Methylation of p15
and/or p16 has been reported in several types of
lymphomas,45 particularly in mucosa-associated lymphoid
tissue (MALT) lymphomas, multiple myelomas, mantle cell
lymphomas, Burkitt's lymphomas, and anaplastic large cell
lymphomas.49-54
In the present work, we studied p15, p16, and p14
methylation status in human lymphomas to verify the role of methylation as a gene-silencing mechanism involved in lymphomagenesis. We specifically investigated the association of gene methylation with
tumor grade and analyzed intra- and inter-tumor variations in the
patterns of methylation.
| |
MATERIALS AND METHODS |
Histopathological analysis.
Biopsy material from 56 non-Hodgkin's lymphomas (NHLs), as well as 5 nonspecific reactive lymphadenopathies from the files of the Department
of Pathology of the University Hospital of Lausanne (Switzerland), was
studied. Snap-frozen tissue was available for DNA extraction of all cases.
Morphological and immunophenotypical analysis was performed on
formalin-fixed paraffin-embedded material. The cases were classified according to the Revised European American Lymphoma (REAL)
classification55 and to the updated Kiel classification for
NHLs.56 The series comprised of 47 B-cell lymphomas (BCL)
and 9 T-cell lymphomas (TCL). The BCL included 8 chronic lymphocytic
leukemia/small lymphocytic lymphomas, 6 mantle cell lymphomas, 1 splenic marginal zone lymphoma with villous lymphocytes, 14 follicle
center cell lymphomas, 13 diffuse large B-cell lymphomas (9 centroblastic, 2 immunoblastic, 2 primary mediastinal), 1 T-cell rich
BCL, 2 high-grade B-cell Burkitt-like lymphomas, and 2 Burkitt's
lymphomas. According to the updated Kiel classification, 29 BCL were
low grade and 18 were high grade. The TCL included 7 peripheral TCL
(PTCL) and 2 anaplastic large cell lymphomas (ALCL).
For the assessment of methylation status and mRNA expression of
p15, p16, and p14, snap-frozen tissue was used.
Hematoxylin and eosin (H&E) sections of the frozen
specimens used for DNA and RNA extraction were examined to ascertain representativity.
Methylation analysis of p15, p16, and p14.
The methylation status of p15, p16, and p14 exon 1 was
determined by restriction enzyme-related polymerase chain reaction (PCR) (REP), as previously described.57 Genomic DNA samples were individually digested with 4 methyl-sensitive (Kspl,
Hpall, Nael, and Eagl) and with 1 non-methyl-sensitive (Mspl) restriction enzyme, extracted with
chloroform/phenol, and precipitated with ethanol before PCR. Undigested
DNA was included as a positive control. A 150-bp fragment of
p16 exon 1 containing 2 Hpall and 1 Kspl site,
a 316-bp fragment of p14 exon 1 containing 1 Hpall and
1 Kspl site, and a 384-bp fragment of p15 exon 1 containing 1 Kspl, 1 Nael, 1 Eagl, and 5 Hpall sites were amplified by PCR. The primer sets and
annealing temperatures used for PCR are given in Table
1 (H through J). Cases were considered
positive for p15, p16, or p14 methylation by REP when
PCR amplification was obtained after digestion with 1 of the
methyl-sensitive restriction enzymes used. By REP, 3 CpG dinucleotides
from p16 exon 1, 10 from p15 exon 1, and 2 from
p14 exon 1 were evaluated.
In addition to REP, 2 other approaches were used to analyze the
methylation status of p16 exon 1: methylation-specific PCR (MSP)58 and bisulfite genomic sequencing
(BGS).59 In both techniques, DNA is chemically modified by
sodium bisulfite, which changes the unmethylated but not the methylated
cytosines into uracil. In MSP, the bisulfite-treated DNA is subjected
to PCR amplification using primers designed to anneal specifically to the methylated bisulfite-modified DNA within a given gene. Thus, a PCR
product is obtained when the sequence covered by the primers is
methylated. MSP was performed as described by Herman et
al,58 with some modifications. Briefly, genomic DNA (0.5 µg) was denatured in 0.3 mol/L NaOH (volume, 20 µL) for 20 minutes
at 42°C. After the addition of 80 µL of a freshly prepared solution
containing 1 mmol/L hydroquinone and 3.8 mol/L sodium bisulfite (pH
5.0), the samples were incubated overnight (16 hours) at 55°C. The
bisulfite-treated DNA was purified on Wizard DNA Clean-Up columns
(Promega, Madison, WI) according to the manufacturer's specifications
and eluted with 50 µL of water. The DNA was treated with 0.3 mol/L
NaOH for 20 minutes at 37°C, precipitated by ethanol, and resuspended
in 20 µL of water. Bisulfite-modified DNA was amplified by PCR using 2 primer sets specific for methylated and 2 primer sets specific for
unmethylated p16 sequence (Table 1, K through N), as
described.58 Because tumor cells are always admixed with
reactive cells in uncultured lymphomas, the PCR amplifications using
primers specific for unmethylated DNA were considered as positive
controls. Eleven CpG dinucleotides from p16 exon 1 were covered
by MSP analysis.
In BGS, bisulfite-treated DNA is amplified by PCR using primers
designed to recognize either methylated, or both methylated and
unmethylated, bisulfite-modified sequences, then cloned and sequenced.
This enables a precise mapping of the methylated CpG dinucleotides
present in a given DNA fragment. First, we cloned the 234-bp PCR
products obtained by MSP, either with primers specific for the
methylated, or with those specific for the unmethylated, p16
exon 1 sequence (Table 1, L and N). This fragment contains 28 CpG
dinucleotides. In some cases, we also cloned a 483-bp PCR fragment of
the bisulfite-modified p16 promoter region obtained with
primers recognizing both the methylated and the unmethylated p16 exon 1 sequence (Table 1, O). This fragment contains 42 CpG dinucleotides. Cloning of PCR products was performed using the pGEM-T
vector system (Promega) according to the manufacturer's recommendations. Five to 10 clones from each PCR product were sequenced
on an ALF Automatic DNA Analysis System (Amersham Pharmacia Biotech,
Uppsala, Sweden).
Mutation analysis by PCR-single-stranded conformation polymorphism
(SSCP).
The 3 exons of the p16 gene and the first exon of p15
and p14 were screened for mutations by PCR-SSCP as described
previously.60 The primers and annealing conditions used for
PCR amplification are given in Table 1 (A through G).
Reverse transcription (RT)-PCR analysis of p15, p16, and
p14 mRNA expression.
Representative tissue from 16 lymphomas (15 BCL and 1 ALCL) and 2 reactive lymph nodes was suitable for mRNA analysis. In all 16 tumors,
the proportion of neoplastic cells in the analyzed sample was more than
80%. Total RNA was extracted from tissue sections using the method of
Chomczynski and Sacchi.61 Five hundred nanograms of total
RNA was reverse transcribed using Moloney-murine leukemia
virus (M-MLV) RT (Promega) and oligo dT primer (2.5 µmol/L) in 75 mmol/L KCl, 3 mmol/L MgCl2, 10 mmol/L
dithiothreitol, 50 mmol/L Tris/HCl, pH 8.3, containing 1 mmol/L each
dNTP and 0.5 U/µL RNasin (Promega). A 210-bp fragment from exon 1 to
exon 2 of p16, a 207-bp fragment from exon 1 to exon 2 of
p14, and a 182-bp fragment from exon 1 to exon 2 of p15
cDNA were amplified by PCR using the primer sets and annealing
conditions indicated in Table 1 (R through T). In parallel, a 238-bp
fragment at the 3' end of the glyceraldehyde-3-phosphate
dehydrogenase (GAPDH ) gene cDNA was amplified as a
positive control (Table 1, U). Twenty-five cycles were performed for
cDNA amplification, and the PCR product was analyzed on a 2% agarose
gel. Under these conditions, and provided that their proportion was
under 20%, p16 and p14 mRNA expression from reactive
cells contaminating the tumor was not detectable (data not shown).
Thus, absence of visible RT-PCR product for p15, p16, or
p14 (with strongly positive GAPDH control) was
considered to indicate absence of expression of these genes.
| |
RESULTS |
Methylation of the p15, p16, and p14 genes was analyzed
in 56 lymphomas and 5 reactive lymph nodes by 3 different technologies: REP, MSP, and BGS (see Materials and Methods). In addition, the p15, p16, and p14 genes were analyzed by PCR-SSCP for
mutation, and their mRNA expression was assessed by RT-PCR. The results are displayed in Table 2.
Methylation status of the p15, p16, and p14 genes and
correlation with lymphoma type.
Methylation of the p16 gene was found in 17 of 56 (30%)
lymphomas: 15 of 47 (32%) BCL and 2 of 9 (22%) TCL. Of the BCL, 6 of
29 (21%) low-grade and 9 of 18 (50%) high-grade (Kiel classification) showed p16 methylation. The incidence of p16 gene
methylation was higher in B-follicle center cell lymphomas (5 of 14)
than in other low-grade lymphomas (1 of 15). Of the high-grade BCL, 6 of 13 diffuse large BCL (2 of 2 immunoblastic, 4 of 9 centroblastic, 0 of 2 mediastinal), 1 of 1 T-cell-rich BCL, 1 of 2 Burkitt-like, and 1 of 2 Burkitt's lymphomas were p16 methylated. The only PTCL showing p16 gene methylation corresponded to a pleomorphic
T-cell lymphoma, predominantly large cell, high-grade (Kiel
classification). One ALCL was shown to have a methylated p16
gene (Table 3).
All the 17 lymphomas with a methylated p16 gene also had a
methylated p15 gene. Overall, methylation of the p15
gene was found in 34 of 56 (61%) lymphomas: 30 of 47 (64%) BCL and 4 of 9 (44%) TCL. Of the BCL, 16 of 29 (55%) low grade and 14 of 18 (78%) high grade (Kiel classification) showed p15 gene
methylation: 3 of 8 lymphocytic, 3 of 6 mantle cell, 1 of 1 marginal
zone, 9 of 14 follicle center cell, 10 of 13 diffuse large B-cell (2 of
2 immunoblastic, 7 of 9 centroblastic, 1 of 2 mediastinal), 1 of 1 T-cell rich, 2 of 2 Burkitt-like, and 1 of 2 Burkitt's lymphomas. Two
of the 7 PTCL were positive for p15 gene methylation; both were
large cell lymphomas, high grade (Kiel classification). Both ALCL
exhibited methylation of the p15 gene (Table 3).
There was no detectable methylation of the p14 gene in any of
the 56 lymphomas. In all 5 reactive lymph nodes, the p15, p16, and p14 genes were unmethylated. The results of three cases are illustrated in Fig 1.
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| Fig 1.
Analysis of p16, p15, and p14 gene
methylation and mRNA expression in 3 diffuse large BCL. The
methyl-sensitive restriction enzymes used for REP are indicated
(HpaII, KspI, NaeI, and EagI);
digestion with the non-methyl-sensitive enzyme MspI serves as
a negative control; undigested DNA (Control) serves as a positive
control. For MSP, 2 primer sets specific for the methylated (M1 and M2)
and 2 for the unmethylated (U1 and U2) bisulfite-modified p16
gene are used. Expression of p16, p15, and p14 mRNA is
analyzed by RT-PCR. The p16 gene is methylated in cases 33 and
36 but unmethylated in case 30. In case 36, p16 methylation is
detected by REP but not by MSP (A and B). The p15 gene is
methylated in cases 33 and 36 but not in case 30. In case 33, all
assessed restriction sites are methylated. In case 36, all sites except
EagI are methylated (C). The p14 gene is unmethylated
in all 3 cases (D). GAPDH and p14 mRNA is present in
all cases; p15 mRNA is detectable in case 30 but not in cases
33 and 36, whereas p16 mRNA is present in cases 30 and 36 but
not in case 33 (E).
|
|
Methylation patterns of p16 exon 1.
Of the 56 lymphomas analyzed for p16 gene methylation by REP
and MSP, 17 were methylated. In 12 cases, methylation was shown by both
methods (REP+/MSP+). In the 5 other cases, it
was detected only by REP, but not by MSP
(REP+/MSP ), indicating partial methylation
in p16 exon 1 (Fig 1). To document this, 5 lymphomas (3 REP+/MSP+ and 2 REP+/MSP) were analyzed by BGS, which
enables a precise mapping of the methylated CpGs in the analyzed DNA fragment.
We first cloned and sequenced PCR products obtained by MSP with primers
specific for either the methylated (REP+/MSP+
cases), or the unmethylated (REP+/MSP cases)
bisulfite-modified p16 exon 1 sequence. In both
REP+/MSP cases, we also cloned and sequenced
a PCR product obtained with primers recognizing both methylated and
unmethylated sequences. In the 3 REP+/MSP+
lymphomas, the different p16 exon 1 methylation patterns
exhibited methylation at all or almost all of the CpG dinucleotides
(Table 4, clones 33.a through 33.e, 42.a
through 42.e, and 44.a through 44.e). In both
REP+/MSP lymphomas, all the sequenced clones
were completely or almost completely unmethylated (Table 4, clones 36.a
through 36.m and 47.a through 47.o); of the 11 CpG sites covered by MSP
analysis, 8 were unmethylated in all clones, explaining the negative
results obtained by MSP with the methylated primer sets.
Expression of p15, p16, and p14 mRNA and correlation
with methylation status.
Suitable tissue for mRNA extraction and RT-PCR analysis was available
in 18 cases (16 lymphomas and 2 reactive lymph nodes). All tissues were
strongly positive for GAPDH and p14 mRNA expression. The p16 mRNA was present in both reactive lymph nodes and in
the 4 p16-unmethylated and 1 p16-methylated lymphomas.
There was no detectable p16 mRNA expression in 11 of 12 lymphomas with a methylated p16 gene (Table 2).
p15 mRNA was detected in both reactive lymph nodes and in the 4 p15-unmethylated lymphomas, but not in any of the 12 lymphomas exhibiting p15 gene methylation (Table 2). p15, p16,
and p14 mRNA expression in 3 lymphomas is illustrated in Fig 1.
Mutation analysis of the p15, p16, and p14 genes by
PCR-SSCP.
All 56 lymphomas and 5 reactive lymph node tissues were screened by
PCR-SSCP for mutations of p16 exon 1 to 3, p15 exon 1, and p14 exon 1. No aberrant migration patterns, indicative of mutation, were observed (Table 2).
| |
DISCUSSION |
Inactivation of p15INK4b and
p16INK4a by homozygous deletion or gene
methylation is probably one of the most common molecular events in
hematological malignancies.52 Homozygous deletion of the 9p21 region containing the p15, p16, and p14 genes is
frequently found in acute lymphoblastic leukemias of both B-cell and
T-cell lineage, but is uncommon in lymphomas. In agreement with other studies,29,34,41,54 we did not find any mutations in the coding regions of the p15 and p16 genes among the 56 lymphomas analyzed. Thus, neither homozygous deletion nor mutation
appears to be a relevant mode of inactivation of these genes during
lymphomagenesis.29,39,41,45,54 Our results indicate that
the principal mechanism of p15 and p16 silencing in
lymphomas is gene methylation.45 A large proportion of
lymphomas showed p15 and/or p16 gene methylation (61%
and 30%, respectively), confirming previously reported
results.49,50,52-54 Both genes were inactivated more
frequently in BCL than in TCL, suggesting that they are more important
in B than in T lymphomagenesis. High-grade (according to the Kiel
classification) BCL were more often p15/p16 methylated (78%
and 50%, respectively) than low-grade B-cell lymphomas (55% and 21%,
respectively). This suggests that p15 and p16 gene
silencing might be associated with aggressive transformation in
lymphoma, and that p15 and p16 gene methylation might
be a useful marker to predict aggressive behavior.
Both p16 and p14 (p19ARF)
null mice develop lymphomas.15,24 However, given the fact
that the p14 gene was also disrupted in the p16 null
mice, it has been proposed that the major oncogenic event might be loss
of p14 rather than of p16.24 We observed absence of p14 gene mutations or methylation and a high level of p14 mRNA expression in all lymphomas analyzed, which does
not suggest a role for p14 inactivation in human
lymphomagenesis. Our results indicate that one of the principal
oncogenic events in human lymphomagenesis is inactivation of the
p15 gene. Therefore, it could be of interest to determine
whether p15 knockout mice develop lymphomas. In our series, all
lymphomas with a methylated p16 gene were also p15
methylated. It is striking that p14, a gene that is localized
between p15 and p16, was always unmethylated even when
both p15 and p16 genes were methylated. A possible
mechanism protecting p14 from de novo methylation might be
binding of the Sp1 transcription factor at Sp1 sites present in the
p14 promoter, as proposed recently.23
The minimal sequence required by the methylation apparatus is a CpG
dinucleotide.62 The present results are the first
demonstrating variation in methylated CpGs within p16 exon 1 from one lymphoma to another. Three cases positive by MSP and REP
displayed a high proportion of methylated and a few scattered
unmethylated CpG dinucleotides by BGS. In contrast, 2 cases positive by
REP but negative by MSP had only a few scattered methylated CpGs within p16 exon 1. The significance of such heterogeneity of
methylation patterns remains unclear, but suggests a complex mechanism
for de novo methylation. Even those tumors with a few methylated CpGs within p16 exon 1 had no detectable p16 mRNA
expression, indicating that low-level methylation is sufficient to
repress p16 transcription. Recently, it has been shown that
methyl-CpG-binding protein 2 (MeCP2), which is involved in
transcriptional repression of methylated genes by forming complexes
with the transcriptional repressor Sin3A and histone deacetylase (HD),
may bind to DNA sequences containing only a single methylated CpG
dinucleotide.63,64 However, it remains to be shown that
transcriptional repression of methylated p15 and p16
involves the MeCP2/Sin3A/HD-complex/pathway. By BGS, we found several
p16 methylation patterns coexisting in DNA extracted from a
primary (uncultured) lymphoma, an observation for which several
explanations might be considered. First, consecutive waves of clonal
progression might yield heterogeneous p16 methylation patterns
coinciding with different tumor regions. This could be confirmed by
methylation analysis of microdissected tumor samples. Secondly, the 2 (or more) p16 alleles in a single tumor cell might have
different methylation patterns. The latter possibility is supported by
observations that several methylation patterns of p16 exon 1 coexist in established colon cancer cell lines (P.C., unpublished data).
| |
ACKNOWLEDGMENT |
The authors acknowledge M.M. Bertholet, M. Correvon, S. Burki, and J. Maillardet for technical assistance.
| |
FOOTNOTES |
Submitted January 19, 1999; accepted May 4, 1999.
Supported by the Swiss Cancer League (P.C.)
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
1734 solely to indicate this fact.
Address reprint requests to Pascal Chaubert, MD, Institut Universitaire
de Pathologie, Bugnon 25, CH-1011 Lausanne, Switzerland.
| |
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ABSTRACT
INTRODUCTION