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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3018-3024
RAPID COMMUNICATION
Somatic Fas Mutations in Non-Hodgkin's Lymphoma:
Association With Extranodal Disease and Autoimmunity
By
Kirsten Grønbæk,
Per thor Straten,
Elisabeth Ralfkiaer,
Vibeke Ahrenkiel,
Mette Klarskov Andersen,
Niels Ebbe Hansen,
Jesper Zeuthen,
Klaus Hou-Jensen, and
Per Guldberg
From the Department of Tumor Cell Biology, Institute of Cancer
Biology, Danish Cancer Society; the Departments of Pathology and
Hematology, Herlev Hospital; and the Departments of Hematology and
Pathology, Rigshospitalet, Copenhagen, Denmark.
 |
ABSTRACT |
Fas (APO-1/CD95) is a cell-surface receptor involved in cell death
signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have
examined the entire coding region and all splice sites of the
Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall,
mutations were identified in 16 of the tumors (11%). Missense
mutations within the death domain of the receptor were associated with
retention of the wild-type allele, indicating a dominant-negative
mechanism, whereas missense mutations outside the death domain were
associated with allelic loss. Fas mutations were identified in
3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas,
2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell
lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia
with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation,
and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that
somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation,
cancer and autoimmunity.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
FAS (ALSO KNOWN AS APO-1 or CD95) is a
transmembrane protein of the tumor necrosis factor (TNF) receptor
family, which mediates programmed cell death (apoptosis) upon
trimerization induced by cross-linking to Fas ligand
(FasL).1,2 Fas is expressed on the surface of activated T
and B lymphocytes, and Fas/FasL induced apoptosis is important for
eliminating autoreactive immature T cells during ontogenesis and for
maintaining peripheral lymphocyte homeostasis.2,3
Disruption of the Fas/FasL apoptotic pathway has been associated with
benign lymphoproliferation, severe multisystem autoimmune disease, and
hypergammaglobulinemia. Lpr mice that harbor deleterious mutations in the Fas gene accumulate
CD4 CD8 (double negative) T cells
in their lymph nodes and spleen, exhibit B-cell lymphocytosis, and
produce large amounts of IgG and IgM autoantibodies, including anti-DNA
antibodies, and rheumatoid (Rh) factor.4 Children who carry
inherited defects in the Fas gene exhibit a similar, albeit
variable, pattern of phenotypes that have been collectively termed
autoimmune lymphoproliferative syndrome (ALPS).5-9
Non-Hodgkin's lymphomas (NHL) are malignant neoplasms whose normal
counterparts are the cells of the immune system.10
Different lines of evidence suggest that an association exists between
NHL and autoimmune disease. Patients with autoimmune diseases,
including systemic lupus erythematosis (SLE), rheumatoid arthritis
(RA), Sjögren's syndrome, and autoimmune thyroid disease, have
an increased risk for hematopoietic cancers, in particular
lymphoma,11-13 and T-cell-rich B-cell (TRB) lymphoma and
Hodgkin's disease have been reported in patients with
ALPS.9 Conversely, approximately 8% of patients with NHL
exhibit autoimmune phenomena.14 Here we show that 11% of
sporadic NHL harbor Fas mutations, and that the majority of
patients with Fas-mutated lymphomas present with extranodal
disease and clinical features suggestive of autoreactive disease.
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MATERIALS AND METHODS |
Patients.
A total of 150 NHLs were included in this study. The patient samples
had been frozen immediately after excision in either liquid
N2 or a mixture of 2-methyl butane and dry ice and stored at  80°C until use. Routinely processed histological samples
were available in all cases. These samples were stained with
hematoxylin-eosin, examined by immunohistology, and then classified
according to the Revised European-American Lymphoma (REAL)
classification.10 Our series included the following
histological subtypes: B-cell chronic lymphocytic leukemia (B-CLL) (n = 17); immunocytoma (n = 1); follicle center cell lymphoma (n = 33);
mucosa-associated lymphoid tissue (MALT)-type lymphoma (n = 5); mantle
cell lymphoma (n = 9); diffuse large B-cell lymphoma (DLC-B) (n = 43);
Burkitt lymphoma (n = 5); peripheral T-cell lymphoma,
unspecified (n = 35); and anaplastic large cell lymphoma of null cell
type (n = 2). Uninvolved normal tissue was available as
paraffin-embedded sections. Ethical committee approval for the study
was obtained.
DNA isolation, denaturing gradient gel electrophoresis (DGGE), and
direct sequencing.
Genomic DNA was isolated by proteinase K digestion and
phenol-chloroform extraction, or by using the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, MN). Paraffin-embedded tissue was
treated with xylene before DNA extraction. Mutations in the Fas
gene were detected by polymerase chain reaction (PCR) amplification of
genomic DNA using the 10 sets of primers listed in
Table 1, followed by DGGE.15
The melting characteristics of each of the nine exons with adjacent
intronic sequences were attained by means of the MELT87 computer
algorithm.16 To modulate the melting properties into the
two-domain profile that is considered optimal for resolution of
mutations, each sequence was tailored by PCR-mediated attachment of a
"GC-clamp."17 PCR was performed in 15-µL reaction
mixtures containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.002% gelatin, 0.2 mmol/L cresol red, 12%
sucrose, 10 pmol of each primer, 100 µmol/L each dNTP, 100 ng of DNA,
and 0.8 U of AmpliTaq polymerase (Perkin-Elmer Cetus, Emeryville, CA).
The cycling parameters were: 38 cycles at 94°C for 20 seconds,
55°C for 20 seconds, and 72°C for 30 seconds. PCR products were
analyzed in a 10% denaturant/6% polyacrylamide-70% denaturant/12%
polyacrylamide double-gradient gel18; (100% denaturant = 7 mol/L urea and 40% formamide). The gel was run at 90 V for 16 hours in
1 × TAE buffer kept at a constant temperature of 54°C
(58°C for exon 1), stained with ethidium bromide, and photographed
under UV transillumination. The biallelic polymorphism at position
670 in the Fas promoter19 was detected by
using primers FAS-734GC and FAS-623 (Table 1) and the PCR and DGGE conditions described above. Direct sequence analysis of PCR products was performed with a nonclamped, 33P-end-labeled primer
using the ThermoPrime Cycle Sequencing Kit (Amersham Life Science,
Cleveland, OH), according to the manufacturer's instructions.
Reverse transcriptase (RT)-PCR analysis.
RNA was extracted using the Purescript Isolation Kit (Gentra
Systems). cDNA synthesis was performed using M-MLV
SuperScript II reverse transcriptase (GIBCO-BRL, Life Technologies,
Gaithersburg, MD) in a total volume of 20 µL 1× buffer
(GIBCO-BRL, Life Technologies) containing 10 mmol/L dithiothreitol
(DTT). Incubations were performed at 42°C for 50 minutes, 72°C
for 5 minutes. Fas cDNA was PCR amplified with primers FAS533
(5 -GCAGAAAGCACAGAAAGGAAA-3) and FAS737
(5-TCTGTTCTGCTGTGTCTTGGA-3) which hybridize to regions in
Fas exons 7 and 9, respectively, and yield a PCR product of 235 bp. Amplifications were performed in a total volume of 25 µL
containing 1× PCR buffer (50 mmol/L KCl, 20 mmol/L Tris pH 8.4, 2.0 mmol/L MgCl2, 0.2 mmol/L cresol red, 12% sucrose,
0.005% [wt/vol] bovine serum albumin [BSA] [Boehringer-Mannheim, Mannheim, Germany]), 2.5 pmol of each primer, 40 mmol/L dNTPs, and
1.25 U of AmpliTaq polymerase (Perkin Elmer Cetus). The parameters used
for amplification were 94°C for 20 seconds, 60°C for 20 seconds, and 72°C for 30 seconds for 40 cycles. Taq polymerase and
dNTPs were added to the reaction tube at an 80°C step between the
denaturation and annealing steps of the first cycle ("Hot
start"). Direct sequence analysis was performed as described above.
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RESULTS |
Genomic DNA was isolated from 150 NHLs and analyzed for mutations in
all 9 exons of the Fas gene by PCR/DGGE analysis
(Fig 1A). Enrichment and direct sequence
analysis of aberrantly migrating bands led to the identification of
mutations in 16 of the samples (11%) (Fig 1B;
Table 2). Normal tissue was available from
9 of 16 mutated cases. None of the normal samples showed evidence of mutations by DGGE, indicating that the mutations detected in the lymphoma specimens had arisen somatically.
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| Fig 1.
Detection of Fas mutations in NHL. (A) The
5-end of exon 9 of the Fas gene was amplified using
primers 9I-F and 9I-R, and mutations were detected by DGGE analysis in
follicle center cell lymphoma (FCC) 17 (E256K), MALT 145 (N248K), DLC-B 156 (N248K), DLC-B 93 (L262F), and DLC-B 86 (D244V).
PBL, DNA isolated from peripheral blood lymphocytes of a normal
volunteer. (B) Direct sequence analysis of heteroduplexes recovered
from the gel shown in (A), revealing the G1008A transition (E256K) in
FCC 17.
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Missense mutations.
The majority (10 of 16) of the mutations were missense variants, all of
which caused nonconservative amino acid substitutions (Table 2). Six of
these mutations were detected in exon 9, which encodes the death domain
region of the Fas receptor. Two different transversions (T to A and T
to G) at position 986 of the Fas cDNA sequence (GenBank
accession no. M67454), both causing the substitution of Asn with Lys at
codon 248, were found in two different tumors, suggesting that this
position may represent a mutational hotspot. The remaining mutations
within the death domain affected codons 244, 256, 262, and 283. Missense mutations outside the death domain involved the last residue
of the signal peptide, which directs the Fas molecule to the
endoplasmatic reticulum; codons 164 and 167 in exon 6, which encodes
the transmembrane region of membrane-bound Fas; and codon 182 in exon
7, which encodes the intracytoplasmic anchoring region.
Allelic status.
Because missense mutations in the death domain of Fas in patients with
ALPS have been suggested to affect receptor function in a
dominant-negative fashion,5 we examined the allelic status of Fas in tumors carrying missense mutations. Six of the
patients were heterozygous for one or both of the known biallelic
polymorphims at positions 67019 and
836,20 allowing evaluation of allelic loss in their tumors by DGGE analysis (Fig 2). All three
informative lymphomas carrying missense mutations in exon 9 showed
equal distribution of the two alleles, indicating retention of the
wild-type allele in the tumor cells. In contrast, all three tumors with
missense mutations in exons 6 or 7 showed unequal distribution of the
two alleles, suggesting that the wild-type allele had been lost (Fig
2). Only 4 of 76 (5%) informative lymphomas in which no Fas
mutations had been detected showed evidence of allelic loss.
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| Fig 2.
Detection of allelic loss of the Fas gene in NHL
by DGGE. A region encompassing the biallelic polymorphism, 670A/G,
in the Fas promoter was amplified with primers FAS-734GC and
FAS-623, and the two alleles were subsequently resolved by
electrophoresis in a denaturing gradient gel. Unequal distribution of
the two alleles was observed in DLC-B 128, anaplastic large cell
lymphoma (ALCL) 72, and DLC-B 157, suggesting that one
Fas allele was lost in the tumor cells. These three tumors
harbor missense mutations in exon 6 or exon 7 of the Fas gene.
In contrast, even distribution of the two alleles was observed in MALT
145, which harbors the N248K mutation in exon 9 of the Fas
gene. PBL, DNA isolated from peripheral blood lymphocytes of a normal
volunteer who is heterozygous for the 670A/G polymorphism.
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Nonsense, frameshift, and splice-site mutations.
The six non-missense mutations included two point mutations introducing
premature termination signals at codons 199 and 208, respectively; one
1-bp insertion causing a frame shift and the introduction of a stop
codon at residue 120; and three mutations affecting normal splicing of
Fas mRNA (Table 2). Two of the splice mutations affected
position +5 of the consensus sequence of the donor splice site of
intron 8, while the remaining mutation was a transition of the
invariable A at position 2 of the acceptor splice site of intron
7. Mutations at these particular splice site positions have been shown
to cause cryptic splice site utilization or exon skipping in various
human disease genes.21 RT-PCR analysis of a region
encompassing exons 7, 8, and 9 in RNA extracted from these three tumors
showed the occurrence of a shorter band in all three cases
(Fig 3). Cloning and sequence analysis
showed that this band lacked the sequence corresponding to exon 8, resulting in a frame shift and the introduction of a stop codon at
residue 221. Together, these data suggest that all three mutations
located in the splice-site consensus regions of exon 8 result in exon skipping. However, the exact ratio of normal to aberrantly spliced mRNA
in tumor cells remains unknown.
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| Fig 3.
RT-PCR analysis of Fas mRNA in NHLs. A region
encompassing exons 7-9 was amplified with primers FAS533 and FAS737 in
three lymphoma samples in which mutations had been identified in the
acceptor splice site of Fas intron 7 (IVS7nt-2a  g;
DLC-B 225), or in the donor splice site of Fas intron 8 (IVS8nt + 5g a, MALT 146; and IVS8nt + 5g c, MALT
67). In all three samples, skipping of exon 8 was demonstrated by the
occurrence of a shorter band that was not present in RNA isolated from
peripheral blood lymphocytes of a normal volunteer (PBL). M, 100-bp
ladder.
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Polymorphisms.
In addition to the known polymorphisms in the enhancer region and in
exons 3 and 7,19,20 we identified two previously
undescribed single base changes, G377A in exon 2 and G563A in exon 4, which are predicted to leave the amino acid sequence unchanged. The A-allele of the G377A polymorphism and the A-allele of the G563A polymorphism were each found at a frequency of 1.7% (5 of 300 independent chromosomes).
Clinical and histological features.
The histological features of the Fas-mutated lymphomas are
outlined in Table 3. Mutations were
identified most frequently in low-grade MALT-type lymphomas (3 of 5;
60%) and DLC-B lymphomas (9 of 43; 21%). All but one of the mutated
cases were B-cell lymphomas. The remaining case was an anaplastic large
cell lymphoma of null cell type.
The clinical features of the patients with Fas-mutated
lymphomas are summarized in Table 4.
Fifteen of 16 patients (94%) showed extranodal disease at
presentation, and 6 developed extranodal recurrences. Of 117 lymphomas
with no detectable Fas mutations, 57 (49%) presented at
extranodal sites, and 32 (27%) showed involvement other than bone
marrow. CLL was excluded from this statement because of its implicit
involvement of extranodal areas.
All three thyroid lymphomas in this series harbored Fas
mutations. One of these (no. 225) was preceded by 4 years of
well-documented Hashimoto's thyroiditis with high titers of
anti-thyroid peroxidase (anti-TPO) antibodies,
hypergammaglobulinemia, elevated thyroid-stimulating hormone (TSH), and
myxoedema. This patient was treated with cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP), but relapsed with a
gastric lymphoma of similar histology. A second case (no. 145),
presenting with thyroid low-grade MALT-type lymphoma and involvement of
neck lymph nodes, had myxoedematous symptoms before lymphoma and
elevated TSH. The last patient (no. 92) with thyroid lymphoma had
massive goiter, elevated TSH level, and myxoedema. In
these latter two cases, thyroid antibodies had not been analyzed.
Another patient (no. 157) presented in 1969 with Sjögren's
syndrome verified by sialography and salivary gland biopsy. In 1976 she
developed universal arthritis, peripheral neuropathy, thrombocytopenia
with positive IgM-Rh factor, antinuclear antibodies (ANA), anti-dsDNA
antibodies, and hypergammaglobulinemia, and a diagnosis of SLE was
made. In 1984 a DLC-B lymphoma of TRB-type was diagnosed in the
salivary gland and regional lymph nodes.
Among the remaining patients in whom somatic Fas mutations had
been identified, six showed a number of paraneoplastic features that
may be associated with autoreactivity. One patient (no. 67) had
conjunctivitis and arthralgy at diagnosis and later developed bursitis
with noduli rheumatici. Another patient (no. 146) had unexplained
recurrent pleural effusions 3 years before the diagnosis of lymphoma.
Two patients (nos. 141 and 156) exhibited monoclonal IgM and
neuropathy; one (no. 128) had persistent abdominal pain that was
diagnosed as severe pancreatitis; and one (no. 193) was an unusual case
of B-CLL with neoplastic skin infiltrates and a long-lasting
maculo-papular skin rash.
In the remaining 6 cases, features of autoreactive/paraneoplastic
disease were either not present (3 cases; nos. 86, 17, and 93), or no
information was available (3 cases; nos. 49, 72, and 69).
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DISCUSSION |
Previous loss of heterozygosity (LOH) and karyotypic studies have
suggested that a putative tumor suppressor gene at chromosome 10q23-25
may be involved in the development of NHL.22 We have recently examined PTEN/MMAC1, a gene mapping to 10q23.3 and
encoding a tumor suppressor commonly altered in many types of human
cancer,23-25 but found that this gene is mutated in less
than 2% of NHL.26 In the present study, we have
systematically examined the Fas gene on 10q24.1 and documented
somatic mutations in 16 of 150 NHLs (11%). These findings, together
with the recent demonstration of a similar frequency of Fas
mutations in multiple myeloma,27 suggest that Fas
mutations may be involved in the development of different types
of lymphoid malignancies. In our series of NHL, the highest frequency
of Fas mutations (60%) was seen in low-grade MALT-type
lymphomas. Most of the remaining lesions were DLC-B lymphomas with a
remarkable preference for extranodal sites. The possibility that some
of the latter cases could be transformed low-grade MALT lymphomas is a
tempting assumption which, however, could not be further elucidated in
this retrospective analysis.
Although functional studies have not yet been performed, most of the
mutations identified in the present study are likely to disrupt or
alter the normal structure and/or function of Fas. Six of the
mutations are predicted to cause premature termination of protein
synthesis, aberrant RNA splicing, or frameshifts, and hence resemble
typical loss-of-function mutations. However, a previous study has shown
that genetic defects resulting in the production of a truncated protein
may be able to confer a dominant-negative effect.5 The
remaining mutations were missense variants resulting in nonconservative
amino acid substitutions. Four of six missense mutations (D244V, E256K,
L262F, and K283N) within the region encoding the Fas death domain
affected codons that are evolutionarily highly conserved.28
Furthermore, alteration of codon 244 has been shown in one case of
ALPS7 and has been shown to cause reduced self association
and binding of the Fas death domain to FADD/MORT1, which is necessary
for transmission of the apoptotic signal.29 Likewise,
alterations of residue 369 in TNFR1, which is homologous to Fas residue
256, have been shown to be associated with abrogation of TNFR1-mediated
cytotoxicity.30 The functional significance of missense
mutations outside of the death domain remains unknown at this stage.
The pattern of Fas inactivation demonstrated in this study is very
similar to that observed in ALPS patients.5-9 In NHL, missense mutations within the death-domain-encoding region of Fas were consistently associated with retention of the
wild-type allele. This finding is in line with previous observations
that ALPS patients carrying a death domain mutation are
heterozygous,5-9 and substantiates the notion that
nonconservative amino acid substitutions in the death domain may act in
a dominant-negative fashion.5 In contrast, missense
mutations outside the death domain were associated with loss of the
wild-type allele, suggesting that a classical two-hit mode of gene
inactivation may be necessary to disrupt gene function in these cases.
Missense mutations outside the death domain have been reported in two
ALPS families, and in both cases were they associated with the ALPS
phenotype only in the presence of concomitant mutation of the second
allele.8,31
An intriguing finding in the present study was the high incidence of
autoreactive phenomena in the group of NHL patients in whose tumors we
had identified Fas mutations. Two cases had well-documented autoimmune diseases (SLE/Sjögren's syndrome and Hashimoto's
thyroiditis, respectively), and eight cases showed various
paraneoplastic features suggestive of autoreactivity, including
bursitis with noduli rheumatici, conjunctivitis, neuropathy,
pancreatitis, and myxoedema. Ninety percent of all myxoedemas are
believed to be caused by autoimmune thyroiditis, and features of
autoimmune thyroiditis have been identified by histology in 5 of 5 and
8 of 8 low-grade MALT lymphomas in two independent
studies.32,33 Furthermore, examination of thyroid B-cell
lymphomas of large cell type has shown that low-grade MALT-type
components may be found consistently if multiple sections are
examined.32 These observations have suggested that most, if
not all, thyroid B-cell lymphomas develop through a step of autoimmune
thyroid disease, and are MALT-type lymphomas with or without features
of transformation.32
Several lines of evidence have suggested a causative role for
Fas alterations in the induction of autoimmune disease. First, inherited defects in Fas in mice and humans result in
lymphoproliferation and systemic autoimmunity caused by the massive
accumulation of autoreactive B and T cells.4-6 Second,
precursor B cells for autoantibody production in Fas/FasL-intact,
SLE-prone mice are resistant to Fas-mediated apoptosis due to
downregulation of their Fas expression.34 Third, induction
of Fas expression has been associated with increased rates of
FasL-induced apoptosis in insulin-dependent diabetes mellitus and
Hashimoto's thyroiditis.35,36
The high incidence of autoimmune phenomena observed among NHL patients
with Fas-mutated tumors suggests that somatic mutation of
Fas may add to the above spectrum of mechanisms causing escape from
self-tolerance. An anergic and potentially self-reactive B cell which
acquires a Fas mutation may no longer be susceptible to
apoptosis. Instead, it may be triggered by CD4+ T cells to
proliferate,3 and eventually may result in the massive
production of autoantibodies. The possible association between
autoimmunity, Fas mutations and lymphomas warrants further study by examination of Fas mutations in lymphomas and matched autoimmune lesions.
The identification of Fas as a mediator of apoptosis in cells of the
immune system led to the speculation that disruption of the normal
Fas-mediated apoptotic pathway may represent an early event in
lymphomagenesis, leading to longer lymphocyte survival and thus
allowing for the accumulation of additional oncogenic events.37,38 This notion was reinforced by recent work by
Plumas et al,39 who showed that malignant B cells from NHL
exhibit intrinsic resistance to lysis mediated by FasL expressed on
cytotoxic T cells. Interestingly, this resistance was not related to
the levels of Fas expression and could not be overcome by induction of
Fas expression. The data from the present study provide direct evidence
that the Fas-mediated apoptotic pathway is abrogated in approximately
10% of NHL cases because of alteration or loss of Fas function.
Whether alterations in the expression and/or function of
components downstream of Fas in the same pathway, including
FADD/MORT1,40,41 caspase 8,42,43 and
FLICE-inhibitory proteins (FLIPs),44 cause resistance to
Fas-mediated apoptosis in the remaining cases will be subject to future
studies.
| |
FOOTNOTES |
Submitted July 1, 1998;
accepted August 5, 1998.
Supported by Grants from the Danish Cancer Society, the Ellen and Aage
Fausbøll Foundation, the Arthur and Poula Søndergaard Foundation, and
the Kaarsen Foundation.
Address reprint requests to Per Guldberg, PhD, Department of Tumor Cell
Biology, Institute of Cancer Biology, Danish Cancer Society,
Strandboulevarden 49, DK-2100 Copenhagen, Denmark; e-mail: perg{at}bio.cancer.dk.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract