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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3410-3415
PTEN Gene Alterations in Lymphoid Neoplasms
By
Akira Sakai,
Catherine Thieblemont,
Axel Wellmann,
Elaine S. Jaffe, and
Mark Raffeld
From the Hematopathology Section, Laboratory of
Pathology, National Cancer Institute, National Institutes of Health,
Bethesda, MD.
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ABSTRACT |
Recently, a novel phosphatase designated PTEN/MMAC1/TEP1 and located
on chromosome 10q23.3 has been implicated as a new tumor suppressor
gene in human cancer. Allelic loss and mutation of this gene has been
reported in epithelial derived tumors, including breast cancer and
prostate cancer, and in glioblastoma multiforme. The present study was
designed to evaluate the potential involvement of PTEN in the
pathogenesis of lymphoid neoplasms. We analyzed 27 hematopoietic cell
lines (representing a variety of lymphoid lineages), 65 primary
lymphoid tumors (including 24 lymphoblastic leukemia/lymphoma [LBL],
30 large B-cell lymphoma [LBCL], 7 Burkitt's lymphoma [BL], and 4 anaplastic large cell lymphoma [ALCL]), and 25 nonmalignant lymph
node controls. Gene deletion and gross rearrangement were evaluated
using Southern blot analysis, and mutations were studied by polymerase
chain reaction (PCR)-single-strand conformation polymorphism (SSCP)
(PCR-SSCP) and sequencing. Six of 27 cell lines (22.2%)
and 3 of 65 primary lymphomas (4.6%) contained alterations of this
gene. A large homozygous deletion spanning exons 2 through 5 was
detected in one LBL cell line, and two insertions potentially resulting
in premature termination, were detected in a second LBL cell line.
Nonconservative nucleotide variations were found in two other cell
lines (one LBCL and one BL) and in one primary case of LBCL. In
addition, two other cell lines (one BL and one myeloma) and two primary
lymphomas, both LBCL, contained small deletions within intron 7. These
deletions mapped to a poly-T-rich tract just 5 to the intron 7/exon 8 spice site. Their significance is unclear, as they may represent
polymorphisms. Overall, our results suggest that abnormalities of the
PTEN gene can contribute to pathogenesis in a small percentage of
malignant lymphomas.
This is a US government work. There are no restrictions on its use.
| |
INTRODUCTION |
RECENTLY, A NEW CANDIDATE tumor
suppressor gene designated PTEN/MMAC1/TEP1 and located on chromosome
10q23.3 was reported by three groups independently.1-3 PTEN
encodes a novel 403-amino acid, dual-specificity phosphatase with
homology both to the protein tyrosine phosphatase (PTP) family and to
two cytoskeletal proteins, tensin and auxilin.1-3 The
protein contains the canonic PTP motif, and recombinant PTEN has been
shown to be capable of catalyzing the hydrolysis of phosphoseryl,
phosphothreonyl, and phosphotyrosyl residues.4
PTEN is reportedly deleted and/or mutated in a significant
fraction of breast cancers,5 prostate cancers,6
endometrial carcinomas,7-9 glioblastomas,10,11
and sporadic melanomas,12 suggesting that it functions as a
tumor suppressor gene in these cancers. In addition, it has also been
implicated in Cowden disease,13 an inherited cancer
syndrome characterized by benign adenomas and malignant neoplasms of
the breast, thyroid, and skin, and in Bannayan-Zonana
syndrome,14 an autosomal dominant disorder characterized by
microcephaly, vascular malformations, and benign neoplasms such as
lipomas and intestinal hamartomatous polyps. Studies in other types of
cancer such as thyroid15 and pancreatic16 carcinoma have shown an absence or a low frequency of mutation or
deletion of the PTEN gene. Although there are many examples of protein
tyrosine kinases that function as oncogenes in tumorigenesis, this is
the first protein tyrosine phosphatase implicated as a tumor suppressor
gene.
To date, there is little information regarding the potential
involvement of PTEN in non-Hodgkin's lymphoma (NHL). At the
chromosomal level, abnormalities of chromosome 10q have been reported
in a modest percentage of NHLs. Juneja et al17 noted
recurrent breaks at 10q22 and 10q26 and Offit et al18 found
breaks in the region of 10q22-24 in 5% of NHL. Most recently,
abnormalities of 10q23-25 were reported in 10.7% of NHL.19
The cytogenetic findings plus the lack of studies investigating PTEN
involvement in NHL encouraged us to examine a series of lymphoid
neoplasms for potential involvement of this gene in lymphomagenesis. In
this report, we present data on 27 hematopoietic cell lines and 65 primary high-grade NHLs for mutations, deletions, or rearrangements of
the PTEN gene.
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MATERIALS AND METHODS |
Cell line studies.
Twenty-seven human hematopoietic cell lines representing a variety of
lymphoma subtypes were selected for this study. These included 6 lymphoblastic leukemia/lymphoma (LBL) cell lines (Molt3, Molt4, HSB,
Jurkat, HUT102, and CEM), 4 anaplastic large cell lymphoma (ALCL) cell
lines (KARPAS299, JB6, SR786, and KIJK), 6 B-cell lymphoma cell lines
(SUDHL4, SUDHL5, SUDHL6, SUDHL7, SUDHL10, and NUDHL1), 6 Burkitt's
lymphoma (BL) cell lines (JD38, CA46, Raji, PA682PB, WMN, and Defaw), 3 myeloma cell lines (KMS5, KMS11, and Jim3), 1 Hodgkin's lymphoma cell
line (L428), and 1 leukemia cell line (YT) with natural killer-like
phenotype.
Cases studied.
A total of 65 samples from patients with aggressive lymphoma referred
to the National Institutes of Health were selected for this study based
on the availability of sufficient tissue for molecular analysis. In
addition, 25 samples from patients with nonmalignant lymphoid
hyperplasias were also studied to assist in identifying polymorphisms.
The lymphoma samples included 24 LBL, 30 large B-cell lymphoma (LBCL),
7 BL, and 4 ALCL. The rationale behind the selection of these
particular lymphoma subtypes was (1) to analyze neoplasms of related
subtype to the cell lines with PTEN alterations and (2) to focus on
aggressive lymphoma variants, since PTEN/MMAC1 was initially described
in advanced cancers. The majority of samples used in this study are
from patients enrolled in clinical studies who provided informed
consent according to the guidelines of the Institutional Review Board
of the National Institutes of Health.
DNA extraction and Southern blot analysis.
High-molecular-weight DNA was extracted from frozen tissue samples or
cell suspensions using a standard phenol/chloroform extraction
procedure as previously described.20 Placental DNA (Oncor,
Gaithersburg, MD) was used as control DNA. After restriction enzyme
digestion with EcoRI or HindIII, the DNA was size-fractionated by
agarose gel electrophoresis and transferred onto nylon membranes (GENE
Screen Plus; New England Nuclear Research Products, Boston, MA). The
filters were sequentially hybridized with random primed 32P-labeled probes for 20 to 24 hours at 42°C and washed
under stringent conditions according to the recommendations of the
supplier. Autoradiographs were developed after 1 to 7 days.
Probes.
PTEN gene deletions (or rearrangements) were assessed with a genomic
2.8-kb EcoRI fragment of PTEN, JL25. A probe to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used to assess equal loading of
DNA in the Southern blot analysis. The JL25 probe was a gift from Dr
Ramon Parsons (Columbia University Cancer Center, New York,
NY). The GAPDH probe was purchased from the American
Tissue Culture Collection (Rockville, MD).
Single-strand conformation polymorphism analysis.
Oligonucleotide primers were synthesized by the solid-phase triester
method. Nine primer sets designed to amplify exons 1 to 9 and
corresponding to those previously described by Liaw et al13
were used. A second alternative primer set to exon 3 was used in some
cases.12 The sequence of the primers listed from the most
5 set to the most 3 set is as follows: exon 1: X1R246, 5-ACTACGGACATTTTCGCATC-3; CONBF1, 5-GAGGATTATTCGTCTTCTCCC-3; exon
2: X2F102, 5-GTTTGATTGCTGCATATTTCAG-3; X2R88,
5-TCTAAATGAAAACACAACATGAA-3; exon 3: X3F135,
5-ATTTCAAATGTTAGCTCATTTTG-3; X3R115, 5-TTTAGAAGATATTTCAAGCATAC-3; exon 3 alternate: 3alt-F, 5-TGTTAATGGTGGCTTTTTG-3; 3alt-R,
5-GCAAGCATACAAATAAGAAAAC-3; exon 4: X4F51,
5-CATTATAAAGATTCAGGCAATG-3; X4R108, 5-GACAGTAAGATACAGTCTATC-3; exon
5: X5F1, 5-ACCTGTTAAGTTTGTATGCAAC-3; X5R1,
5-TCCAGGAAGAGGAAAGGAAA-3; exon 6: X6F575,
5-CATAGCAATTTAGTGAAATAACT-3; X6R169, 5-GATATGGTTAAGAAAACTGTTC-3; exon 7: X7F50, 5-TGACAGTTTGACAGTTAAAGG-3; X7R147,
5-GGATATTTCTCCCAATGAAAG-3; exon 8: X8F1,
5-CTCAGATTGCCTTATAATAGTC-3; X8R1, 5-TCATGTTACTGCTACGTAAAC-3; and
exon 9: X9F528, 5-AAGGCCTCTTAAAAGATCATG-3; X9N1738R,
5-TTTTCATGGTGTTTTATCCCTC-3.
The polymerase chain reaction (PCR) was performed in standard buffer
conditions as described previously21 with 100 to 200 ng
genomic DNA, 200 nmol/L of each primer, 200 mmol/L dNTPs, 1 µCi
[ -32P]dCTP (specific activity, 6,000 Ci/mmol), 10 mmol/L Tris hydrochloride (pH 8.3), 1.5 to 2.5 mmol/L
MgCl2, 50 mmol/L KCl, 0.01% gelatin, and 0.5 U Ampli Taq
DNA Polymerase (Boehringer Mannheim, Indianapolis, IN), plus 6%
dimethyl sulfoxide for the primer set of exon 5 and exon 1, in a final
volume of 10 µL. After an initial denaturation at 94°C for 3 minutes, 30 cycles of denaturation (94°C for 1 minute), annealing
(55°C for the primer sets of exons 3, 5, and 7; 56°C for the
additional primer set of exon 3; and 58°C for the primer sets of
exons 1, 2, 4, 6, 8, and 9 [for 1 minute]), and extension (72°C for
1 minute) were performed on DNA thermal cycler 480 (Perkin-Elmer Applied Biosystems, Foster City, CA). The final extension was performed
for 10 minutes.
Samples of exons 1 to 4, 6, 7, and 9 were loaded onto an MDE gel (FMC
Corp, Rockland, ME) containing 10% glycerol, and samples of exons 5 and 8 were analyzed using a 6% acrylamide gel containing 10%
glycerol. To obtain optimal separation of the single-stranded conformers, the ratio of methylene-bis-acrylamide to acrylamide was
1:19. Gel electrophoresis was performed at 8W for 12 to 16 hours.
Autoradiography was performed using an intensifying screen and an
exposure time of 4 to 36 hours at  70°C.
Sequencing strategy.
After detection of a variant allele, DNA was extracted from the excised
SSCP gel fragment by overnight incubation in 60 µL distilled water at
4°C or 65°C for 10 minutes and subsequently reamplified by PCR. The
PCR products were sequenced directly using a cycle sequencing method
(AmpliCycle Sequencing Kit; Perkin-Elmer Applied Biosystems) and
[-32P]dCTP. The product of the exon 8 fragment was
sequenced using dye-termination cycle sequencing and an automated
sequencer (Perkin-Elmer Applied Biosystems 373) following ligation to
pCR2.1 (TA cloning kit; Invitrogen, Carlsbad, CA). The primers for
sequence analysis were the same primers already listed. One additional
primer for sequence analysis of exon 1 and five additional primers to
the exon 8 fragment were also synthesized to assist in sequencing: exon
1-1F, 5-TCTAAGAGAGTGACAGA-3; exon 8-1, 5-CATTCTTCATACCAGGACCAG-3; exon 8-2, 5-ATAATGACAAGGAATATCTAG-3; exon 8-3, 5-CTTGTCATTATCTGCACGCTCT-3; exon 8-4, 5-CACATCACATACATACAAGTC-3;
and exon 8-5, 5-CTGGTCCTGGTATGAAGAATGT-3.
Following the sequencing reactions, 8 µL of each termination reaction
was added to 10 µL stop solution and heated at 95°C for 5 minutes,
and 3 µL was loaded onto a sequencing gel consisting of 6%
polyacrylamide and 7 mol/L urea in TBE buffer. Gel electrophoresis was
performed at 55W for 2 to 3 hours and subjected to autoradiography for
16 hours at 70°C.
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RESULTS |
Analysis of cell lines.
We initially examined 27 hematopoietic cell lines representing a
variety of cell lineages for gross deletion or rearrangement of the
PTEN gene by Southern blot analysis using probe JL25. Homozygous deletion of the PTEN gene was detected in one LBL cell line (CEM; Fig
1). None of the other cell lines showed
either a rearrangement or deletion of PTEN. Because the JL25 probe
includes only a portion of the PTEN gene, we further mapped the extent
of homozygous deletion in CEM using PCR primers to the PTEN exons (the
same as used for PCR-SSCP). PCR products were generated from exon
primer pairs 1 and 6 to 9 but not from exon primer pairs 2 to 5, indicating that the region of homozygous deletion was limited to exons
2 to 5 (data not shown).
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| Fig 1.
Southern blot analysis of PTEN gene.
High-molecular-weight DNA was digested with HindIII, and the
blot was hybridized with (top panel) the JL25 probe or (bottom panel)
GAPDH to estimate DNA loading. CEM (lane 10) showed homozygous deletion
of the PTEN gene. Lane 1, placental DNA; lane 2, SUDHL4; lane 3, SUDHL5; lane 4, SUDHL6; lane 5, SUDHL10; lane 6, NUDHL1; lane 7, KMS5;
lane 8, KMS11; lane 9, Jim3; lane 10, CEM; lane 11, HUT102; lane 12, L428; lane 13, YT.
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To investigate whether mutations of the PTEN gene were present in the
cell lines, we next screened the PTEN coding region (exons 1 through 9)
by PCR-SSCP using previously published primer sets as described in
Materials and Methods. Five cell lines (Jurkat, SUDHL10, Jim3, Raji,
and PA682PB) had variant conformers in PCR-SSCP analysis (Fig
2). Sequence analysis showed that small
deletions, insertions, and single-nucleotide alterations accounted for
these alterations (Table 1). The Jurkat
cell line contained two different paired alterations within exon 7 (four variant bands) without "normal" conformers present. Two
variant bands corresponded to an allele containing a 9-bp insertion
preceded by a 2-bp deletion that disrupted codon 234 (Fig 3). This
abnormality resulted in several downstream stop codons. The second pair
of variant conformers was the result of a 39-bp insertion after codon
246 that contained a stop codon (TGA) at the new codon 247 (data not
shown). The presence of two pairs of variant bands suggests involvement
of both alleles or intratumoral heterogeneity. The SUDHL10 cell line showed variant conformers in exons 3 and 5, without normal conformers present. Sequence analysis showed that the exon 3 alteration occurred in codon 68, resulting in the substitution of tyrosine for histidine (TAC to CAC; Tyr to His), and the exon 5 alteration occurred in codon
162, resulting in the substitution of aspartic acid for histidine (GAC
to CAC; Asp to His). The alteration in PA682PB occurred in exon 6 and
was the result of a G to C substitution in codon 166, resulting in the
substitution of valine for leucine (Val to Leu; GTA to CTA; Fig
3). Again, the normal conformers were not
present. CEM, in which the deletion of the PTEN gene was detected by
Southern blot analysis, showed no products for exons 2 through 5 (as
previously mentioned) and a normal SSCP pattern for exons 1, 6, 7, 8, and 9. Although Jim3 and Raji displayed variant conformers in the
PCR-SSCP of exon 8, no alterations were detected in exon sequences.
Instead, Jim3 had a 2-bp deletion in a 13-bp poly-T tract located just
proximal to the 5 exon 8 splice site, and Raji contained a 38-bp
deletion involving the proximal two Ts of the same poly-T tract and the
preceding 36 bps. In both of the latter cell lines, normal conformers
were also present. Altogether, we identified sequence alterations in 2 of 6 LBL cell lines, 1 of 6 LBCL cell lines, 1 of 3 myeloma cell lines,
and 2 of 6 BL cell lines (Table
2).
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| Fig 2.
Examples of PCR-SSCP analysis of PTEN exons (A, exon 1;
B, exon 3; C, exon 6; D, exon 7; E, exon 8). DNA was prepared and
subjected to PCR-SSCP analysis. In each analysis, lane 1 contains
control DNA (placental). Alterations are present in exon 1, lane 5 (primary LBCL), exon 3, lane 4 (SUDHL10), exon 6, lane 3 (PA682PB),
exon 7, lane 5 (Jurkat), and exon 8, lanes 2, 11, and 16 (primary case
1706, Jim3, and primary case 1517, respectively).
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| Fig 3.
Sequence analysis of SSCP-positive cell lines. (A) A  G transition in codon 16 (TAT TGT; Tyr His) in primary LBCL
(case 2734) (reverse sequence depicted). (B) G C transversion in
codon 166 (GTA CTA; Val Leu) in PA682PB. (C) 2-bp deletion
followed by 9-bp insertion (GGCCCATGG) at codon 234 in Jurkat cell
line. Control sequences are derived from placental DNA.
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Analysis of primary cases.
Initial results from the cell lines encouraged us to study a larger
series of primary lymphomas and control samples. Because all of the
cell lines with PTEN alterations were derived from high-grade
neoplasms, we focused our attention primarily on related high-grade
primary tumors. PCR-SSCP analysis was performed on 65 primary tumors,
including 24 LBL, 30 LBCL, 7 BL, and 4 ALCL. Southern blot analysis was
also performed on the 24 LBL cases, since these samples had a
sufficiently high number of tumor cells to allow reliable
interpretation of potential deletions. None of the LBLs showed
deletions or rearrangements of PTEN by Southern blot analysis. Among
the entire group of primary cases, 3 of 65, all LBCL, showed SSCP
alterations (Table 2 and Fig 2). In one case, sequencing of the variant
conformer detected with the exon 1 primer set revealed an A to G
transition located 12 bp before the initiation codon plus a second
mutation at codon 16 that resulted in the substitution of a tyrosine
for a cysteine (Tyr to Cys; TAT to TGT; Fig 3). This case lacked the
normal set of conformers. In the other two LBCL cases, variant
conformers were detected in the exon 8 SSCP analysis. One retained the
normal conformers as well. Similar to the results for Jim3 and Raji
cell lines, these cases showed small deletions in and around the intron
7 poly-T tract 5 to exon 8. Case 1517 showed a 2-bp deletion in the
poly-T tract, while case 1706 had the identical 38-bp deletion that was
present in the Raji cell line involving the first two bases of the
poly-T tract and the preceding 36 bp. None of the 25 nonneoplastic
patient samples displayed variant conformers by SSCP.
| |
DISCUSSION |
In the present study, we examined 27 hematopoietic cell lines and 65 high-grade lymphoid neoplasms for mutation or deletion of the newly
described PTEN/MMAC1/TEP1 tumor suppressor gene. We identified
alterations of coding sequences in 4 of 27 hematopoietic cell lines,
while another 2 cell lines showed small deletions within intron 7 unaccompanied by alterations of coding or splice-junction sequences. Of
65 primary cases, one showed a single nucleotide alteration in exon 1 and two others showed small deletions in intron 7 outside of classic
splice-junction sequences.
Five of the nine alterations identified involved exon sequences, two of
which were predicted to interfere with translation of an intact
protein. The CEM LBL-derived cell line showed homozygous loss of exons
2 to 5, which encode the critical phosphatase domain of PTEN. The
Jurkat LBL cell line showed two variant conformers, one with a 2-bp
deletion followed by a 9-bp insertion that resulted in a frameshift,
and the other with a 39-bp insertion containing a stop codon. The
presence of two different mutated conformers suggests that either both
alleles of Jurkat are mutated or there is intratumoral heterogeneity
with respect to the PTEN/MMAC1 locus. The SUDHL10 and PA682 cell lines
each contained nucleotide variations different from the published
germline sequence. SUDHL10 contained two alterations, one resulting in
the substitution of tyrosine for histidine at codon 68 (exon 3) and the
other resulting in the substitution of an aspartic acid residue for the
wild-type histidine at position 162 (exon 5). The nucleotide variant in PA682 was relatively conservative, resulting in the substitution of
leucine for the germline valine at position 166 (exon 6). One primary
LBCL had a sequence variation at codon 16 (exon 1) resulting in the
substitution of tyrosine for the germline cysteine. In addition, this
case also had a nucleotide transition (A to G) located 12 bp before the
initiation codon. The normal conformers were present but much fainter
than the variant conformers in this case. Although we did not perform a
loss of heterozygosity analysis for this study, the fact
that the normal conformers either were not observed in the cell lines
or were of diminished intensity in the primary case raises the
possibility that the normal allele was lost in the tumors.
In four samples, we could not identify alterations in the coding
sequences, although variant conformers were detected in the exon 8 SSCP
analysis. All but one of these variants were associated with the
presence of the normal conformer set. These alterations were found to
be the result of small deletions (2 to 38 bp) occurring within a
poly-T-rich tract in intron 7, which is located just before the start
of exon 8. Normal tissue from our patients was not available to
determine with certainty whether these deletions were polymorphisms.
However, a similar deletion of 39 bp in this region was reported by
Okami et al22 in a primary head and neck cancer and shown
to be a polymorphism, suggesting that our deletions are likely
polymorphisms also. The fact that we did not identify any deletions in
25 control samples indicates that they are rare.
Sequence alterations in the cell lines were not confined to a
particular type of aggressive lymphoid neoplasm, indicating that PTEN
variants are not specific to a particular subtype of tumor. Two
occurred in T-cell LBL cell lines, 2 in cell lines derived from BL, 1 in a cell line derived from LBCL, and 1 other in a myeloma cell line.
In the primary tumors, sequence alterations were identified in only 3 LBCLs, and 2 of these 3 were exon 7 deletions. Since the frequency of
PTEN variants in the primary tumor group is low, a larger number of
cases must be studied to identify prevalence rates with more accuracy.
Our study has identified PTEN sequence variations in a small percentage
of lymphoid neoplasms. The frequency of alterations was higher in cell
lines than in primary tumors, and this finding may reflect selection
for PTEN/MMAC1 mutations during cell line development. Several
questions remain regarding the extent and relevance of PTEN alterations
in lymphoid neoplasms that are not addressed adequately in the present
study. First, in only two LBL cell lines have we shown definitive
evidence of mutation (ie, homozygous deletions or nonsense mutations).
In all of the other cell lines and cases, the alterations identified
were either nucleotide substitutions or intronic deletions. Although
the intron deletions may represent rare polymorphisms as discussed
earlier, we would argue that the nonconservative nature of several of
the missense variants (SUDHL-10 and case 2734), their absence in the
normal control population, and the apparent loss of the normal allele in SSCP analysis make these alterations more likely to be somatic mutations rather than polymorphisms. However, since normal tissues from
the lymphoma samples and cell lines were not available for study, we
cannot formally exclude the possibility that these missense variants
represent rare polymorphisms. Second, we did not examine low-grade
lymphomas, choosing instead to focus on high-grade neoplasms because
they most closely correlated with the types of cell lines we studied,
and because initial studies of PTEN/MMAC1 suggested that this gene is
preferentially involved in more advanced or aggressive tumors, as the
name MMAC itself suggests: mutated in multiple advanced cancers.
However, recently, at least one study has suggested that abnormalities
of PTEN/MMAC1 may also occur early in some types of neoplasia such as
thyroid cancer15 and melanoma.12 Thus, it may
also be worthwhile to expand the series of lymphomas studied to include
low-grade neoplasms as well. Third, the current study used techniques
to specifically identify coding region mutations or, in a subset of the
cases studied, larger gene deletions. It is important to note that
inactivation of tumor suppressor genes can also occur through
mechanisms that do not alter gene coding regions, such as gene
methylation, and through other abnormalities involving noncoding
sequences such as promoter sequences.
| |
FOOTNOTES |
Submitted February 10, 1998;
accepted July 1, 1998.
Address reprint requests to Mark Raffeld, MD, Laboratory of Pathology,
National Cancer Institute, Bldg 10, Room 2N110, 9000 Rockville Pike,
Bethesda, MD 20892; e-mail: mraff{at}box-m.nih.gov.
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