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From the Molecular Neuro-Oncology Laboratory,*
Department of Pathology and Neurosurgical Service, Massachusetts
General Hospital and Harvard Medical School, Boston, Massachusetts; the
Department of Biostatistics,
Harvard School
of Public Health, Boston, Massachusetts; and the Departments of
Clinical Neurological Sciences and Oncology,
University of Western Ontario and London Regional Cancer Centre,
London, Ontario, Canada
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Introduction |
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Allelic loss of chromosome 10q is one of the most frequent genetic alterations in gliomas, and has been reported in 74 to 87% of glioblastomas,5-7 37 to 75% of anaplastic astrocytomas,6-8 and 13 to 31% of anaplastic oligodendrogliomas.4,9,10 Although chromosome 10q loss in malignant gliomas usually involves all or most of the long arm, the 10q25-26 region has been suggested as the primary tumor suppressor candidate region.8,11-13 To date, three genes have been potentially implicated as targets of 10q loss in glioblastomas: PTEN, DMBT1, and ERCC6.
The PTEN gene at 10q2314-16 is mutated in multiple sporadic cancers that undergo 10q loss, including glioblastomas (28 to 46%) and anaplastic astrocytomas (5 to 23%).6,7,17 PTEN negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and thereby affects control of cell cycle and cell survival.18,19 Ectopic expression of wild-type PTEN in PTEN-mutant gliomas markedly sensitizes these cells to irradiation, but not to five chemotherapeutic drugs,20 raising the possibility that PTEN status may relate to therapeutic sensitivity in malignant gliomas. However, mutations only rarely occur in other types of tumors that lose 10q, such as malignant meningioma and pancreatic cancer, suggesting the presence of other 10q tumor suppressors.21,22
The DMBT1 gene at 10q25.3-26.1 encodes a secreted or membrane-linked protein, which seems to participate in epithelial differentiation and in immune regulation.23 DMBT1 has been proposed as a candidate tumor suppressor gene for glioblastoma, medulloblastoma, lung cancer, and gastrointestinal cancers based on homozygous deletions and lack of expression in these tumors.24-27 DMBT1, however, has a repetitive genomic structure, including 14 scavenger receptor cysteine-rich domains, and is therefore potentially susceptible to chromosomal instability.28 Indeed, a subset of normal individuals harbor hemizygous DMBT1 deletions, indicating that homozygous deletions in tumors may be a result of pre-existing constitutional deletions uncovered by allelic loss.23
Finally, the most centromeric 10q candidate, the ERCC6 gene at 10q11.2-21.2, is responsible for complementation group B of Cockayne syndrome, an autosomal recessive disorder characterized by postnatal growth failure, mental retardation, and cutaneous photosensitivity.29 ERCC6 is involved in a subpathway of nucleotide excision repair (transcription-coupled repair) for preferential repair of damage to the transcribed strand of active genes.30,31 Of note, mutations in exon 2 of the ERCC6 gene have been noted in 17.5% of high-grade gliomas.32
To date, no extensive analysis of these 10q candidate glioma suppressor genes has been reported for anaplastic oligodendrogliomas, which undergo molecular alterations that are often distinct from astrocytic malignant gliomas such as glioblastoma.33 Moreover, because our previous studies suggested that chromosome 10q loss may denote tumors that respond less often to chemotherapy,4 the identification of a 10q anaplastic oligodendroglioma gene could provide biological information relevant to understanding either chemoresistance or overall tumor behavior. We therefore analyzed the PTEN, DMBT1, and ERCC6 genes as well as the regional pattern of 10q loss in a large series of anaplastic oligodendrogliomas, and addressed the relevance of the genetic alterations to pathogenesis, chemosensitivity, and prognosis.
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Materials and Methods |
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Seventy-two anaplastic (grade III) oligodendrogliomas were classified and graded according to World Health Organization criteria34 by at least two neuropathologists, and cases with definite astrocytic components were excluded. Of the 72 patients, 47 were newly diagnosed patients who underwent chemotherapy as an integral part of initial treatment strategy; 45 patients received the PCV regimen of procarbazine, lomustine (CCNU), and vincristine, one received carmustine (BCNU) and one received temozolamide. Thirty-seven of these 47 patients received radiation therapy after completing a chemotherapy program or at the time of tumor recurrence after chemotherapy. Twenty-five of the 72 patients were treated with chemotherapy at recurrence after initial treatment with radiation therapy. Neuroradiological responses to chemotherapy were noted in 24 of the 36 evaluable (ie, with neuroradiologically assessable residual disease after surgery) tumors (67%) treated with chemotherapy as an initial treatment regimen, and in 23 of the 24 evaluable tumors (96%) treated with chemotherapy at recurrence. These investigations have been approved by the Massachusetts General Hospital Subcommittee on Human Studies and the Review Board for Health Science Research Involving Human Subjects at the University of Western Ontario. Tumor DNA was extracted from formalin-fixed, paraffin-embedded sections.35 Constitutional DNA was extracted from blood leukocytes or from formalin-fixed, paraffin-embedded sections of adjacent, uninvolved brain or other tissues.
Analysis of Allelic Loss of Chromosome 10q
Allelic loss of chromosome 10q was assessed at 14 polymorphic
loci, with particular emphasis on the ERCC6,
PTEN, and DMBT1 regions: at D10S196, D10S109,
D10S1687, D10S608, D10S215, D10S2491 (
20 kb from the 5' end of the
PTEN gene36
), D10S583, D10S185, D10S88, D10S187,
D10S587 (near DMBT124
), D10S1723, and D10S169 (from
centromeric to telomeric, Figure 1
) using
microsatellite analysis;35
and at the ERCC6
locus with a single nucleotide polymorphism in exon 2 (135G/C,
Leu45Leu) using single-strand conformation polymorphism (SSCP) analysis
(see below).
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The entire coding sequence and intron/exon borders of PTEN were screened for mutations using SSCP.37,38 Forward primers to amplify exon 1 and exon 3 were redesigned to avoid primer overlap and to allow amplification of DNA extracted from archival materials (ex 1f: 5'-CATCCTGCAGAAGAAGCCCC-3', 182 bp; ex 3f: 5'-TTGTTAATGGTGGCTTTTTG-3', 169 bp). In tumors with 10q loss, the 5' UTR 252 bp upstream of the open reading frame was also examined.38 The primers are intronic (except for exon 8-2) and therefore do not amplify the processed PTEN pseudogene.39,40 Because mobility shifts caused by PTEN mutations could be subtle because of high A-T content,7 most polymerase chain reaction (PCR) fragments were examined with more than one gel condition. For SSCP of ERCC6 exon 2, novel primer sets were designed to amplify three overlapping fragments covering 91% of the coding region of exon 2, including all reported mutation sites.32 ERCC6 products were separated on 8% and/or 10% nondenaturing polyacrylamide gel (AA:BIS 19:1) containing 10% glycerol at room temperature at 6 to 8 W. Tumors with altered PTEN or ERCC6 migration patterns were cycle-sequenced (fmol DNA cycle sequencing system; Promega, Madison, WI) bidirectionally using separately amplified PCR products.
Reverse Transcriptase-PCR
Two glioma cell lines (Gli13, Gli46) that have a T insertion in a stretch of 15 T before exon 8 of PTEN were investigated by reverse transcriptase-PCR for expression of an aberrant transcript. Gli46 was heterozygous, whereas Gli13 was homozygous, for the insertion. Total RNA was extracted from these two cell lines as well as from two cell lines (Gli36, Gli49) with wild-type sequence, using TRI reagent (Molecular Research Center, Inc., Cincinnati, OH). Reverse transcription with Superscript II and the oligo (dT) primer (Life Technologies, Inc., Rockville, MD) was followed by 35 cycles of PCR using ex 7-2f and ex 9-2r as primers.38 PCR products were separated on 1.2% Tris borate-ethylenediaminetetraacetic acid (TBE)-agarose gel and visualized by ethidium bromide staining.
Multiplex PCR
Homozygous deletions of the PTEN gene were assayed using a modification of a comparative multiplex PCR approach described previously.38 Two sets of oligonucleotide primers were used to amplify a 165-bp fragment of the 3' part of PTEN exon 5 (ex 5-2f, ex 5-2r), and a 171-bp fragment of intron 7 of the desmin gene (in7f, in7r) as a control. The desmin gene is on chromosome 2q, a site rarely altered in oligodendrogliomas.10 PCR was performed in a final volume of 10 µl containing 1 to 10 ng genomic DNA, 50 mmol/L KCl, 1.5 mmol/L MgCl2, 10 mmol/L Tris-HCl, pH 8.3, 0.2 mmol/L of each dNTP, 1 µmol/L of each primer, 0.5 U Taq polymerase (Fisher Scientific, Pittsburgh, PA). PCR conditions consisted of initial denaturation at 95°C for 5 minutes, 31 cycles of 95°C for 30 seconds, 52°C for 30 seconds, and 72°C for 40 seconds, and a final extension step of 10 minutes at 72°C. PCR products were separated on 4% TBE-agarose gel and visualized by ethidium bromide staining. Quantitation of the bands was performed with the Image-Pro Plus program (Media Cybernetics, Silver Spring, MD), and the PTEN:desmin ratio was calculated. Because DNA extracted from paraffin-embedded tissues tended to show lower PTEN:desmin ratios than DNA extracted from blood, titration assays using serial mixtures of normal DNA and a PTEN homozygously deleted cell line DNA was not applicable. Instead, homozygous deletions were scored by comparison to the ratios of tumors with PTEN mutations accompanied by allelic loss.
For homozygous deletions of DMBT1, two multiplex PCR assays were used. Because most reported homozygous deletions (23 of 27) within the DMBT1 gene involved the g14ext/g14 locus in intron 18,24-27 these two closely positioned STSs were used as target sequences. A 190-bp sequence from chromosome 8 (c12) and a 187-bp sequence of the APEX nuclease gene on chromosome 14q were used as controls for g14ext and g14, respectively. All primer sequences, except the forward primer to amplify STS g14 (5'-ATTAGGGCTGCTGAGCAAAG-3'), have been published.24,41 PCR was performed for 29 cycles at annealing temperature of 60°C to amplify g14ext/c12, and the annealing temperature was gradually decreased from 63°C to 56°C with 30 cycles in total for amplification of g14/APEX. The products were separated on 3% TBE-agarose gels. Homozygous deletions were scored by comparing the DMBT1:control ratio of the test tumor to that of mixture consisting of 30% constitutional DNA of each case and 70% U343MG cell line DNA, which has a homozygous deletion at the g14ext/g14 locus.
Long-Range PCR
Long-range PCR was used to evaluate constitutional DMBT1 deletions. The extent of the deletion was initially estimated based on published Southern blot data of a constitutional hemizygous deletion involving the g14ext/g14 locus in a normal individual (G3 configuration),23 and was further defined by several PCR amplifications with unique sequence primers for each exon/intron using the homozygously deleted U343 cell line. The primers were designed in DMBT1 intron 10 (L1595: 5'-CTGCTGAGCATTGCCTGTGTTCTA-3', 32921 to 32944) and intron 26 (L1629: 5'-TCAAAGTCAAAGAAGCAGTGACACCCTA-3', 51129 to 51102) (referenced sequence: GenBank AJ 243211). PCR was performed with 20 ng of blood DNA as template and the Expand Long Template PCR system (Roche Molecular Biochemicals, Mannheim, Germany). PCR conditions consisted of initial denaturation at 94°C for 2 minutes, 28 cycles of 94°C for 30 seconds, 66°C for 30 seconds, and 68°C for 6 minutes, and a final extension step of 5 minutes at 68°C. The products were separated on 0.8% Tris acetate-ethylenediaminetetraacetic acid (TAE)-agarose gels. The sequences of PCR products from case 1968 and other deletion cases (not included in this study) were confirmed for more than 300 bp of both 5' and 3' ends, as well as for unique sequences flanking the deletion. Sensitivity and specificity of the assay was verified by comparison to Southern blot data with probe DMBT1/sr1sid2 (generous gift from Dr. Jan Mollenhauer, Heidelberg, Germany) and by long-range PCR data using a different antisense primer (L1591: 5'-GTCATATCAGCTCTGAATAGAAAAGTGC-3', 49875 to 49848). Long-range PCR amplifying 12.3 kb of DMBT1 sequence (primers: L1547, 5'-GACTTTAGCCATTAGGACGTGC-3', within the deletion; L1550, 5'-AACAGGATTCCACGGGAGAC-3', outside the deletion) was used to confirm DNA quality.
Analysis of the other Molecular Genetic Factors
Tumors included in this study were also analyzed for other molecular genetic changes common to malignant gliomas: allelic losses of 1p and 19q, mutations of exons 5 to 8 of TP53, homozygous deletions of CDKN2A, and EGFR amplification. These assays and their results are detailed elsewhere.42
Statistical Analysis
To avoid the potential selection bias associated with the group of 25 patients treated with chemotherapy at recurrence, statistical analysis was performed only on the 47 patients who were initially treated with chemotherapy. Odds ratios were used to measure the pair-wise associations among genetic alterations. Response to chemotherapy was defined radiographically, as a decrease in tumor size of 50% or greater. Survival time was measured from diagnosis, and censored at the time of last follow-up. Logistic regression was used to model response, and Cox proportional hazard regression to model survival. Univariate models and multivariate models that adjusted for 1p loss and 10q loss were examined. Survival distributions were estimated using Kaplan-Meier curves.
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The D10S196, D10S608, D10S2491, D10S185, D10S187, D10S587, and
D10S1723 loci were studied in all cases; the other loci were studied in
49 to 91% of cases. Five tumors showed equivocal results and were
excluded from deletion mapping. Fourteen of the remaining 67 tumors
demonstrated allelic loss (Figure 1)
; this included 12 of 45 tumors
initially treated with chemotherapy. Case 1896 showed loss at only the
most distal marker, which was considered nonspecific. All 14 cases with
allelic loss had deletions that involved both the PTEN and
DMBT1 regions. The ERCC6 region appeared spared
in cases 1826 and 1968. Cases 1760 and 1948 demonstrated retention of
heterozygosity flanked by allelic loss at adjacent markers (Figure 2)
, which often indicates homozygous
deletion.43
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All fragments covering the entire coding sequence of
PTEN and ERCC6 exon 2 were successfully analyzed
in all 72 anaplastic oligodendrogliomas. Six tumors showed
tumor-specific SSCP migration shifts of PTEN. Sequencing
demonstrated two tumors with small deletions resulting in frame shifts
and predicted premature protein termination, one tumor with mutation at
a splice donor site, and three tumors with missense mutations (Table 1)
. Five of six tumors with mutations had
allelic loss of 10q, whereas a single tumor (case 1722) retained
heterozygosity at all informative loci including those flanking
PTEN (Figure 1)
. Case 1722 had combined allelic losses of 1p
and 19q, but lacked TP53 mutation, CDKN2A
deletion, and EGFR amplification. Seventeen tumors had an insertion of
a T into a 15 T stretch at the splice acceptor site before exon 8
[IVS7(-3) to (-2)insT]; this insertion was also present in
corresponding constitutional DNA. Because an alternative
PTEN transcript excluding exon 5 has been reported in a
tumor in which the only sequence change identified (in the tumor and
corresponding blood) was a T insertion into a polyT tract in intron
4,7
the possible expression of splice variants was
investigated by reverse transcriptase-PCR in two glioma cell lines with
the T insertion at the splice acceptor site in intron 7. Reverse
transcriptase-PCR to amplify 3' part of exon 7, exon 8, and the coding
region of exon 9 failed to reveal any aberrant transcript, suggesting
that the T insertion before exon 8 does not affect exon 8 splicing
(data not shown). No tumor-specific SSCP migration shifts were noted in
exon 2 of the ERCC6 gene.
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All 72 anaplastic oligodendrogliomas were assayed for homozygous
PTEN and DMBT1 deletions. For the PTEN homozygous
deletion assay, PTEN:desmin ratios were
equivalent in nine normal DNA samples extracted from
paraffin-embedded tissues, and PTEN:desmin
ratios were constant over a range of 0.05 to 5 ng/µl of template DNA
concentration. PTEN:desmin ratios in tumors with
mutations accompanied by allelic losses ranged from 0.55 to 0.72, with
a mean value of 0.65. Case 1760, which had findings suggestive of
homozygous PTEN deletion on loss of heterozygosity studies
(see above), demonstrated a markedly lower ratio (0.16 to 0.29, over
repeated experiments) than those tumors with mutations and was
therefore considered to have homozygous PTEN deletion
(Figure 3A)
. The other cases with allelic
loss showed ratios indistinguishable from those of the mutation cases,
and no other tumor had decrease of PTEN amplification
comparable to case 1760.
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. These two tumors had
allelic loss of chromosome 10q, but did not have detectable
PTEN mutations or deletions (Figure 1)
. The homozygous
deletions in these two tumors were confirmed by the g14:APEX
multiplex assay (data not shown). Constitutional Hemizygous DMBT1 Deletion
The possibility of constitutional hemizygous deletion of the
g14ext/g14 locus was investigated by long-range PCR in six patients for
whom blood DNA was available and whose tumors had chromosome 10q loss.
Because the wild-type PCR product would be greater than 18 kb, only the
allele with the intragenic deletion is amplified. Long-range PCR
demonstrated constitutional deletion within the DMBT1 gene
in patient 1968; the homozygous deletion in the tumor thus arose after
allelic loss of the wild-type allele (Figure 4)
. Partial sequencing and exon by exon
(or intron) investigation by PCR unique to each exon/intron showed that
the deletion spanned 12.7 kb from intron 14 to exon 25 (or exon 14 to
intron 24; exon 14 and exon 25 are identical). Homologous recombination
between DMBT1 repeat 2-3 and 2-7 was most likely responsible
for the deletion.28
Unfortunately, blood DNA was not
available on case 1828.
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Twelve of the 14 cases with 10q loss were newly diagnosed tumors
for which chemotherapy was planned at the time of diagnosis, and were
included in the statistical analysis. Allelic loss of chromosome 10q
was negatively associated with 1p loss (odds ratio = 0.024,
P < 0.001), the strong predictor for increased
chemosensitivity and longer survival4
found in 27 of the
47 cases included in the statistical analysis. Accordingly, response to
chemotherapy was obtained in only 2 of 10 evaluable cases with allelic
loss of 10q. Loss of 10q was negatively associated with
chemotherapeutic response (P = 0.002), but was
no longer predictive of poor response among patients whose tumors did
not have 1p loss (P = 1.00). The patients whose
tumors had 10q loss had significantly shorter survival times than
patients whose tumors had both 10q alleles (P <
0.001; median survival with 10q loss = 15.3 months; without 10q
loss = 123.4 months), and allelic loss of chromosome 10q was
significantly associated with decreased survival time even after
adjusting for 1p loss (Table 2
, models 1
and 2).
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, and PTEN alterations were
independently predictive of decreased survival time even after
adjusting for 10q and 1p loss (Table 2
, models 3 to 6). The two tumors
that had homozygous deletions within DMBT1 gene did not
respond to PCV chemotherapy, and had short survival times (16 months
and 49 months).
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because PTEN negatively regulates the PI3K-Akt pathway, and Akt suppresses apoptosis and promotes cell survival by phosphorylating and inhibiting inducers of apoptosis,19 the relationship between PTEN status and therapeutic sensitivity is of interest. Gene transfer of wild-type but not mutant PTEN markedly sensitizes PTEN-deleted glioma cells to irradiation and CD95 ligand-induced apoptosis, whereas PTEN gene transfer has no effect on chemosensitivity to vincristine, cytarabine, teniposide (VM26), cisplatin, and BCNU.20 On the other hand, adenovirus-mediated transfer of wild-type PTEN restores doxorubicin sensitivity in bladder cancer cell lines.45 In the present study, PTEN alterations were negatively associated with response to chemotherapy, but were no longer predictive of poor response after adjusting for either 10q loss or 1p loss. Moreover, the presence of PTEN-mutated tumors that showed complete or near-complete responses, including the case with the Asp326Gly mutation, suggests that PTEN is not likely to have a major regulatory role in chemosensitivity to procarbazine, lomustine, and vincristine in gliomas.
The prognostic relevance of PTEN inactivation seems to vary according
to tumor type. For instance, PTEN mutation in endometrial
cancer has been associated with favorable clinical and pathological
characteristics, whereas PTEN mutation in pediatric
malignant astrocytomas has been associated with decreased
survival.46,47
In glioblastomas, tumors with a universally
poor prognosis, the issue remains controversial.38,48
In
this study of anaplastic oligodendrogliomas, PTEN
alterations were associated with decreased survival, even after
adjusting for 10q and 1p loss (Table 2
, model 6). Notably, even the two
tumors with PTEN mutations that responded markedly to
chemotherapy had unexpected short survival times. Overall, therefore,
PTEN gene alterations clearly have a role in the
pathogenesis of some anaplastic oligodendrogliomas and are associated
with an aggressive tumor phenotype regardless of chemosensitivity. The
mechanism for this association is unclear, but could relate to
abrogating PTEN function in the control of cellular proliferation.
Homozygous deletions and lack of expression of DMBT1 have suggested DMBT1 as a tumor suppressor gene in glioblastoma, medulloblastoma, lung cancer, and gastrointestinal cancers.24-27 However, two concerns give pause to accepting DMBT1 as a tumor suppressor: lack of experimental evidence linking DMBT1 to tumorigenesis, and constitutional hemizygous deletions in a subset of normal individuals.23 These constitutional hemizygous deletions are germline polymorphisms; their presence indicates that homozygous deletions in tumors could arise when allelic loss of the chromosome 10q bearing an intact DMBT1 gene occurs in the presence of a constitutionally deleted DMBT1 allele. In the present study, the two anaplastic oligodendrogliomas that had homozygous DMBT1 deletions were not accompanied by PTEN alterations, which could support the hypothesis that DMBT1 is a second target of 10q loss in anaplastic oligodendrogliomas. However, at least one of these two homozygous DMBT1 deletions simply reflects allelic loss unmasking a constitutional deletion polymorphism, which would argue against DMBT1 as a classical tumor suppressor gene. Nonetheless, Mollenhauer and colleagues23 proposed a possible role for DMBT1 in cancer immune surveillance, as reported for another scavenger receptor cysteine-rich protein, Mac-2-bp/90K,23,49 and so the functional significance of DMBT1 deletions remains unclear at the present time.
Mutations of exon 2 of the ERCC6 gene have been reported in 7 of 40 (17.5%) malignant astrocytic tumors.32 These findings, as well as the role of ERCC6 in nucleotide excision repair, prompted us to study ERCC6 in anaplastic oligodendrogliomas. Deletion mapping showed that the ERCC6 locus was lost in most of the tumors with 10q loss, but was not preferentially deleted relative to the PTEN and DMBT1 loci. Mutation analysis of ERCC6 exon 2 failed to demonstrate mutation in all 72 anaplastic oligodendrogliomas, suggesting that ERCC6 exon 2 is not a mutational target in anaplastic oligodendrogliomas. Cockayne syndrome is an autosomal recessive disorder and, despite both alleles being affected by severe alterations leading to protein truncation in many patients,50,51 there is no increased frequency of skin cancers. On the other hand, mice homozygously mutant for the murine ERCC6 homologue are more susceptible to skin cancer than are wild-type mice.52 Mutation analysis of the entire coding sequence and study of ERCC6 expression in a large number of gliomas will be needed to fully evaluate ERCC6 in glioma tumorigenesis.
The present study documents allelic loss of chromosome 10q in 27% of anaplastic oligodendrogliomas treated with chemotherapy at the time of diagnosis, and that 10q and 1p losses are inversely related to one another. In contrast to anaplastic oligodendrogliomas with 1p loss, tumors with 10q loss were associated with poor chemosensitivity and short survival. These observations suggest similarities between anaplastic oligodendrogliomas with 10q loss and malignant astrocytomas with 10q loss, including glioblastomas, which are universally associated with poor prognosis. In addition to our previous studies,4 Smith and colleagues53 observed loss of 1p in 73%, and combined losses of 1p and 19q in 64%, of oligodendrogliomas with consensus histological diagnosis by at least two of the three neuropathologists. Such findings suggest that anaplastic oligodendrogliomas with 10q loss or without 1p loss do not simply reflect misdiagnosis of glioblastoma. Indeed, retrospective histological review confirmed that the diagnoses of the 10q-deleted anaplastic oligodendrogliomas in this study were consistent with current criteria for anaplastic oligodendrogliomas,34 and some of the tumors with 10q loss were histologically indistinguishable from those with combined losses of 1p and 19q. The present observations and the literature thus emphasize the therapeutic and prognostic importance of molecular classification in the assessment of malignant gliomas. Once all of these molecular assays, including the more laborious screens for PTEN mutations, become clinically practical in terms of cost and efficiency, genetic testing should become a routine component of anaplastic oligodendroglioma management.
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Footnotes |
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Supported by National Institutes of Health grants CA57683 and MRC-MOP-37849.
Accepted for publication March 16, 2001.
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