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Short Communication |
From the Division of Gastrointestinal/Liver Pathology, the
Departments of Pathology*
and
Surgery,
The Johns Hopkins University School
of Medicine, Baltimore, Maryland; the Department of
Pathology,
Memorial Sloan-Kettering Cancer
Center, New York, New York; and the Department of
Pathology,
Children’s Hospital and Regional
Medical Center, Seattle, Washington
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although considered by some to be of embryonic origin based on their histological appearance,19 the molecular events underlying the genesis of these rare neoplasms have been primarily unexplored. A potential molecular association between pancreatoblastoma and the related embryonal tumor hepatoblastoma is suggested by the occurrence of both tumor types in young patients with Beckwith-Wiedemann syndrome,11,20 raising the possibility that genetic events on chromosome 11p might play a role in pancreatoblastomas as they have been shown to do in hepatoblastomas.21-25 In addition, one of the pancreatoblastomas included in the series reported here arose in a patient with familial adenomatous polyposis (FAP). Among patients with FAP, hepatoblastomas occur at increased frequency and hepatoblastomas in these patients can be demonstrated to harbor somatic, second-hit mutations of the adenomatous polyposis coli (APC) gene on chromosome 5q.26-29 This apparently first reported occurrence of a pancreatoblastoma in the setting of FAP further raised the possibility that alterations in the APC/ß-catenin pathway might play a role in FAP-associated and sporadic pancreatoblastomas.
We therefore undertook a comprehensive molecular characterization of pancreatoblastomas for genetic alterations found in other pediatric blastomas including allelic loss on chromosome 11p and alterations of the APC/ß-catenin pathway, and for mutations in the K-ras oncogene and p53 and DPC4 tumor suppressor genes that characterize the more common adult pancreatic ductal adenocarcinomas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study population consisted of nine patients with pancreatoblastomas who underwent biopsy and/or surgical resection between 1967 and 2000. One case was from The Johns Hopkins Hospital, four cases were from Memorial Sloan-Kettering Cancer Center, and four cases were from Children’s Hospital and Regional Medical Center in Seattle. In one case, tissues from both biopsy of the pancreatoblastoma and its subsequent resection after chemotherapy were available, and both samples were analyzed separately. Pancreatoblastomas were diagnosed based on characteristic histological features that included varying proportions of sheet-like and acinar growth, as well as squamoid corpuscles, the presence of which serves to distinguish these tumors from acinar cell carcinomas of the pancreas.2
Immunohistochemistry for ß-Catenin, p53, and Dpc4
Immunoperoxidase stains using diaminobenzidine as the chromogen were performed on the Techmate 1000 automatic staining system (BioTek Solutions, Tucson, AZ). Deparaffinized sections of formalin-fixed tissue at 5-µm thickness were stained with ß-catenin antibody (1:500 dilution, mouse monoclonal; Becton Dickinson Transduction Laboratories, Lexington, KY), p53 antibody (1:100 dilution, mouse monoclonal clone D07; DAKO, Carpinteria, CA), and Dpc4 antibody (1:100 dilution, monoclonal clone B8; Santa Cruz Biotechnology, Santa Cruz, CA). Heat-induced antigen retrieval using steam for 20 minutes at 80°C was used before incubation with anti-ß-catenin, anti-p53, and anti-Dpc4.
For ß-catenin, immunohistochemical labeling was evaluated for the
presence of nuclear, cytoplasmic, and membranous ß-catenin
accumulation in both the neoplasms and the normal surrounding tissues
(including nonneoplastic pancreatic ductal and acinar cells, and
hepatic parenchyma or stromal fibroadipose tissue in the case of
metastases). Nuclear and cytoplasmic accumulation of ß-catenin in the
pancreatoblastomas was graded according to the percentage of neoplastic
cells with strong immunolabeling. For p53, the percentage of positively
labeled nuclei was recorded; we considered strong nuclear labeling in
30% of tumor cells as the cutoff for p53 positivity. For Dpc4,
neoplasms were classified as showing intact Dpc4 expression if they
showed the normal pattern of strong, diffuse cytoplasmic labeling and
labeling of scattered nuclei. They were classified as showing loss of
Dpc4 expression if they showed no cytoplasmic or nuclear Dpc4 labeling.
Negative (normal saline) and positive controls were performed with each
labeling. For anti-ß-catenin, the positive control consisted of a
juvenile nasopharyngeal angiofibroma with intense nuclear ß-catenin
accumulation (accompanied by a ß-catenin gene mutation
shown previously by DNA sequencing). For anti-p53 an ovarian serous
carcinoma with nuclear p53 accumulation was used, and for anti-Dpc4 a
pancreatic ductal adenocarcinoma with Dpc4 loss was used.
DNA Extraction
Microdissection of the pancreatoblastomas for DNA extraction was performed from formalin-fixed, paraffin-embedded specimens. A 271/2-guage-needle tip was used for microdissection of routinely processed, 5-µm hematoxylin and eosin-stained slides under a low-power (x4) objective. Genomic DNA was extracted as described previously.30 Corresponding normal control DNA was extracted from adjacent nonneoplastic tissue (adjacent pancreatic acini/stroma in four cases, duodenum in one case, lymph node in one case, hepatocytes in two metastatic tumors, and inflamed granulation tissue surrounding a peritoneal implant in one metastatic tumor).
Mutation Analysis of the ß-Catenin Gene
Genomic DNA from each sample was amplified by polymerase chain
reaction (PCR) using the primer pair: 5'-ATGGAACCAGACAGAAAAGC-3'
(sense) and 5'-GCTA-CTTGTTCTTGAGTGAAG-3' (antisense). These
amplified a 200-bp fragment of exon 3 of the ß-catenin
gene that encompasses the region for GSK-3ß phosphorylation. PCR
reactions were performed under standard conditions in a 50-µl volume
containing 38 µl of Platinum PCR SuperMix (Life Technologies,
Rockville, MD), 5 µl of both 5' and 3' oligonucleotides (final
concentration of 1 µmol/L), and 2 µl (
50 ng) of genomic DNA. PCR
conditions consisted of an initial denaturation at 94°C for 3
minutes, 40 cycles of 94°C for 1 minute, 58°C for 1 minute, and
72°C for 2 minutes, and a final extension at 72°C for 7 minutes.
Negative controls using water in place of DNA template were performed
with each PCR reaction. PCR products were purified with spin columns
using the QIAquick PCR purification kit (Qiagen, Inc., Valencia, CA)
before sequencing. Automated sequencing of purified PCR products was
performed on an ABI Prism 3700 DNA Analyzer (Applied Biosystems, Inc.,
Foster City, CA) using the internal primers:
5'-AAAGCGGCTGTTAGTCACTGG-3' (sense) and 5'-CCTGTTCCCACTCATACAGG-3'
(antisense), and the resulting sequence data were analyzed with the
Sequencher analysis program (Gene Codes, Ann Arbor, MI). All mutations
were verified in both sense and antisense directions using PCR products
from independent reactions.
Base substitutions in codons 32 and 33 were further confirmed by HinfI restriction endonuclease assay (Life Technologies). The 200-bp PCR product for ß-catenin contains two HinfI restriction endonuclease sites, yielding 7-bp, 55-bp, and 138-bp DNA fragments after digestion of the wild-type allele. ß-catenin mutations in codons 32 and 33 yield only 62-bp and 138-bp fragments after digestion because of ablation of the first HinfI site.
Mutation Analysis of the APC Gene
Mutation analysis of the APC gene was performed on cases that did not show detectable ß-catenin mutations. Four sets of oligonucleotide primers (A1: 5'-CAGACTTATTGTGTAGAAGA-3' and A2: 5'-CTCCTGAAGAAAATTCAACA-3' for codons 1260 to 1359; B1: 5'-AGGGTTCTAGTTTATCTTCA-3' and B2: 5'-TCTGCTTGGTGGCATGGTTT-3' for codons 1339 to 1436; C1: 5'-GGCATTATAAGCCCCAG-TGA-3' and C2: 5'-AAATGGCTCATCGAGGCTCA-3' for codons 1417 to 1516; D1: 5'-ACTCCAGATGGATTTTCTTG-3' and D2: 5'-GGCTGGCTTTTTTGCTTTAC-3' for codons 1497 to 1596) were used to amplify the mutation cluster region of the APC gene.31 PCR reactions were performed in 50-µl volumes using the reaction mixture described above. PCR conditions consisted of an initial denaturation step of 94°C for 3 minutes, 40 cycles (94°C for 1 minute, 55°C for 1 minute, and 68°C for 1.5 minutes for APC-B, -C, and -D primer pairs and 94°C for 1 minute, 52°C for 1 minute, and 68°C for 1.5 minutes for APC-A), followed by a final extension at 72°C for 7 minutes. PCR products were purified and sequenced as described above using the same primers as for genomic DNA amplification. Mutations were verified in both sense and antisense directions.
Mutation Analysis of the K-ras Gene
The oligonucleotide primers 5'-GAGAATTCATGACTGAATATAAACTTGT-3' (sense) and 5'-TCGAATTCCTCTATTGTTGGATCATATTCG-3' (antisense) were used to amplify a region in exon 1 of K-ras spanning codons 12 and 13. PCR reactions were performed in 50-µl volumes using the reaction mixture described above, with an initial denaturation at 94°C for 3 minutes, 40 cycles of 94°C for 1 minute, 50°C for 1 minute, and 72°C for 1 minute, and a final extension at 72°C for 7 minutes. PCR products were purified and sequenced as described above using the internal primer 5'-ATTCGTCCACAAAATGAT-3'.
Allelic Loss on Chromosome 5q
Analysis for loss of heterozygosity (LOH) on 5q was performed on
cases that did not show detectable ß-catenin mutations.
LOH was assessed by microsatellite assays using PCR amplification of
three microsatellite markers (D5S82, D5S299, and D5S346) as previously
described.32
Briefly, assays were performed in 96-well
plates in 10-µl volumes, each containing 5 µl of PCR Master
(Boehringer Mannheim, Mannheim, Germany), 3.5 µl of water, 1 µl of
genomic DNA, 0.06 µl of 3' oligonucleotide, and 0.4 µl of
end-labeled 5'oligonucleotide. The 5' oligonucleotide had been
end-labeled with [
-32P]-ATP (Dupont-NEN,
Boston, MA) using T4 polynucleotide kinase (New England Biolabs,
Beverly, MA). For D5S82 and D5S299, 38 cycles of 95°C for 30 seconds,
55°C for 30 seconds, and 72°C for 1 minute were performed, and for
D5S342, 38 cycles of 95°C for 30 seconds, 58°C for 30 seconds, and
72°C for 1 minute were performed. LOH was considered to be present
when there was complete or near-complete disappearance of a
heterozygous band as compared with nonneoplastic control tissue in at
least one informative marker.
Allelic Loss on Chromosome 11p
LOH on 11p was evaluated for all pancreatoblastomas using the microsatellite markers TH (a tetranucleotide repeat polymorphism on 11p15.5-p15) and D11S1984 (a dinucleotide repeat on 11p15.5). Assays were performed and interpreted as described above using annealing temperatures of 62°C for TH and 55°C for D11S1984.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Seven of the pancreatoblastomas arose in pediatric patients ranging from 3 to 13 years (mean, 5.6 years) and two cases were in adults of ages 45 and 51 years. Five patients (56%) were female and four (44%) were male. One pancreatoblastoma (case P5) arose in a patient with FAP, a 51-year-old Caucasian woman. None of the patients was known to have Beckwith-Wiedemann syndrome.
Alterations in the APC/ß-Catenin Pathway
Strong nuclear and cytoplasmic accumulation of ß-catenin protein
was present in seven of nine (78%) pancreatoblastomas, ranging from 15
to 90% of the neoplastic cells in positive cases. The nuclear and
cytoplasmic labeling were highly correlated; neoplastic cells with
strong nuclear labeling also showed strong cytoplasmic labeling. In the
majority of cases (five of seven) that demonstrated ß-catenin
accumulation, the labeling was patchy in nature, and was diffusely
present in only two cases. Although a firm relationship between
ß-catenin labeling and morphological pattern of tumor growth was not
discernable, we noted a general tendency for areas of acinar
differentiation to lack strong nuclear and cytoplasmic ß-catenin, and
for areas of sheet-like growth and squamoid corpuscles to show
ß-catenin accumulation in those neoplasms with labeling (Figure 1)
. In addition, stromal cells in fibrous
tissue between lobules of neoplastic epithelial cells did not show
ß-catenin accumulation. Nonneoplastic pancreatic acini and
hepatocytes showed the expected membranous and faint cytoplasmic
labeling, but no nuclear or strong cytoplasmic ß-catenin.
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. All three cases with mutations at
codons 32 and 33 demonstrated the expected ablation of the
HinfI recognition site (Figure 2)
. The same
ß-catenin mutation in codon 32 was present in both the
separately analyzed initial biopsy and after chemotherapy resection
specimens from patient P1. In all pancreatoblastomas with
ß-catenin gene mutations, a mixture of the wild-type and
mutant peaks was present, as would be expected because of the dominant
effect of ß-catenin gene alterations. The somatic nature
of the ß-catenin mutations was supported by the presence
of only wild-type ß-catenin in corresponding normal
tissues from these patients.
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. Sequencing of normal
tissue from this patient revealed a germline truncating 5-bp deletion
mutation in the APC mutation cluster region spanning codons
1309 to 1311. Allelic loss on chromosome 5q was also present in the
pancreatoblastoma from this patient on LOH assays. DNA sequencing of
this neoplasm tissue also showed complete loss of the wild-type DNA
sequence in the region of the patient’s germline mutation, confirming
that the allelic loss was of the wild-type allele and therefore
represented a second-hit APC alteration. No APC
mutations or 5q LOH were detected in two other sporadic
pancreatoblastomas that did not demonstrate ß-catenin
mutations (amplifiable DNA for APC analysis was not obtained
from the remaining sporadic pancreatoblastoma).
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Allelic Loss on 11p
Allelic loss on 11p15.5 was present in six of seven (86%)
pancreatoblastomas that contained amplifiable DNA and were informative
in one or both 11p microsatellite markers (Figure 4)
. All three cases that were informative
at both TH and D11S1984 showed LOH on both markers in the
pancreatoblastomas. Because parental tissue was not available in any of
the cases, we could not determine the parental origin of the lost
allele in those pancreatoblastomas with 11p LOH.
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Infrequent (two of nine cases, 22%) loss of Dpc4 protein
expression was present in the pancreatoblastomas. In one
pancreatoblastoma, Dpc4 expression was diffusely lost throughout all
neoplastic epithelial cells, whereas the intervening fibrous bands
between neoplastic lobules retained the normal pattern of cytoplasmic
and nuclear Dpc4 immunolabeling (Figure 5)
. In the other case, focal loss of Dpc4
was present in the neoplastic epithelial component, and the fibrous
stroma again retained normal cellular Dpc4. All of the remaining
pancreatoblastomas demonstrated normal Dpc4 labeling of epithelial and
stromal cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eighty-six percent of pancreatoblastomas in this series (six of seven informative cases) demonstrated LOH for TH and D11S1984, microsatellite markers near the WT-2 locus on chromosome 11p15.5. Several cases of pancreatoblastoma have previously been reported to occur in young patients in association with Beckwith-Wiedemann syndrome,11,20 a maldevelopmental syndrome characterized by tissue overgrowth and organomegaly and an increased risk for embryonal tumors including Wilms’ tumor, hepatoblastoma, and rhabdomyosarcoma.33,34 The heterogeneous congenital and acquired manifestations of Beckwith-Wiedemann syndrome involve dysregulation of growth- and cell cycle-regulatory genes on a heavily imprinted region of chromosome 11p15.5.33,34 Previous studies of hepatoblastomas have shown frequent allelic loss on 11p ranging from 25 to 75% of sporadic cases,21-25 and in particular, selective loss of the maternal allele.21 The high rate of 11p allelic loss in pancreatoblastomas in our series provides the first molecular evidence for a common genetic relationship between pancreatoblastomas, Beckwith-Wiedemann syndrome, and related embryonal malignancies. Because parental tissue was not available for analysis in our patients, evaluation of the parental origin of allelic loss in pancreatoblastomas was not possible.
The second most common genetic alteration in pancreatoblastomas in this
study— mutations involving the APC/ß-catenin pathway—is
of particular interest because this pathway has also been implicated
frequently in the development of
hepatoblastomas.25,29,35-40
Among patients with FAP
(characterized by germline mutation in the APC gene on
chromosome 5q and an increased rate of development of colorectal and
extra-colonic malignancies), the risk of hepatoblastoma is markedly
increased (1000-fold more than that of the general population), even
though most hepatoblastomas represent sporadic, non-FAP and
non-Beckwith-Wiedemann-associated tumors.26,27
One
hepatoblastoma arising in association with germline APC
mutation has been demonstrated to have biallelic inactivation of the
APC gene,29
and in sporadic hepatoblastomas
APC alterations including truncating mutations and 5q
allelic loss have been reported at widely varying frequencies from 0 to
69%.29,35,37-39
Unlike hepatoblastomas, pancreatoblastomas have not previously been known to arise in association with FAP, and our patient with FAP and a pancreatoblastoma represents the first such occurrence reported to date. The demonstration of biallelic APC inactivation in this patient’s pancreatoblastoma (germline-truncating mutation with loss of the wild-type allele) suggests that the relationship is not coincidental and that alterations in the APC pathway played an etiological role in the development of this patient’s pancreatoblastoma. One of the functions of APC tumor suppressor protein involves regulation of the cellular level of ß-catenin, which acts in part as a downstream transcriptional activator in the Wnt signaling pathway.41,42 APC, along with glycogen synthase kinase-3ß (GSK-3ß) and AXIN1, promotes phosphorylation of serine/threonine residues encoded in exon 3 of the ß-catenin gene.41,43,44 Phosphorylation is followed by ubiquitin-mediated degradation of ß-catenin protein.45,46 Loss of ß-catenin regulatory activity resulting in abnormal accumulation of ß-catenin protein can occur either by truncating APC mutations or by stabilizing ß-catenin mutations at GSK-3ß phosphorylation sites.44,47,48 This pathway can therefore be targeted by either inactivating APC tumor suppressor gene mutations or by activating mutations of the ß-catenin oncogene.49,50
Among eight sporadic pancreatoblastomas, we identified mutations in exon 3 of the ß-catenin gene in five (62%) cases. All were 1-bp missense mutations, located either at serine GSK-3ß phosphorylation sites in codons 33 and 37 (two cases) or around serine/threonine phosphorylation sites in codons 32 and 34 (three cases). Those cases containing exon 3 mutations in codons 32 and 34 did not involve loss of a phosphorylation site but may still be expected to interfere with normal degradation of the ß-catenin gene product.50 The strong correlation between the presence of abnormal ß-catenin protein accumulation by immunohistochemistry and the presence of ß-catenin or APC gene alterations in our pancreatoblastomas supports this association.
Overall, somatic alterations of the APC/ß-catenin pathway were identified in 67% (six of nine) pancreatoblastomas, indicating an important role for this pathway in pancreatoblastomas in addition to other embryonal malignancies.51 Interestingly, we were able to demonstrate APC inactivation only in the pancreatoblastoma arising in association with FAP, whereas the sporadic pancreatoblastomas instead showed a predominance of ß-catenin mutations. Among hepatoblastomas, only two studies of neoplasms from Asian patients have reported APC alterations in sporadic hepatoblastomas,35,37 whereas other studies of Western and Taiwanese patients have failed to detect APC alterations and have instead shown frequent involvement of the ß-catenin gene in the genesis of these tumors.25,36,38-40 Both geographic/ethnic differences as well as the relative susceptibility of neoplastic cells to somatically acquire a single ß-catenin hit as opposed to the two hits required for APC inactivation may underlie some of this discrepant genetic constitution in the FAP-associated and sporadic tumors.
In contrast to the frequent involvement of the APC/ß-catenin pathway and chromosome 11p losses in pancreatoblastomas, we found no evidence for K-ras oncogene mutations by DNA sequencing or p53 tumor suppressor gene alterations by immunohistochemistry in these neoplasms. Our findings are in agreement with and expand those of Hoorens and colleagues,15 who found neither K-ras mutation nor p53 overexpression in one case of pancreatoblastoma arising in an adult. Although our sequencing for K-ras was designed to detect mutations only in codons 12 or 13 of the K-ras oncogene, there is little evidence that mutations in K-ras codon 61 play a significant role in pancreatic carcinomas. Previous investigations of adult pancreatic ductal adenocarcinomas, for example, have demonstrated that K-ras mutations occur almost exclusively in codon 12; codon 12 base substitutions were detected in 28 of 30 cases, 18 of 18 cases, and 35 of 35 cases, respectively, in the studies of Smit and colleagues,52 Tada and colleagues,53 and Luttges and colleagues.54 Among these adult pancreatic adenocarcinomas, K-ras gene activation occurs early in the neoplastic progression of almost all tumors,55,56 whereas p53 inactivation is a relatively late event in neoplastic progression, but can be demonstrated in up to 70% of invasive pancreatic adenocarcinomas.55,57-59 Loss of Dpc4 tumor suppressor protein, present diffusely in only one of our pancreatoblastomas and focally in a second case (interestingly, both neoplasms with Dpc4 loss occurred in adult patients), also contrasts with adult ductal adenocarcinomas, among which slightly more than one-half have DPC4 inactivation.60,61 This pattern of genetic alterations in pancreatoblastomas, unique among the pancreatic malignancies studied to date, underscores the distinctive morphological, epidemiological, and clinical manifestations of these rare neoplasms.
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Acknowledgements |
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Footnotes |
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Supported by a National Cancer Institute SPORE grant in gastrointestinal cancer (P50-CA62924).
Accepted for publication August 2, 2001.
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