Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas

Frequent alterations in the APC/β-catenin pathway and chromosome 11p

Susan C. Abraham, Tsung Teh Wu, David S. Klimstra, Laura S. Finn, Jae Hyuk Lee, Charles J. Yeo, John L. Cameron, Ralph H. Hruban

Research output: Contribution to journalArticle

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Abstract

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/β-catenin pathway and chromosome 11p, using immunohistochemistry for β-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the β-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/β-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the β-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of β-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracoIonic manifestation of FAP.

Original languageEnglish (US)
Pages (from-to)1619-1627
Number of pages9
JournalAmerican Journal of Pathology
Volume159
Issue number5
StatePublished - 2001
Externally publishedYes

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Catenins
Adenomatous Polyposis Coli
Molecular Biology
Chromosomes
Hepatoblastoma
Mutation
Adenocarcinoma
ras Genes
Loss of Heterozygosity
Neoplasms
DNA Sequence Analysis
Exons
Immunohistochemistry
Beckwith-Wiedemann Syndrome
APC Genes
Pancreatoblastoma
Germ-Line Mutation
Multigene Family
Tumor Suppressor Genes
Pancreatic Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : Frequent alterations in the APC/β-catenin pathway and chromosome 11p. / Abraham, Susan C.; Wu, Tsung Teh; Klimstra, David S.; Finn, Laura S.; Lee, Jae Hyuk; Yeo, Charles J.; Cameron, John L.; Hruban, Ralph H.

In: American Journal of Pathology, Vol. 159, No. 5, 2001, p. 1619-1627.

Research output: Contribution to journalArticle

Abraham, Susan C. ; Wu, Tsung Teh ; Klimstra, David S. ; Finn, Laura S. ; Lee, Jae Hyuk ; Yeo, Charles J. ; Cameron, John L. ; Hruban, Ralph H. / Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : Frequent alterations in the APC/β-catenin pathway and chromosome 11p. In: American Journal of Pathology. 2001 ; Vol. 159, No. 5. pp. 1619-1627.
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abstract = "Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/β-catenin pathway and chromosome 11p, using immunohistochemistry for β-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the β-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86{\%} (six of seven informative cases). Molecular alterations in the APC/β-catenin pathway were detected in 67{\%} (six of nine), including five neoplasms with activating mutations of the β-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of β-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracoIonic manifestation of FAP.",
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T1 - Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas

T2 - Frequent alterations in the APC/β-catenin pathway and chromosome 11p

AU - Abraham, Susan C.

AU - Wu, Tsung Teh

AU - Klimstra, David S.

AU - Finn, Laura S.

AU - Lee, Jae Hyuk

AU - Yeo, Charles J.

AU - Cameron, John L.

AU - Hruban, Ralph H.

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AB - Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/β-catenin pathway and chromosome 11p, using immunohistochemistry for β-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the β-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/β-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the β-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of β-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracoIonic manifestation of FAP.

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