A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer Maps to Chromosome 4q32-34

Eberle, Michael A.; Pfützer, Roland H.; Pogue‐Geile, Kay L.; Bronner, Mary P.; Crispin, David A.; Kimmey, Michael B.; Duerr, Richard H.; Kruglyak, Leonid; Whitcomb, David C.; Brentnall, Teresa A.

doi:10.1086/339692

Cited by 112 publications

(60 citation statements)

References 22 publications

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“…1 Pogue-Geile et al used a two-pronged approach to discover this gene. First, they hypothesized that abnormalities in the expression of genes within the area of linkage on 4q32-34 may help localize the putative familial pancreatic cancer gene.…”

Section: Introductionmentioning

confidence: 99%

Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells

Salaria

Illei

Sharma

et al. 2007

Cancer Biology & Therapy

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Background: It has recently been suggested that overexpression of palladin in sporadic pancreatic cancer may contribute to pancreatic cancer's invasive and migratory abilities. This hypothesis was based on reverse transcriptase-polymerase chain reaction analyses of bulk pancreatic tissue, yet pancreatic cancer is a complex admixture of neoplastic epithelial cells and desmoplastic stroma.Design: Immunohistochemical labeling of tissue microarrays was used to define the patterns of palladin protein expression in 177 ductal adenocarcinomas of the pancreas. Western blot analysis was used to determine the epitope(s) of palladin recognized by the antibody as well as the relative levels of palladin expression in short-term cultures of stromal fibroblasts, non-neoplastic ductal cells and pancreatic cancer cell lines.Results: Immunolabeling revealed that the palladin protein was strongly overexpressed in non-neoplastic stromal cells in 171 (96.6%) of the 177 evaluable pancreatic cancers. By contrast, the overexpression of palladin protein by the neoplastic epithelial cells relative to normal pancreatic epithelium was observed in only 22 (12.4%) of the 177 cancers. Western blot analysis confirmed that the antibody recognizes the ∼90 kDa isoform of palladin, and demonstrated that fibroblast cell lines had higher expression of palladin than pancreatic cancer cell lines.Conclusions: The overexpression of palladin relative to normal pancreas in the majority of pancreatic cancers is limited to non-neoplastic stromal cells. This observation highlights the limitations of relying on bulk tissues when analyzing gene expression. Since palladin is not overexpressed in most pancreatic cancer cells, the overexpression of palladin is not likely to be responsible for pancreatic cancer cells invasive and migratory abilities.

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Section: Introductionmentioning

confidence: 99%

Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells

Salaria

Illei

Sharma

et al. 2007

Cancer Biology & Therapy

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“…Unfortunately, little is known about the role of these mutant genes in the development of sporadic and familial pancreatic cancer, due in part to the lack of identifiable early-stage patients. Furthermore, it is hypothesized that the major cause(s) of inherited susceptibility to pancreatic cancer remains to be identified (see, e.g., Eberle et al 2002).…”

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confidence: 99%

Ductal Pancreatic Cancer in Humans and Mice

Tuveson¹,

Hingorani²

2005

Cold Spring Harbor Symposia on Quantitative Biology

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Animal models of cognate human conditions permit the rigorous exploration of mechanisms of disease pathogenesis and provide systems to devise and test therapeutic and detection strategies. Although inbred mouse strains offer many advantages over other animals for investigations of malignant disease, mice unfortunately do not develop PDA spontaneously or even following carcinogen treatment. Recent technological developments in conditional gene targeting have enabled the generation of mutant mouse cancer models of PanIN and PDA that closely mimic human pancreatic cancer and are thus suitable for investigations of the human disease process. In this paper, we summarize the knowledge of the human disease that has informed the ability to generate accurate mouse models of pancreatic cancer and describe potential biological and clinical applications. EPIDEMIOLOGY OF PANCREATIC CANCEREpithelial carcinomas account for the majority of cancer deaths in the United States, and among them, pancreatic cancer is the fourth most common with the highest case-fatality ratio. Pancreatic ductal adenocarcinomas (PDA) comprise more than 90% of pancreatic cancer cases and are its most lethal form among an assortment of additional histological subtypes including cystic neoplasms, acinar carcinomas, and islet cell endocrine tumors. Risk factors associated with the development of PDA include increased age, tobacco usage (Silverman et al. 1994), African heritage (Ahlgren 1996), and a family history of pancreatic cancer . Despite the relatively large numbers of patients stricken with PDA, estimated at 32,180 for 2005, our expanding knowledge of critical aspects of this disease remains terribly inadequate and undoubtedly contributes to our inability to intervene meaningfully. The impetus to investigate the biological underpinnings of PDA is further motivated by the predicted doubling in PDA incidence over the next two decades as the population ages (Hruban et al. 2006a). Nonetheless, the public investment in pancreatic cancer research is woefully inadequate relative to other malignancies, and consequently, the number of investigators pursuing PDA is unfortunately restricted. GENETICS OF PDA AND PanINPDA is thought to evolve from a preinvasive precursor state termed pancreatic intraepithelial neoplasms (PanINs) because PanINs demonstrate cytological and genetic changes that reflect those evident in invasive PDA. PanINs are divided into three stages characterized by increasing degrees of cellular and architectural atypia. PanIN-1A lesions are flat and contain tall columnar ductal cells in distinction to the short cuboidal cells that line normal pancreatic ducts; PanIN-1B lesions additionally demonstrate mild papillary architecture in the ducts but no nuclear atypia; the PanIN-2 stage signifies cells with moderate nuclear atypia and loss of cellular polarity; PanIN-3s represent the carcinoma-in-situ stage of pancreatic cancer, characterized by marked atypia, dysregulated growth, cribriform structures, and pinched-off clusters of epithelial cells...

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“…Genomewide linkage screen of a family, noted as 'family X', has shown significant linkage to chromosome 4q32-34 (Eberle et al, 2002). Pogue-Geile et al (2006) later found a mutation, inducing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S), in a highly conserved region of the gene encoding palladin (PALLD), segregating in all affected family members and absent in unaffected family members.…”

Section: Familial Pancreatic Cancer Associated Palld Gene (Mim 164757)mentioning

confidence: 99%

The Genetics of Pancreatic Cancer

Dagan¹,

Gershoni‐Baruch²

2012

Pancreatic Cancer - Clinical Management

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A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer Maps to Chromosome 4q32-34

Cited by 112 publications

References 22 publications

Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells

Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells

Ductal Pancreatic Cancer in Humans and Mice

The Genetics of Pancreatic Cancer

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