Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis.
No mutations were identified in mitogen-activated protein kinase kinase 4 (0 of 22), MADH4 (0 of 22), or ACVR1B (0 of 29), making it unlikely that germ-line mutations in these genes account for a significant number of inherited pancreatic cancers.
Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear.
Unlike the high incidences of Smad4 mutation or deletion in pancreatic cancer and gastrointestinal cancers, Smad4 gene is seldom mutated or deleted in hepatocellular carcinoma (HCC).
In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations.
This study indicates that apart from the functional loss of DPC4 due to mutations or homozygous deletion, a lack of the TGF-beta receptors, particularly RII and RIII, may contribute to a loss of TGF-beta signaling in a population of pancreatic cancers.
DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-beta (TGFbeta)-suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGFbeta growth-inhibitory and transcriptional responses were found to be DPC4-independent.
A panel of human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice and pancreatic cancer cell lines were studied. p15 gene alterations, mainly homozygous deletions that involved exons 1 and/or 2, were found in the 62.5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations were found in one of eight xenografts and in two of seven cell lines.
Therefore, we examined 45 primary human pancreatic adenocarcinomas and 12 pancreatic cancer cell lines for DPC4 alterations by single-strand conformational variant (SSCV) analysis and a PCR-based deletion assay.
As a central player in TGF-β signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer.
Genetic mutations, such as activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A, inactivation of the tumor-suppressor gene TP53 and deleted in pancreatic cancer 4 (DPC4) gene defects are seen in those with pancreatic cancer.
This review describes: 1.The main genetic alterations found in pancreatic cancer (EGF-R overexpression, SST-2 somatostatin receptor loss of expression, k-ras, p53 mutations and DPC4 mutations) and the effect of their replacements by gene therapy on tumor growth; 2.
In the present study, we analyzed 15 human pancreatic cancer cell lines for genetic alterations of the K-ras, p53, p16, and SMAD4 genes, which are very frequent targets for mutation in pancreatic cancer; these cell lines are useful resources in cancer research.
The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC.
This study was performed to examine the expression patterns and association of Jab1 and Smad4 in PC cells for gaining a further understanding of PC pathogenesis.
However, <i>smad4/DPC4</i> is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies.