Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic carcinoma.
OBJECTIVE
The pathogenesis of pancreatic cancer is poorly understood. The multigenetic nature of carcinogenesis has been best documented in colon cancer. The relevance of this model was suggested for other epithelial tumors. Only advanced stages of pancreatic cancer are usually detected because of late diagnosis. Analysis of accumulated, diverse genetic changes could allow further understanding of putative mechanisms involved in tumor development. Activated c-Ki-ras oncogene has been shown to be a frequent event. However, additional alterations of tumor suppressor genes are expected. Therefore, concomitant genetic changes of p53 and deleted in colon carcinoma (DCC) in pancreatic carcinoma cell lines and primary tumors were analyzed.


METHODS
p53 protein and transcript expression were revealed by immunocytochemistry and immunohistochemistry, immunoassay, and Northern blot analysis. p53 mutations were identified by sequence analysis. DCC expression was investigated by reverse-transcription polymerase chain reaction.


RESULTS
p53 overexpression was observed in 9 of 12 cell lines. p53 point mutations were confirmed in seven cell lines overexpressing p53. The majority of cell lines showed concomitant p53 and DCC alterations. Four of 6 primary tumors overexpressing p53 also showed loss of DCC expression.


CONCLUSIONS
p53 and DCC genetic changes are associated with pancreatic cancer and the frequently activated c-Ki-ras oncogene. Therefore, the multihit model of carcinogenesis could prove relevant for pancreatic cancer.
Simon
B
B
Department of Internal Medicine, Philipps University, Marburg, Germany.
Weinel
R
R
Höhne
M
M
Watz
J
J
Schmidt
J
J
Körtner
G
G
Arnold
R
R
D001483:Base Sequence; D015152:Blotting, Northern; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D015345:Oligonucleotide Probes; D016159:Tumor Suppressor Protein p53