Tumor-suppressive pathways in pancreatic carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 57; no. 9; pp. 1731 - 1734
• Main Authors: ROZENBLUM, E, SCHUTTE, M, KERN, S. E, GOGGINS, M, HAHN, S. A, PANZER, S, ZAHURAK, M, GOODMAN, S. N, SOHN, T. A, HRUBAN, R. H, YEO, C. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-05-1997
• Subjects: Adenocarcinoma - genetics; Biological and medical sciences; BRCA2 Protein; Carrier Proteins - genetics; Cyclin-Dependent Kinase Inhibitor p16; DNA Mutational Analysis; DNA, Neoplasm - genetics; DNA-Binding Proteins; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes, p53; Genes, ras; Genes, Tumor Suppressor; Heterozygote; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Neoplasm Proteins - genetics; Pancreatic Neoplasms - genetics; Sequence Deletion; Smad4 Protein; Trans-Activators - genetics; Transcription Factors - genetics; Tumors; Adenocarcinoma; Human; Tissue; Carcinoma; C-Onc gene; Digestive diseases; Malignant tumor; Mutation; Pancreas; Carcinogenesis; Pancreatic disease; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445

During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.