Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas

Abstract

The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.

Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors

“…Genomic DNA from fresh-frozen tissue samples and blood was isolated using the QIAamp tissue and blood kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. Genomic DNA from paran-embedded tissue was extracted by the salting-out method as described previously (Bartsch et al, 1995).…”

Alterations of CDKN2 (MTS1/p16INK4A) gene in paraffin-embedded tumor tissues of human stomach, lung, cervix and liver cancers

“…C D K N 2 was found to be homozygously deleted at a high frequency in cell lines from many different types of cancer such as melanoma, leukemia, glioma, breast cancers and astrocytoma (Kamb et al, 1994;Nobori et al, 1994). In addition, a high frequency of mutations of CDKN2 have been observed in tissues from pancreatic adenomas (Bartsch et al , 1995), T-cell leukemias (Hebert et al, 1994), biliary tract cancers (Yoshida et al, 1995), esophageal cancers (Mori et al, 1994) and non-small cell lung cancers (Washimi e t a l., 1995;Xiao et al, 1995). In contrast to the observations in some malignancies, no deletions and rare alterations of CDKN2 were identified in breast cancers (Xu et al, 1994), malignant mesothelioma (Cheng et al, 1994), small cell lung cancers (Okamoto et al, 1995), head and neck cancers (Zhnag et al, 1994), thyroid cancers ( Tung et al, 1996), ovarian cancers (Campbell et al , 1995;Rodabaugh et al, 1995) and esophageal cancers (Okamoto et al, 1994;Suzuki et al, 1995).…”

Mutations of CDKN2 (MTS1/p16(INK4A)) and MTS2/p15(INK4B) genes in human stomach, hepatocellular, and cholangio-carcinomas

“…R e c e n t l y, the C D K N 2 and M T S 2 / p 1 5 I N K 4 B genes, encoding inhibitors of cyclin dependent kinases (Serrano et al , 1993;Hannon and Beach, 1994), were shown to be located at chromosome 9p21 and to be candidate tumor suppressor genes, when it was found to be homozygously deleted at high frequency in cell lines from many diff e r e n t types of cancer (Kamb et al, 1994;Nobori et al, 1994). In addition, mutations of C D K N 2 have been observed frequently in T-cell leukemias (Hebert, 1994), pancreatic adenomas (Bartsch et al, 1995), biliary tract cancers ( Yoshida et al, 1995), esophageal cancers (Mori et al , 1994), and non-small cell lung cancers (Washimi et al , 1995;Xiao et al, 1995). In contrast to the observations in the foregoing malignancies, mutations of C D K N 2 w e r e identified at low frequency in breast cancers (Xu et al , 1994), malignant mesothelioma (Cheng et al, 1994), small cell lung cancers (Okamoto et al, 1995), head and neck cancers (Zhang et al, 1994), thyroid cancers (Okamoto et al, 1994;Tung et al, 1996) and esophageal cancers ).…”