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

Abstract

IntroductionStomach, lung, cervix and hepatocellular cancers are the most common cancers in Korea. Various environmental factors and genetic factors are involved in the formation and development of cancers. Genetically, many human tumors have been reported to have abnormalities in oncogenes as positive regulators or tumor suppressor genes as negative regulators (Levine, 1993). A variety of oncogenes and tumor suppressor genes such as SV40T, E1A/E1B of adenovirus, E6/E7 of HPV-16, p53 and Rb has been identified as affecting cell growth through the regulation of the cell cycle (Hunter et al. , 1994;Peter and Herskowitz, 1994).R e c e n t l y, the CDKN2 and M T S 2 genes, encoding inhibitors of cyclin dependent kinases (Serrano et al. , 1993;Hannon and Beach, 1994), were identified to be located at chromosome 9p21 and to be candidate tumor suppressor genes. The protein product of CDKN2 , p16, prevents pRb phosphorylation by inhibiting Cdk4-cyclin D complex, and thereby regulates the progression of G1 to S phase in the cell cycle. 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). In some tumors, especially the reported mutation frequency of C D K N 2 was controversial, varying from 0 to 52% in esophageal carcinomas (Mori et al., 1994; Okamoto et a l., 1994;Suzuki et al., 1995), 7 to 83% in non-small cell lung cancers (de-Vos et al., 1995;Nakagawa et al. , 1995;Xiao et al., 1995), and 4 to 36% in B-ALL (Schroder et al., 1995;Guidal-Giroux et al., 1996). These varying results might arise in part from the inevitable contamination of nonneoplastic cells in any resected tumor. In order to evaluate more accurately the alterations of CDKN2 in

Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-hetero- zygosity on chromosome 16q21-q23 and 9p21-p23

“…Inactivation of this gene has been found in a variety of human cancers caused by different mechanisms, including mutation, homozygous deletion of MTS1/p16 loci or hypermethylation of 5 CpG island [25][26][27]. In our specimens, the 9p21-p23 showed high frequency of genetic alteration, but somatic mutation of MTS1/ p16 was infrequent in primary hepatic carcinoma, a finding similar to that found among Australian population [28].…”

Detection of Aberrantp16INK4AMethylation in Sera of Patients with Liver Cirrhosis and Hepatocellular Carcinoma

“…The degree of p16 INK4A methylation shows a wide range of variation (from 0 to 94%) in tumor tissues of HCC patients (8, 15-22), and this change has been detected in the sera of such patients (20). …”

Microenvironmental Regulation of Proliferation in Multicellular Spheroids Is Mediated through Differential Expression of Cyclin-Dependent Kinase Inhibitors

“…This association obstructs CDK/cyclin interaction, and the subsequent phosphorylation and inactivation of the retinoblastoma (Rb) protein and thereby inhibits the gene expression required for G 1 -to S-phase progression (15). The INK4 CKI family has been implicated in cell differentiation and senescence (16 -18) and has received a lot of attention because of the observation that some members are often mutated or deleted in human cancers (19,20). The other CKI family includes p21 waf1/cip1 , p27 Kip1 , and p57 Kip2 .…”