From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.
To investigate whether CDKN2B and CDKN2 are involved in esophageal tumorigenesis, we studied homozygous deletion, intragenic mutation, and messenger RNA (mRNA) expression of CDKN2 and CDKN2B in nine esophageal squamous cancer cell lines.
Although these data could not be used to identify p16 or p15 as the definitive tumor suppressor gene in this region that is involved in bladder carcinogenesis, they suggest that homozygous deletion is a common mechanism of loss of tumor suppressor gene function in this region.
These observations support a role for p15/p16 gene inactivation in bladder carcinogenesis and/or the promotion of cell growth in vitro and lend support to the hypothesis that homozygous deletion centred on 9p21 is a mechanism by which both p15 and p16 genes are co-inactivated.
Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16INK4/CDKN2, can cooperate in multistep tumorigenesis.
This suggests that CDKN2 is not involved in ovarian tumorigenesis and that another gene(s) may be the target of the frequent 9p allelic losses observed.
In this aspect, the potential role of the CDKN2 gene at 9p21-p22 in ovarian carcinogenesis was assessed in an extended panel of ovarian tumors, 11 human ovarian carcinoma cell lines, and 1 cervical tumor cell line.
Alterations of the p16INK4 gene were detected in 6 (2 insertions and 4 homozygous deletions) of 22 metastatic non-small cell lung cancers (NSCLCs; 27%), but none were detected in 25 primary NSCLCs, 15 primary small cell lung cancers (SCLCs), or 9 metastatic SCLCs, indicating that mutation in the p16INK4 gene is a late event in NSCLC carcinogenesis.
Our results suggest that the MTS1 gene is not mutated with increased frequency in primary breast tumors, and thus may not play a major role in breast carcinogenesis.
The frequency of mutations and deletions detected differs markedly between cell lines (44%) and primary tumors (10%) suggesting that while p16/CDKN2 may play a role in tumorigenesis in some head and neck squamous cell carcinomas, inactivation of p16/CDKN2 probably occurs more frequently in cell lines as a result of adaptation to cell culture.
These results suggested that the MTS1/CDK4I gene is a tumor suppressor the inactivation of which plays an important role during carcinogenesis of the squamous cell type of esophageal carcinoma.
These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.
Our frequent detection (80%) of p16 and p15 gene deletions might suggest that these deletions are closely related to carcinogenesis in primary malignant lymphoma of the brain.
Studies of biochemical and biological functions of both wild-type and mutant proteins are central to our understanding of the role of p16INK4a mutations in tumorigenesis, a summary of these studies is also included in the present update.
As reported previously, the mutational spectrum of CDKN2 in melanomas differs from that of internal malignancies and supports the involvement of UV in melanoma tumorigenesis.
From the data, it can be argued that p16/CDKN2 and p53 mutations are relatively late occurrences in human oral tumorigenesis and that genetic alterations of the ras genes may not play a significant role in squamous neoplasia.
Our data point to p53 and p16 as gene targets of oral carcinogenesis, with chemicals in the betel quid possibly functioning in these tumors as carcinogens.