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.
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.
CDKN2 is not deleted with high frequency in primary breast carcinomas, and the p16 gene does not play a role in breast carcinogenesis via this mechanism.
To explore the involvement of CDKN2 in prostate carcinogenesis, alterations of CDKN2 were examined in 116 human prostate tissues and cell lines and xenografts.
Inactivation of p16INK4, an inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), may be essential for oncogenesis in non-small cell lung cancer (NSCLC).
The CDKN2 gene appears to be the major tumor suppressor gene on chromosome 9p21, and it is thought to be involved in the tumorigenesis of various lymphoid malignancies.
These data show that losses on either side of 9p21-22, both or either of which may be deleted, are involved in pituitary tumorigenesis and provide evidence for distinct suppressor gene loci, in addition to MTS1, on chromosome 9p.
Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.
Although two-hit inactivation was not evident in any of the mutation cases and further investigation would be needed to elucidate the role of altered p16INK4, these results suggest that the p16INK4 gene mutations are relatively frequent and its inactivation might be important in ampullary carcinogenesis.
Genetic and epigenetic changes of the MTS1 gene were not correlated with the grade and stage of tumors, indicating that these alterations are early events in urothelial carcinogenesis, in which functional inactivation by hypermethylation is a predominant mechanism.
The low mutation frequency of 12% is consistent with that of three previous studies involving Japanese and Caucasian patients (8, 16 and 21% frequency: Esteve et al., 1996, Igaki et al., 1995 and Zhou et al., 1994). p16 gene mutations do not appear to play a major role in esophageal carcinogenesis.
However, in contrast to other G1 phase regulatory proteins, such as cyclin D, retinoblastoma protein and p16INK4A, cyclin A seems not to be commonly involved in tumorigenesis.
Malignant mesothelioma expresses pRb, which, together with the cytogenetic data, suggests the involvement of CDKN2A and/or CDKN2B in its tumorigenesis.
A larger study on VIN lesions and genetic coding is suggested to further investigate the role of p16INK4, Rb, and other factors in tumorigenesis and progression of vulvar cancers.