Loss of heterozygosity studies in melanoma and pancreatic carcinoma from gene carriers strongly support the view that CDKN2 is a general tumour suppressor gene predisposing not only to melanoma but also to other malignancies.
These findings suggest that, although p16/CDKN2 may play a role in the pathobiology of pancreatic cancer, inactivation of this putative tumor suppressor gene occurs more frequently in cell lines than in primary ductal pancreatic carcinomas.
The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma.
Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS).
Mutations of K-ras and p16 have been described in hyperplastic and dysplastic pancreatic ductal lesions believed to be the non-malignant precursors of pancreatic carcinoma.
The implications of the capacity of the INK4a/ARF locus to encode a third transcript, and for pancreatic cancer, in which the INK4a/ARF locus is nearly always altered, are considered.
These data indicate that AdexCACSp16 has the potential to induce p16 gene expression and control pancreas cancer cell proliferation and that the adenovirus p16 expression vector AdexCACSp16 might be a possible method of gene therapy to improve the surgical therapeutic results for pancreas cancer.
We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations.
There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P =.004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi.
Using a novel improved primer extension and preamplification polymerase chain reaction, we analyzed microdissected paraffin-embedded specimens of pancreatic carcinoma (n = 29) and their corresponding pancreatic intraductal lesions (PIL, n = 331) for loss of heterozygosity (LOH) of p16(INK4), DPC4, and p53 by microsatellite analysis and for p53 protein by immunohistochemistry.
They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer.
This study shows for the first time that p16(INK4a) alterations can be observed in a considerable number of PanIN1 in chronic pancreatitis tissues not associated with pancreatic cancer.
Rb phosphorylation is mediated by cyclin-dependent kinases (CDKs), whose activity is enhanced by cyclins and inhibited by CDK inhibitors. p16(INK4A) is a member of a family of inhibitors specific for CDK4 and CDK6. p16(INK4A) is deleted and inactivated in a wide variety of human malignancies, including familial melanomas and pancreatic carcinoma syndromes, indicating that it is an authentic human tumor suppressor.