The Genetics of Pancreatic Cancer
-- The Discoveries
Why are p16 mutations important? Mutations of the p16 gene occur in pancreatic cancer at a rate higher than that reported in any other tumor type. Nearly 90% of tumors lose one copy (termed loss of heterozygosity, or LOH) by deletion. In 40% of cases, the other copy is also lost (termed a homozygous deletion, or HD). In another 40%, a small mutation in the p16 gene inactivates its function. The remainder of tumors usually turn off the p16 gene by a process called methylation that, strictly speaking, is not a form of mutation. p16 is one of the inhibitors for enzymes (termed cyclin-dependent kinases, or CDKs) which drive a cell's progression through the division cycle.
Wasn't there a controversy? Initial reports of mutational analyses of p16 in human tumours were controversial, and it was suggested that mutations in the p16 gene might be selected by or induced upon tissue culture. This would make it an artifact unrelated to human tumorigenesis. The first convincing evidence for human tumor acquiring mutations at a high rate came through the mutational screen for pancreatic carcinoma. Mutations and deletions, performed on pancreatic cancer xenografts, were confirmed in all available original primary tumours. Also, comparisons of parallel xenografts, where multiple grafts were taken from the same primary tumours, showed consistent results, thus excluding any in vitro artifacts. p16 gene mutations were variably reported in esophageal squamous cell carcinoma and in the germline of some patients with familial melanoma, but were largely absent in a wide variety of other tumours that exhibit a high frequency of 9p loss. In part, it turns out that p16 sustains deletions of both copies, and these changes were initially missed since this type of mutation is difficult to see when geneticists examine human tumors directly. p16 inactivations are now thought to be nearly as common as p53 mutations in multiple types of human cancer.
Can I get familial pancreatic cancer from a p16 mutation? There is a syndrome called familial atypical mole/melanoma, which is due to p16 mutations that are passed on within a family from parent to child. The risk of pancreatic cancer is higher within these families. But to date, all pancreas cancer families reported to have an inherited p16 mutation have also had melanomas within the family. Consult your doctor if you think your family might have this syndrome, since testing is available to identify those family members carrying the mutant p16 gene. Knowing who is at risk can allow them to take preventative action and to attempt to identify skin lesions at an early, curable stage.
What about p15? There is at least one other candidate tumour-suppressor gene, p15, located near p16. Because the homozygous deletions involving p16 frequently extend into distant flanking markers, p15 is known to be involved as well by those homozygous deletions of 9p in pancreatic carcinoma. But p15 is not mutated in pancreatic cancer, and therefore there is no direct evidence of p15 being a tumor-suppressor gene in this tumor type.