The Genetics of Pancreatic Cancer
-- The Discoveries
Why are K-ras mutations important? Mutations of the K-Ras gene occur in over 90% of pancreatic carcinomas. No other human tumor comes close in mutational frequency. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors, eventually toward the nucleus where these signals affect the production and regulation of other key proteins. It is interesting that although most mutations in genes are expected to cause their inactivation, with the Ras genes the opposite happens - they become more active in signalling. This is because of the engineering design of the protein. The ras signal is turned off by a molecular switch, which depends on an enzyme activity. In picturesque terms, the nucleotide GTP (guanidine triphosphate) engages the switch to keep it in the "on" state. A portion of the Ras protein has an enzyme activity (a GTPase) which cleaves the GTP. This turns the switch "off" after the brief "on" period. In reality, the mutations of Ras do indeed inactivate a function, as most mutations are expected to do. The GTPase is inactivated by the mutations. But this now means that GTP continues to engage the switch, and the Ras signalling function is unable to be turned "off". A number of drug companies are now investigating ways to abate the signalling function of Ras, which could provide a rational therapy for pancreatic cancer.
Where do they occur? Ras mutations involve only certain amino acids, those which interfere with the GTPase function. In pancreatic cancer, mutations are essentially seen only at the twelfth position, (codon or amino acid 12), with rare exceptions seen at codon 13. Most mutations in pancreatic cancer change a glycine at codon 12 to a valine or aspartate. The mutation to serine is quite unusual in pancreatic cancer, a peculiar finding since it is a common mutation in other tumor types which have K-ras mutations.
When do they occur? It is now known that K-ras mutations occur long before the formation of the actual cancer. They form in the precancerous stages, within lesions termed PIN, or Pancreatic Intraepithelial Neoplasia. These are ducts with clones of early neoplastic cells which have not yet invaded through the duct wall. In reality, these lesions are among the most common neoplasms of humans, occurring in nearly a third of elderly people. They are often unfortunately called "hyperplasias", a term which implies the lack of neoplastic character. Indeed, a rough estimate suggests that less than 1% of the lesions ever become invasive, which is to say, become a cancer. Thus, in many respects, they are similar to the adenomas of the colon; nearly a third of people will develop adenomas, yet only a small proportion will progress to colon cancer. A major effort of the Kern laboratory is to determine which of the genetic changes in PIN mark the lesions at high risk for invasion. K-ras mutations are uncommon in the early forms of PIN, but are found in the majority of advanced lesions. PIN having K-ras mutations will probably develop in 10% of persons during life. Thus, K-ras mutations are still not the specific marker of high-risk lesions that they would like to identify for diagnostic purposes. It should be obvious that a major goal is the diagnosis of pancreatic neoplasms at the earliest possible date, preferably in the advanced PIN lesions and prior to the formation of frank cancer which invades through the duct wall and spreads to other organs of the patient.
These studies are done in collaboration with Dr. Ralph Hruban and his efforts to study K-Ras mutations.