Looking Far Afield for Pancreas Cancer Clues

Consider the lab mouse. The rodent is used to model tumor growth in countless studies of genes and cancer. About 99 percent of mouse genes also appear in humans. Mouse and human also are similar when one compares the DNA code within these genes. Mice get cancer, and they get more cancer when genetically engineered with human cancer-causing genes. But Allan Balmain, PhD, has strayed from his geneticist colleagues in his choice of mouse. Other researchers, to help carefully control experimental variables, use only genetically uniform laboratory strains of the species Mus musculus. Several years ago, Balmain began breeding their country cousins, a Mediterranean field mouse known as Mus spretus. Like humans, but unlike the old lab strains, these field mice exhibit a wealth of genetic diversity. Why is that important? Clearly, common DNA variations in genes that we inherit from our mothers and fathers affect us in more substantial ways than simply determining whether our eyes are blue or brown. Some gene variations alter disease risk, including risk for diseases that – like cancer – arise most often later in life. Balmain shares with most cancer geneticists an interest in rare gene mutations – DNA alterations – that arise within cells over a lifetime. If a mutation hits the wrong gene in the wrong place, it may set the stage for cancer to develop eventually. But Balmain also is exploring the subtler influence of more common variations in the genes we are born with. Balmain uses Mus spretus, as well as inbred lab mice, to explore how different inherited versions of the same gene affect cancer risk. He can manipulate genes and interbreed mice of both species to determine how gene variants act in mice with different genetic backgrounds. He can investigate how the effects of rare mutations that arise in cancer-associated genes are influenced by the activity of other genes and gene variants. He can apply what he learns from human DNA to mice, and vice versa. The amount of raw data generated by these experiments is tremendous. Previous generations of biological scientists did not have the tools to collect so much data, nor the task of analyzing such a complex array of information. UCSF postdoctoral fellows in mathematics and computational biology have developed unique and powerful programs to visualize and quantify the degree to which the activity of one gene affects others. These studies have led to new discoveries of biochemical relationships among the proteins encoded by these genes, some of which Balmain already has identified as being important in cancer. While continuing these experiments, Balmain next plans to collaborate with pharmaceutical industry scientists to target an old foe in a new way. The nemesis is a mutated gene that drives the growth of almost every tumor that arises in the ducts of the pancreas. Mutations that rev up this same gene, called K-ras, also appear to drive the development of tumors in many different organs. UCSF boasts several researchers who are seeking strategies to block the activity of mutated K-ras and its molecular partners in cellular crime. (See Pancreas Cancer News 2005 PDF.) For his part, Balmain has found that the same K-ras mutation can act differently when it arises in different inherited forms of the gene. Furthermore, the version of the K-ras gene we inherit from one parent may influence and sometimes work against the activity of the gene copy we inherit from the other parent. (Our cells contain 23 chromosomes from each parent – matching pairs.) In other words, some lucky individuals may inherit a version of K-ras that can inhibit the activity of the mutant gene on the other chromosome, in effect acting as a tumor suppressor. These people may be less likely to develop an aggressive malignant tumor. Balmain has begun collaborative studies with UCSF epidemiologist Elizabeth Holly, PhD, to evaluate how this wrinkle in K-ras genetics affects pancreatic cancer risk and survival. In addition, Balmain has confirmed that there is more than one way to splice bits of DNA together to form the complete K-ras gene, and this too may be important in cancer and its treatment. Allan Balmain’s research is funded in part by a generous donation from the Schwartz Foundation.