BJALCF Sponsors Powerful Lung Cancer Genetics Research

Lung Cancer research at UCSF is poised to leap forward, thanks to a big bank. No, not some teetering financial institution down the street. What UCSF has is an invaluable tissue bank.

When it comes to lung tumors, the quantity and quality of UCSF’s chilly-vault holdings are hard to beat. They’re a treasure trove that will help researchers determine how cancer survival odds and responses to treatments are affected by specific genetic abnormalities within tumors - and even by normally inherited variations in genes.

The Lung Cancer tissue bank now enables researchers at the UCSF Helen Diller Family Comprehensive Cancer Center to explore more deeply the role of specific genes in Lung Cancer, according to David Jablons, MD, chief of thoracic surgery at UCSF and leader of the Thoracic Oncology Program.

“There are so many genes that are interrelated that we never suspected had anything to do with one another,” Jablons says. “This systems genetics approach to cancer is a whole new frontier.”

The frozen samples were gathered from hundreds of Lung Cancer patients over more than a decade. For most patients, the tissue bank also holds matching normal lung and blood samples for comparison. Jablons and colleagues have annotated the tissue bank data with information on the clinical care and outcomes for patients.

Why so many samples? Tumors share distinctive features that set them apart from normal cells, but individual tumors differ from one another in how they look, and in how they grow and spread. They also differ from one another in how they act metabolically.

More to the point for the newest studies, tumors all have abnormal genes, but each tumor exhibits its own individual pattern of abnormal gene activity. It takes many samples to track down the impacts of these genetic differences.

The tumor cells contained in the samples within the UCSF bank will help researchers identify microscopic molecules that can be used to help guide treatment, and will help these scientists envision new treatment strategies for throwing a wrench into the gears that drive relentless tumor growth.

But a person’s normal genes, inherited from mom and dad, also can play a role in how well that person will fare when stricken with cancer. Relatively few researchers have explored the role of normal genetic variations in cancer. Most cancer scientists study the genetically abnormal tumor tissue. In any case, there is a shortage of normal, matching tissue from cancer patients for studying how one’s genetic background influences cancer.

Jablons has led several fruitful research collaborations with doctoral scientists in recent years. Recently, with postdoctoral fellow Dan Raz, MD, he demonstrated that analysis of a small group of genes is a better predictor of lung cancer survival than gauging clinical stage and tumor size among patients diagnosed at an early stage.

Jablons’ patient, long-term devotion to collecting normal as well as tumor tissue now might yield even bigger results through a new collaboration with fellow UCSF laboratory cancer researcher Allan Balmain, PhD. The Bonnie J. Addario Lung Cancer Foundation is sponsoring the project.

Balmain has pioneered the exploration of genetic background in cancer. He introduced a new field mouse species to the lab to jump-start the field. Balmain has bred longstanding strains of genetically identical lab mice with the field mice, which are more cancer-resistant and genetically diverse. Balmain tracked genetic variations in the offspring and has successfully identified constellations of normal genetic variations that affect cancer risk.

There are no breeding experiments in humans, of course. Even so, Balmain is hopeful that the same sort of genetic analysis in the human tissue collected by Jablons’ surgical team will lead to breakthrough insights.

Balmain has a good track record in making important discoveries by looking at old problems from a new perspective. He most recently extended his successful record with Lung Cancer findings that he and colleagues Minh To, PhD, and Christine Wong, PhD, presented in the October 2008 issue of the scientific journal Nature Genetics.

Researchers have long known that within cancers, defects in the genetic code - mutations - frequently occur in a gene called Kras. These Kras mutations are believed to drive the growth of many tumors, including many Lung Cancers.

It turns out that cells have a couple of ways to splice together the genetic instructions for making the Kras protein. The cells use either a piece of genetic code called 4A, or a different piece of the gene, called 4B. In the past, researchers focused on the more common 4B form, known to contribute to cancer when it becomes mutated.

But in a clear demonstration that the activity of normal genes can indeed influence cancer risk, Balmain found that a normal form of 4A, when present in the cell at the same time as a mutant 4B, can suppress the cancer-associated mutant. This protective function may be important in stopping cancer, and might even be worth mimicking in developing new drugs to fight cancer, Balmain suggests.

On the other hand, the 4A form of Kras might give rise to the normal pool of cells from which common lung cancers, called adenocarcinomas, commonly arise, Balmain says. It’s only later that the 4B form of Kras becomes activated and triggers tumor growth from among the cells in this pool.

“4B may be responsible for proliferation and maintenance of tumor cells that arise,” Balmain says, “but 4A is responsible for the initial cell fate decision, because the mice with no 4A are completely resistant to cancer.”