The National Cancer Institute (NCI) has awarded City of Hope nearly $3.5 million over five years to support investigations led by Smita Bhatia, M.D., into the genetic reasons why some cancer survivors develop second malignancies.

Smita Bhatia is hunting down the reasons new cancers appear in some cancer survivors. (Photo by Darrin S. Joy)

About 6 percent of all childhood cancer survivors live through their first cancer only to be diagnosed with another solid tumor or hematologic cancer later, said Bhatia, chair of the Department of Population Sciences and principal investigator on the R01 grant. Risk of a second cancer among these survivors is 10 times higher than cancer risk in the general population.

“The central question is this: Why do some people escape these second cancers, and others do not?” said Bhatia. “We believe it comes down to differences at the DNA level.”

If they can understand the factors that predispose people to second cancers, scientists may be able to develop a test to predict which patients are vulnerable, and perhaps offer them initial therapy that is less toxic.

The new grant, provided through the NCI’s Office of Cancer Survivorship, brings together the expertise of scientists at 147 of the world’s top medical centers — and their crucial data. Scientists already have reached about two-thirds of their goal of amassing 3,600 cases of pediatric and adult cancer survivors diagnosed with a second cancer, as well as 3,600 survivors who have stayed cancer free.

“This is the largest such study ever done,” Bhatia said.

As Bhatia explained, radiation and chemotherapy increase risk for second cancers. Chemotherapy may bring on acute leukemia (such as acute lymphocytic leukemia or acute myelogenous leukemia) in the years after treatment. And radiation may result in brain, breast or thyroid cancers, or sarcomas in bone tissue.

In the study, researchers will focus on candidate genes that influence how the body deals with cancer treatment. They include genes with these functions:

• Metabolism of drugs — Differences in these genes may affect how the body breaks down chemotherapy.
• DNA repair — Radiation can damage the DNA of healthy cells, along with cancerous ones; differences in the body’s ability to repair this damage may influence cancer risk.
• Transport mechanisms — This includes genes responsible for pumping chemotherapy in and out of cells.

The scientists are investigating about 1,000 single nucleotide polymorphisms, or SNPs, in about 100 candidate genes. SNPs are variations within the code in genes. Some SNPs make genes more effective, while others make them work more poorly.

By looking at these SNPs in thousands of people diagnosed with second cancers and others who remain cancer free, the scientists hope to identify which genes are most significant to the development of second malignancies.

Using funding from groups including The Leukemia & Lymphoma Society, the research team also is analyzing the occurrence of other effects of cancer treatment, such as congestive heart failure and stroke, in the patients in their study.

“Studies like these are very difficult to mount, so it’s important to learn as much as we can from them,” Bhatia said.

Fellow study investigators include pharmacologist Mary Relling, Pharm.D., of St. Jude Children’s Research Hospital, and geneticist Lue-ping Zhao, Ph.D., at the Fred Hutchison Cancer Research Center.