Tracing cancer's family ties

As a pediatric oncologist, Dr. Debra Friedman often has the unfortunate job of telling parents their child has cancer. Inevitably, the shocked parents have two questions: Why did my child get cancer? Will my other children get cancer?

Friedman's next unfortunate job is to answer, "I don't know" to both, and to explain that these are active areas of research.

Some of that research is beginning to shed some light on the second question. A recent study Friedman led that was published in the August issue of Cancer Epidemiology, Biomarkers & Prevention found that the siblings of long-term childhood cancer survivors had a significantly increased risk of cancer overall, and for several cancer types, also being diagnosed with the same cancer. For siblings of children with cancers such as leukemia, Hodgkin lymphoma, Wilms tumor, neuroblastoma and bone tumors, the risk of getting the same cancer was 1.5 times greater than in race and gender-matched controls. The risk for siblings also was elevated if their brother or sister had developed a second cancer.

Although the findings may seem alarming, they really are not, said Friedman, a researcher in the Clinical Research Division and associate professor of pediatrics at the University of Washington School of Medicine. And like many such studies, there are more questions raised and answered.

"You have to understand that these are childhood-cancer survivors. They and their siblings were still relatively young even though the survivors were treated between 1970 and 1986," Friedman said. "The median age of the childhood-cancer survivors and the siblings was in the 20s when the self-reported survey data were collected in the mid-late 1990s. Cancer in people in their 20s is still very rare. Having a risk that is 1.5 times greater than that of the general population, or 50 percent higher, is still very small."

Friedman said well-described, known cancer predisposition syndromes do not explain the excess cancer rates. More research needs to be done to better understand the genetic contribution to childhood cancer, she said.

"What this study tells us is that we need, as investigators, to do more work to better define some of these patterns of cancer among family members," she said. "That could then lead to molecular studies where we can look for genes that are involved in these cancers and then be able to provide these families with targeted genetic counseling with respect to their risk."

Taken this way, the study met its goal, which was to look for a potential genetic contribution to childhood cancer by examining a large group of survivors — almost 14,000 — and their first-degree relatives. The survivors were enrolled in the Childhood Cancer Survivor Study, which encompasses 27 institutions in the United States and Canada and is funded by the National Cancer Institute.

The mystery of pediatric cancers

"Childhood cancer is rare compared to adult cancers," Friedman said. "The cause of most pediatric cancers is unknown and the genetic contribution to childhood cancer is equally unknown. There are only a handful of syndromes that include specific childhood cancers, and the molecular basis for those symptoms is not fully understood. Most childhood cancers are not part of known family syndromes."

The study looked at mothers, fathers, siblings and offspring, but only found a clear statistically significant increased risk among siblings. The higher risk was not associated with every type of childhood cancer. Finally, the risk of cancer among both siblings and offspring of patients who had more than one cancer was higher than that of the patients who only had one cancer. "This suggests that patients who get multiple cancers may well be genetically predisposed to cancer, as may be their families," Friedman said.

Offspring of cancer survivors is another large group Friedman and colleagues are worried about. "There was a suggestion of increased risk in offspring in this study, however, the number of offspring was very small because these survivors are still fairly young. As we see more offspring, we are going to be looking at this group very carefully."

Environmental factors

Friedman theorized that the increased cancer risk among siblings might be explained in the genetic interaction of the siblings' environments. "These siblings are brought up in the same environments so they have, largely, the same environmental exposures and they share genetic material with one another. So, the increased risk is likely explained by some gene or genes for which there also may need to be a relevant environmental exposure. For example there may be a gene that increases the risk of lymphoma in these families, which we'll only see the expression of if these genes are exposed to some environmental condition."

Friedman said the next step is collect more data from the families in which a sibling of a childhood cancer survivor was subsequently diagnosed with cancer. "We're proposing to go back to this group and get updated family histories to see if we can establish patterns among family members that can then lead us to develop genetic studies."