Genetics may play a larger role in second cancers among childhood cancer survivors than previously thought

A new St. Jude's Research study shows that genetics need to be considered in assessing risk of second cancers in pediatric cancer survivors. Photo credit – St. Jude's Research Hospital

CANCER DIGEST – July 6, 2025 – A pediatric cancer survivor’s genetics, as well as the type of treatment received, need to be considered by the physicians monitoring these patients for secondary cancers, a new study by St. Jude’s Research Hospital shows.

Secondary cancers are the primary cause of death for long-term pediatric cancer survivors. In an effort to find the factors most likely to contribute to a second cancer, researchers at St. Jude’s used two large databases of pediatric cancer survivors, the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. Together the two contain a dataset of more than 12,000 survivors including treatment exposures, outcomes, genetic information and lifestyle factors.

Led by Achal Neupane, PhD the St. Jude’s researchers analyzed data from 12,344 pediatric cancer survivors looking at radiotherapy and chemotherapy exposures, genetic predisposition, and lifestyle factors such as physical activity, smoking and alcohol consumption. The researchers assigned polygenic risk scores for each type of cancer, meaning they assessed the risk of cancer based on a number of genetic risk factors. The findings were published in the June 2025 Lancet Oncology.

They found that radiation exposure was the most significant contributor to secondary cancer risk accounting for about 40 percent of the risk. This was not a surprise as it confirmed other long-term studies that identified radiation as a significant risk factor. As such modern therapies have lowered radiation doses or completely removed radiation therapies in favor of other treatments.

That said, determine the contribution of chemotherapy and genetics to secondary cancer was more complex. Depending on cancer type, they found that chemotherapy contributed between 8 percent and 35 percent of the risk of secondary cancer. The risk from genetic predisposition contributed between 5 percent and 37 percent of the risk of secondary cancer.

Senior author Yadav Spot, PhD of St. Jude’s Department of Epidemiology and Cancer Control said that while the type of treatment has always been considered a factor in secondary cancers, the combination of datasets for the first time allowed the investigators to assess the role of genetics.

"Our findings showed that genetics can be equally or more important than chemotherapy in some second cancers, which is counter to conventional wisdom in the field," Sapkota said in a press release.

Similarly, lifestyle factors such as diet and exercise differed from expectations. These factors appeared to contribute much less to secondary cancer, accounting for about 1 percent to 6 percent of the risk of a second cancer. The research team noted in their study that the subjects in the study were all in their 20s and 30s and that lifestyle factors may not have had enough time to affect cancer risk.

"Historically, we have paid attention to survivors' treatment exposures when determining second cancer risk," Sapkota said. "Our study suggests that we need to better account for genetic predisposition in this population." 

Sources: St. Jude’s Research Hospital press release and Lancet Oncology