The high percentage attributed to radiation also serves as a historical marker. Many of the survivors in the study were treated in eras when radiation doses were higher and fields were broader than they are today. Modern oncology has already begun to pivot, lowering radiation dosages or eliminating them entirely in favor of more targeted therapies—a trend that this study’s findings strongly validate.
Genetics can be more important than chemotherapy and lifestyle for second cancer risk
While the link between radiation and future cancer was largely expected, the study’s findings regarding genetics and chemotherapy revealed a more nuanced and surprising hierarchy of risk.
The researchers discovered that chemotherapy’s contribution to subsequent cancer risk ranged from 8% to 35%, depending on the specific type of secondary cancer. For years, chemotherapy-induced DNA damage was considered the primary culprit alongside radiation. However, the St. Jude team found that genetic predisposition often played a comparable or even larger role.
To quantify this, the scientists employed a sophisticated tool known as a polygenic risk score (PRS). Unlike tests for rare genetic mutations (such as BRCA1), a polygenic risk score looks at hundreds of common genetic variants that, when combined, can indicate a person’s susceptibility to a disease. When the researchers applied these scores to the survivor cohorts, they found that genetics contributed between 5% and 37% of the risk for secondary cancers.
"Polygenic risk scores are developed for all kinds of diseases for personalized medicine, but generally with precision below what is required for clinical utility in the general population," explained co-author Yutaka Yasui, PhD, of the St. Jude Department of Epidemiology and Cancer Control. "Among survivors of childhood cancer and for estimating their risk of certain types of subsequent cancer, however, they may provide useful information in conjunction with therapy exposures."
The realization that a survivor’s DNA might be a more potent predictor of future illness than their history of chemotherapy is a significant departure from traditional thinking. "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.
The study also examined lifestyle factors, such as diet, smoking habits, and physical activity. Interestingly, these factors appeared to contribute the least to secondary cancer risk in this specific population, accounting for only 1% to 6%. However, Sapkota and his colleagues were quick to add an important caveat: the survivors in the study were primarily in their 20s and 30s.
At these ages, the cumulative damage of poor lifestyle choices—which often takes decades to manifest as cancer in the general population—may not yet have reached a measurable threshold. "We know healthy lifestyle choices are important for survivors," Sapkota emphasized. "In this study, we focused only on the risk of second cancers, which may not be strongly impacted by lifestyle at this young age. However, other research has shown the benefits of healthy choices on other late effects, such as protecting cardiac wellbeing, so it is still important for clinicians to encourage—and patients to seek—a healthy lifestyle."
