For decades, the narrative of childhood cancer has been one of remarkable medical triumph. Thanks to advancements in chemotherapy, radiation, and surgical techniques, the five-year survival rate for pediatric malignancies has climbed to over 80%. However, for the hundreds of thousands of survivors now reaching adulthood, that initial victory often comes with a persistent shadow: the risk of developing a second, unrelated cancer later in life.
While the medical community has long recognized that the very treatments used to save a child’s life can sow the seeds of future illness, the exact interplay between those treatments, a patient’s lifestyle, and their underlying genetic makeup has remained difficult to untangle. Now, a landmark study from St. Jude Children’s Research Hospital has provided the most comprehensive quantification to date of how these various factors contribute to the risk of secondary cancers.
The research, published today in The Lancet Oncology, offers a paradigm-shifting look at the long-term health of survivors. By analyzing data from two of the world’s most significant survivor cohorts, scientists have demonstrated that a survivor’s genetic predisposition can be just as influential—and in some cases, more influential—than the chemotherapy they received years prior.
Comparing contributions to second cancers in survivors
Secondary cancers are not merely a side effect; they represent the leading cause of non-relapse mortality for long-term survivors of childhood cancer. Understanding why some survivors develop these malignancies while others do not is critical for evolving the standard of follow-up care.
"We found the burden of second cancer in survivors of childhood cancer is largely contributed by pediatric treatment exposures and genetic predisposition," said the study’s corresponding author, Yadav Sapkota, PhD, of the St. Jude Department of Epidemiology and Cancer Control. "We’ve known treatment exposures and genetics were associated with second cancer risk, but this is the first time we’ve been able to attribute the proportion of their contributions to that risk at the population level."
To reach these conclusions, the research team utilized an unprecedented depth of data. They drew from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and the Childhood Cancer Survivor Study (CCSS), which together represent the largest and most thoroughly documented survivor cohort in North America. By examining more than 10,000 survivors, the researchers were able to cross-reference detailed treatment records with genetic sequencing, lifestyle surveys, and long-term health outcomes.
The scale of the study was a vital component of its success. "This kind of high-impact discovery is only possible in the CCSS and SJLIFE cohorts, that in combination, have more than 12,000 survivors with genetic sequencing," noted co-author Greg Armstrong, MD, MSCE, chair of the St. Jude Department of Epidemiology and Cancer Control.
The most prominent factor identified in the study was radiation exposure. According to the data, radiation remains the most significant contributor to secondary cancer risk, accounting for approximately 40% or more of the risk observed in the population. This finding reinforces decades of clinical observation regarding the long-term adverse effects of ionizing radiation on developing tissues.
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."
Changing care for survivors of childhood cancer
The implications of this research for the future of survivorship care are profound. Currently, most follow-up protocols for childhood cancer survivors are based heavily on the "treatment summary"—a document detailing the types and doses of drugs and radiation a patient received as a child.
The St. Jude findings suggest that this approach, while necessary, is incomplete. By failing to account for genetic predisposition, clinicians may be missing a critical piece of the risk profile for many patients.
"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."
Integrating genetic testing into standard survivorship care could allow for a "precision medicine" approach to follow-up. For example, a survivor who received moderate doses of chemotherapy but carries a high polygenic risk score for breast or colorectal cancer might be prioritized for more frequent or earlier screenings. Conversely, understanding these risks can empower survivors to take a more active role in their own healthcare. Armed with data about their unique combination of genetic and treatment-related risks, patients can better advocate for the specific screenings they need.
The ultimate goal of the study is to reduce the mortality rate associated with the late effects of cancer treatment. As more children survive their initial diagnosis, the medical community’s responsibility shifts toward ensuring those survivors can lead long, healthy lives.
"Second cancers remain the leading cause of mortality for childhood cancer survivors," Sapkota concluded. "Now that we have quantified the contributions of treatment, genetics and lifestyle to the risk of secondary disease, we have a better understanding of where to focus efforts to prevent, detect and treat these cancers, and hopefully extend these survivors’ lives."
The study was a collaborative effort involving a wide range of experts. Achal Neupane of St. Jude served as the first author. The research also included contributions from Siddhant Taneja, Jennifer French, Matthew Ehrhardt, Tara Brinkman, Rachel Webster, Jun Yang, Kirsten Ness, Melissa Hudson, Gregory Armstrong, Leslie Robison, and Yutaka Yasui, all of St. Jude. External collaborators included Qi Liu of the University of Alberta; Cindy Im, Lucie Turcotte, and Joseph Neglia of the University of Minnesota; Monica Gramatges of the Baylor College of Medicine; Rebecca Howell of the University of Texas MD Anderson Cancer Center; and Smita Bhatia of the University of Alabama at Birmingham.
The research was supported by multiple grants from the National Cancer Institute and by ALSAC, the fundraising and awareness organization of St. Jude Children’s Research Hospital. As genomic technology becomes more accessible, the researchers hope that these findings will soon translate into clinical guidelines that offer a more personalized and protective roadmap for survivors everywhere.
