Corresponding author Yadav Sapkota, PhD, St. Jude Department of Epidemiology and Cancer Control
Physicians caring for survivors of childhood cancer later in life should be aware that survivors’ genetics, in addition to their lifesaving cancer treatment, contribute to the risk for secondary cancers. This finding comes from scientists at St. Jude Children’s Research Hospital who quantified different factors’ contributions to the risk of a second cancer, the primary cause of mortality for long-term survivors. The new research used data from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and Childhood Cancer Survivor Study (CCSS), two of the world’s premier childhood cancer survivor studies, which are housed at St. Jude. The study was published today in The Lancet Oncology.
“We found the burden of second cancer in survivors of childhood cancer is largely contributed by pediatric treatment exposures and genetic predisposition,” said corresponding author Yadav Sapkota, PhD, 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.”
Comparing contributions to second cancers in survivors
Previous research has examined how particular treatment exposures, genetics and lifestyle factors are associated with increased risk of second cancers in isolation. However, their relative contribution at the population level has not been assessed. To address this knowledge gap, St. Jude scientists compared over 10,000 survivors from St. Jude LIFE and CCSS, collectively the largest survivor cohort in North America. That large dataset included treatment exposures and outcomes, genetic information, lifestyle factors, and the presence or absence of a second cancer, allowing the researchers to evaluate the contribution of these factors to the occurrence of second cancers.
“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,” said co-author Greg Armstrong, MD, MSCE, St. Jude Department of Epidemiology and Cancer Control chair.
Radiation exposure was the most significant contributor to secondary cancer risk, accounting for about 40% or more of the risk. Prior research has also described the long-term adverse effects of radiation, so modern therapies have already lowered radiation doses or completely removed radiation exposure as other treatments became more effective, a change which this study further supports.
Genetics can be more important than chemotherapy and lifestyle for second cancer risk
While the impact of radiation exposure was straightforward, the researchers found more complex relationships to risk for chemotherapy and genetics. Depending on the cancer type, chemotherapy contributed from 8% to 35% of subsequent cancer risk. While the potential late effects of chemotherapy have been well-described, genetic predisposition’s contribution to second cancer risk in survivors was less well recognized. The researchers wanted to better understand that predisposition, so they looked at hundreds of common genetic variants previously associated with developing cancer in the general population, called a polygenic risk score, and some rare genetic variants, then looked at those variants’ relationship to second cancers in St. Jude LIFE and CCSS participants. That polygenic risk score approach revealed that depending on the cancer type, polygenic risk score contributed to 5% to 37% of the risk.
“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,” said co-author Yutaka Yasui, PhD, 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.”
“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.
Similarly, lifestyle factors, such as diet and exercise, differed from expectations as they appeared to contribute much less, accounting for 1% to 6% of second cancer risk. However, survivors in this study were primarily in their 20s and 30s, which may mean that lifestyle factors did not yet have enough time for effects to become apparent.
“We know healthy lifestyle choices are important for survivors,” Sapkota said. “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
“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.” Those with a strong predisposition could receive more regular and intense cancer screenings to catch a second cancer early when they are more likely to respond to treatment. Survivors armed with the knowledge of their unique combination of treatment-related, genetic and lifestyle risk factors could also better advocate to their health care providers about the need for such screening.
“Second cancers remain the leading cause of mortality for childhood cancer survivors,” Sapkota said. “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.”
Authors and funding
The study’s first author is Achal Neupane, of St. Jude. The study’s other authors are Siddhant Taneja, Jennifer French, Matthew Ehrhardt, Tara Brinkman, Rachel Webster, Jun Yang, Kirsten Ness, Melissa Hudson, Gregory Armstrong, Leslie Robison and Yutaka Yasui; St. Jude; Qi Liu; University of Alberta; Cindy Im, Lucie Turcotte and Joseph Neglia; University of Minnesota; Monica Gramatges, Baylor College of Medicine; Rebecca Howell, University of Texas MD Anderson Cancer Center and Smita Bhatia; University of Alabama at Birmingham.
The study was supported by grants from the National Cancer Institute (R01HL173881, R01CA216354, R21CA261833, U24CA55727, U01CA195547 and CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.