Cancer treatments and genetic predisposition contribute to second cancer risk

Among long-term survivors of childhood cancer, the risk of developing a subsequent malignancy, such as thyroid cancer, sarcoma, or meningioma, is primarily associated with treatment exposures, genetics, and lifestyle factors. Previous research has examined these factors individually; however, their relative contribution, or the attributable risk of each of these factors at the population level, has not been established. The high frequency of subsequent cancers and their elevated risk for early mortality in survivors underscores the need to better understand the role these factors play and develop strategies for risk reduction.

To answer this question, St. Jude scientists, led by Yadav Sapkota, PhD, Department of Epidemiology & Cancer Control, compared data from over 10,000 survivors from the St. Jude Lifetime Cohort Study and Childhood Cancer Survivor Study. The 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.

The results, published in The Lancet Oncology, showed that radiation exposure was the most significant contributor to secondary cancer risk, accounting for approximately 40% or more of the risk. Prior research describing the long-term adverse effects of radiation has already led modern therapies to limit radiation exposure as much as possible, a change this study further supports. The researchers also found that chemotherapy contributed 8%- 35% of the risk, depending on the subsequent cancer type.

While the potential late effects of chemotherapy have been well described, genetic predisposition’s contribution to second cancer risk in survivors was not fully understood. To understand that predisposition better, the researchers examined hundreds of genetic variants previously associated with developing cancer in the general population to calculate a polygenic risk score, then assessed its relationship to second cancers. The approach revealed that, depending on the cancer type, the polygenic risk score contributed to 5%-37% of the risk. These findings illustrate that genetics can be equally or more important than chemotherapy exposure for the development of some second cancers.

Similarly, lifestyle factors, such as diet and exercise, differed from expectations as they appeared to contribute much less, accounting for 1%-6% of second cancer risk. However, survivors in this study were primarily in their 20s and 30s, and lifestyle factors likely had not yet had time for effects to become apparent.

“Now that we have quantified the contributions of treatment, genetics, and lifestyle to the risk of secondary disease,” said Sapkota, “we have a better understanding of where to focus efforts to prevent, detect, and treat these cancers, and hopefully extend cancer survivors’ lives.”

Those with a strong genetic predisposition could receive more regular and comprehensive 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 screenings.