Investigators have found that common inherited genetic factors capable of predicting cancer risk in the general population may also help to predict childhood cancer survivors who may be at elevated risk of new cancers later in life, according to a recent study published by Gibson et al in Nature Medicine. The findings indicate genetics may play a vital role in the development of subsequent malignancies in this patient population and suggest common inherited genetic variants could potentially inform screening and long-term follow-up in those most at risk.
Background
Childhood cancer survivors are known to have a higher risk of developing additional cancers later in life as a result of the adverse effects of cancer therapy or rare inherited genetic factors.
Genome-wide association studies have identified thousands of common inherited genetic variants associated with the risk of different types of cancers. The risk associated with a single common genetic variant is typically low; however, the effects of large numbers of genetic variants can be bundled into a polygenic risk score to provide a more comprehensive estimate of a patient’s genetic risk. Although polygenic risk scores have demonstrated the potential to predict the risk of cancer in the general population, it has not been known whether such scores are also associated with the risk of subsequent cancers among childhood cancer survivors.
“Knowledge about [patients’] genetic makeup could potentially be useful in managing their risk of subsequent cancers,” explained lead study author Todd M. Gibson, PhD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. “The hope would be that, in the future, we can incorporate genetics along with treatment exposures and other risk factors to provide a more complete picture of a survivor’s risk of subsequent cancers to help guide their long-term follow-up care,” he added.
Study Methods and Results
In the recent study, the investigators used data from genome-wide association studies involving large populations of healthy participants to assess the contribution of common inherited genetic variants to the risk of subsequent cancer in childhood cancer survivors.
The investigators examined the association between polygenic risk scores and the risk of basal cell carcinoma, female breast cancer, thyroid cancer, squamous cell carcinoma, melanoma, and colorectal cancer among 11,220 childhood cancer survivors from two large cohort studies. For all of the cancer types except colorectal cancer, polygenic risk scores derived from genome-wide association studies in the general population were associated with the risk of these same cancer types among childhood cancer survivors.
They then looked at basal cell carcinoma, breast cancer, and thyroid cancer—malignancies that occurred most often in the combined data set and were strongly linked to radiation therapy—to determine the joint effect of polygenic risk scores and treatment history. They discovered the risks associated with the combination of higher-dose radiation therapy exposure and higher polygenic risk scores were greater than would be expected based on the sum of the risk associations for each individual risk factor.
Among the childhood cancer survivors, high polygenic risk scores were associated with a 2.7-fold increased risk of basal cell carcinoma compared with low polygenic risk scores. A history of higher radiation therapy exposure to the skin was associated with a 12-fold increased risk compared with lower radiation therapy exposure to the skin. However, childhood cancer survivors who had high polygenic risk scores and higher doses of radiation therapy to the skin had an 18.3-fold increased risk of basal cell carcinoma compared with those who had low polygenic risk scores and received lower radiation therapy doses to the skin.
Additionally, by the age of 50, childhood cancer survivors with higher polygenic risk scores and higher radiation therapy exposure had a greater cumulative incidence of basal cell carcinoma, breast cancer, or thyroid cancer vs those with lower polygenic risk scores or lower radiation therapy exposure. For instance, among female survivors who had radiation to the chest, 33.9% of those with high polygenic risk scores were diagnosed with breast cancer by the age of 50 compared with 21.4% of those with low polygenic risk scores.
After evaluating the combined effect of common genetic variants and the patients’ history of radiation therapy, they found the resulting elevated risk of cancer was greater than the sum of the individual associations for radiation therapy and genetic factors alone.
Conclusions
The investigators stressed that one of the limitations of the study was that the populations included in the analysis were predominantly of European ancestry. Therefore, additional studies with more diverse populations may be needed to confirm the findings. Despite the fact that polygenic risk scores are not yet becoming part of routine clinical practice, they may help inform screening approaches or other clinical decisions in the future.
“Although these results suggest that polygenic risk scores could play a role in improving guidelines for long-term follow-up of childhood cancer survivors exposed to radiation [therapy], right now, they are not sufficient on their own to alter existing guidelines,” Dr. Gibson concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
