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Polygenic Risk Scores Help Inform Adult Cancer Risk in Childhood Cancer Survivors

Childhood Cancer Survivor

NEW YORK – New research suggests that the risk of childhood cancer survivors developing a malignancy again in adulthood may be informed by their treatment history along with cancer-specific germline polygenic risk scores (PRS) derived from the broader population.

"These findings suggest that polygenic risk scores may be useful for improving our ability to identify survivors at the highest risk of specific types of cancer, which could contribute to improved guidelines and education to allow survivors to engage in prevention strategies and ensure they receive appropriate screening and monitoring to detect any future cancers early," first author Todd Gibson, a researcher with the National Cancer Institute's cancer epidemiology and genetics division, said in an email.

Though prior studies have documented increased secondary cancer risk in childhood cancer survivors, the team explained, it remains to be seen whether this rise in adult cancer risk is due to individuals' cancer treatment history, germline genetic risk contributing to both childhood and adult cancers, or a combination of treatment and genetic factors.

As they reported in Nature Medicine on Thursday, researchers at NCI, St. Jude Children's Research Hospital, and other centers in the US and the UK brought together genetic risk insights from previous genome-wide association studies, focusing on PRS with ties to half a dozen cancer types: female breast cancer, colorectal cancer, thyroid cancer, melanoma, basal cell carcinoma, and squamous cell carcinoma.

In a group of 11,220 childhood cancer survivors enrolled through the St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study, the team found that all but one of the cancer-specific PRS — the one for colorectal cancer — were linked to the risk of developing cancer as adults.

"Previous studies have shown that certain rare genetic variants can substantially impact cancer risk in survivors of childhood cancer, but a relatively small number of individuals will have one of these rare variants," Gibson said. "Our study provides evidence that combining the small effects of many different common variants using polygenic risk scores can provide additional information about survivors' risk of specific cancers."

By taking a closer look at a handful of cancer types that are frequently treated with radiation therapy, particularly breast cancer, thyroid cancer, and basal cell carcinoma, meanwhile, the investigators saw signs that the combination of PRS profiling and insights into past exposure to high-dose radiation treatment improved adult cancer risk prediction compared to either measure alone.

Such results suggested that "polygenic risk scores can be informative in survivors already known to be at higher cancer risk due to the radiation treatment they received for their childhood cancer," Gibson explained, noting that "the combination of a high polygenic risk score and childhood exposure to radiation was associated with a more-than-additive increased cancer risk."

The team found that childhood cancer survivors classified as having a high genetic risk of basal cell carcinoma were roughly 2.7 times as likely to develop the skin cancer as their low PRS counterparts, for example, while past history of intense skin radiotherapy coincided with a 12-fold increase in basal cell carcinoma incidence.

In contrast, individuals who had high PRS-based genetic risk as well as high levels of past radiation therapy appeared to be 18.3-fold as likely to develop basal cell carcinoma compared to their low PRS, low radiation counterparts.

Likewise, the incidence of breast or thyroid cancer was especially enhanced in childhood cancer survivors with a history of radiation treatment and higher-than-usual PRS relative to individuals at the low-risk end of the cancer PRS spectrum or with lower levels of radiation exposure.

"For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS," the authors reported. "These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk."

Together, the results pointed to the possibility of using germline genetic profiles to help manage future cancer risk in childhood cancer survivors, the authors explained. Even so, they cautioned that the current study centered on childhood cancer survivors of European descent and called for further analyses in more diverse human populations, along with efforts to evaluate the PRS-informed approach in clinical settings.

"[A]lthough our findings suggest the potential utility of polygenic risk scores for enhancing risk stratification and refining follow-up guidelines related to subsequent cancers in childhood cancer survivors," Gibson said, "further work is needed to validate these findings and to directly evaluate their clinical utility."