Polygenic Risk Score and Chemotherapy-Related Subsequent Malignant Neoplasms in Childhood Cancer Survivors

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In a study reported in the Journal of Clinical Oncology, Im et al found that a polygenic risk score (PRS) may be useful in stratifying risk for subsequent malignant neoplasms among nonirradiated survivors of childhood cancer according to chemotherapy received.

Study Details

The study involved evaluation of subsequent malignant neoplasms among long-term childhood cancer survivors of European (n = 9,895) and African (n = 718) genetic ancestry from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort Study. A validated 179-variant PRS associated with pleiotropic adult cancer risk from the UK Biobank Study was computed for each survivor.

Key Findings

A total of 1,594 survivors developed subsequent malignant neoplasms, with basal cell carcinoma (n = 822), breast cancer (n = 235), and thyroid cancer (n = 221) being the most common. More survivors with European ancestry developed subsequent malignant neoplasms (15.2%)—notably, basal cell carcinoma (7.9%)—than survivors with African ancestry (3.9% and 0.1%).

Subsequent malignant neoplasm risk association with the PRS was “modest” among irradiated survivors with European ancestry (n = 4,630; hazard ratio [HR] for top vs bottom PRS quintiles = 1.22, P = .048). No significant association was found among irradiated survivors with African ancestry.

However, among nonirradiated survivors with European ancestry (n = 4,322), hazard ratios were significant for those treated with alkylating agents (17% vs 6%, HR = 2.46, P < .01), anthracyclines (20% vs 8%, HR = 2.86, P < .001), epipodophyllotoxins (23% vs 1%, HR = 12.20, P < .001), or platinums (46% vs 7%, HR = 8.58, P < .01). A significant association for epipodophyllotoxin-related subsequent malignant neoplasm risk was also observed among nonirradiated survivors with African ancestry (n = 414, P < .01).

Among nonirradiated survivors with European ancestry, the addition of PRS to a risk model using only clinical predictors improved the receiver operating characteristic area under the curve from 0.58 to 0.62 (P = .069) for alkylating agents, 0.60 to 0.64 (P = .076) for anthracyclines, 0.63 to 0.71 (P = .049) for epipodophyllotoxins, and 0.58 to 0.68 for platinums (P = .052).  

The investigators concluded, “A pleiotropic cancer PRS has strong potential for improving subsequent malignant neoplasm clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer susceptibility mutations.”

Cindy Im, PhD, of the Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Leukemia and Lymphoma Society, National Marrow Donor Program Be The Match Foundation, and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.