Contributions of cancer treatment and genetic predisposition to risk of subsequent neoplasms in long-term survivors of childhood cancer: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.
Level 3 - non-randomized controlled study
Prospective follow-up of two large retrospectively constructed survivor cohorts
PubMed 40449499 · doi:10.1016/S1470-2045(25)00157-3
What was done
Researchers analyzed data from 12,344 childhood cancer survivors from two cohorts with prospective follow-up: the St Jude Lifetime Cohort (SJLIFE, n=4,401) and the Childhood Cancer Survivor Study (CCSS, n=7,943). Using multivariable piecewise-exponential models, they calculated attributable fractions for the first occurrence of subsequent neoplasms (SNs) attributable to radiotherapy, chemotherapy, genetic predisposition (comparing top two tertiles to lowest tertile of polygenic risk scores [PRSs] from external general populations), and lifestyle factors (physical activity, smoking, alcohol consumption, obesity, and diet).
What was found
Among eligible survivors (49.6% men, 50.4% women; 88.4% White; median follow-up 24.2 years in SJLIFE and 28.0 years in CCSS), cancer treatments and genetic predisposition jointly contributed to 30% (95% CI 6–49 for sarcoma) to 92% (95% CI 89–94 for meningioma) of incident SNs. Radiotherapy exposure contributed the largest proportion, accounting for 44.7% (95% CI 41.9–47.5) of SNs in survivors aged ≥35 years and 40.0% (95% CI 37.1–43.3) in those <35 years in SJLIFE. Elevated PRS accounted for 1% (95% CI 0–7 for meningioma) to 52% (95% CI 39–62 for thyroid cancer), exceeding chemotherapy contributions (3% [95% CI 1–6] for subsequent malignant neoplasms to 35% [95% CI 19–49] for sarcoma). Lifestyle factors contributed negligibly.
Why it matters
This study establishes that radiation therapy and baseline genetic susceptibility explain most subsequent neoplasms in childhood cancer survivors. Integrating polygenic risk scores with treatment histories can substantially refine long-term surveillance and risk stratification.
Limits
The cohort was predominantly White (88.4%), limiting the generalizability of polygenic risk score calibrations to other ancestral populations. Individual chemotherapy agent contributions and exact dose-response relationships were not detailed in the abstract, and lifestyle factors were subject to observational measurement constraints.