Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Hematology Oncology Division, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
J Clin Oncol. 2023 Sep 20;41(27):4381-4393. doi: 10.1200/JCO.23.00428. Epub 2023 Jul 17.
Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases.
SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models.
A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% 6%; HR, 2.46; < .01), anthracyclines (20% 8%; HR, 2.86; < .001), epipodophyllotoxins (23% 1%; HR, 12.20; < .001), or platinums (46% 7%; HR, 8.58; < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 0.63) and platinum-exposed (AUC,0.68 0.58) survivors.
A pleiotropic cancer PRS has strong potential for improving SMN 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.
化疗暴露与随后的恶性肿瘤（SMN）风险有关。随着放射治疗（RT）的使用减少，遗传易感性在化疗相关 SMN 中的作用应得到明确界定。
评估了来自儿童癌症幸存者研究和圣裘德终身队列研究的欧洲裔（EUR；N=9895）和非洲裔（AFR；N=718）遗传背景的长期儿童癌症幸存者中的 SMN。为每个幸存者计算了一个来自英国生物银行研究（>400,000 人）的与多效性成人癌症风险相关的 179 个变异多基因风险评分（PRS）。比较PRS 最高和最低五分位数的 SMN 累积发生率，并使用比例风险模型估计风险比（HR）。
共有 1594 名幸存者发生了 SMN，基底细胞癌（n=822）、乳腺癌（n=235）和甲状腺癌（n=221）最为常见。尽管 PRS 与 RT 暴露的 EUR 幸存者的 SMN 风险关联非常小（HR，1.22；P=.048；n=4630），但在未接受放疗的 EUR 幸存者（n=4322）中，接受烷化剂（17% 6%；HR，2.46；<.01）、蒽环类药物（20% 8%；HR，2.86；<.001）、表鬼臼毒素（23% 1%；HR，12.20；<.001）或铂类药物（46% 7%；HR，8.58；<.01）治疗后，30 年 SMN 累积发生率和 HRs 显著增加。该 PRS 还显著改变了未接受放疗的 AFR 幸存者中与表鬼臼毒素相关的 SMN 风险（n=414；<.01）。PRS 归因于预测的改善在接受表鬼臼毒素（AUC，0.71 0.63）和铂类药物（AUC，0.68 0.58）治疗的幸存者中最大。
多效性癌症 PRS 具有很强的潜力，可改善特定化疗药物治疗的未接受放疗幸存者的 SMN 临床风险分层。基于治疗和罕见癌症易感性突变的多基因风险筛查方法可能是早期筛查策略的有价值补充。
