Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, United Kingdom.
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York.
Int J Radiat Oncol Biol Phys. 2022 Nov 1;114(3):494-501. doi: 10.1016/j.ijrobp.2022.06.098. Epub 2022 Jul 15.
Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity.
Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression.
Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10).
Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.
我们旨在检验癌症易感性的更新多基因风险评分（PRS）是否会影响放射治疗毒性的风险。
分析包括来自 Radiogenomics 和 REQUITE 联盟队列的 9717 名患有乳腺癌（n=3078）、前列腺癌（n=5748）或肺癌（n=891）的患者。患者接受了潜在的根治性放射治疗，并前瞻性地评估了毒性。种系基因分型涉及全基因组单核苷酸多态性（SNP）阵列，其中未分型的 SNP 进行了推断。通过对每个癌症的文献确定的癌症易感性风险等位基因进行求和来生成 PRS：352 个乳腺癌、136 个前列腺癌和 24 个肺癌。PRS 采用癌症易感性的对数优势比（OR）进行加权。2 年和 5 年（乳腺癌、前列腺癌）或 6 至 12 个月（肺癌）的标准化总平均毒性（STAT）评分量化了毒性。主要分析检验了晚期 STAT，次要分析研究了急性 STAT，以及使用多变量回归的个别终点和 SNP。
PRS 的增加并未增加乳腺癌（OR，1.000；95%置信区间 [CI]，0.997-1.002）、前列腺癌（OR，0.99；95% CI，0.98-1.00；加权 PRS OR，0.93；95% CI，0.83-1.03）或肺癌（OR，0.93；95% CI，0.87-1.00；加权 PRS OR，0.68；95% CI，0.45-1.03）患者发生晚期毒性的风险。急性毒性也出现了类似的结果。次要分析鉴定出与乳腺癌疼痛相关的 rs138944387（OR，3.05；95% CI，1.86-5.01；P=1.09×10）和与乳腺癌水肿相关的 rs17513613（OR，0.94；95% CI，0.92-0.97；P=1.08×10）。
具有增加的多基因易患乳腺癌、前列腺癌或肺癌的患者可以安全地接受放射治疗，而不会增加预期的毒性风险。一些个体 SNP 增加了特定毒性终点的可能性，需要在独立队列和功能研究中进行验证，以阐明生物学机制。
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