McWilliam Alan, Marshall Deborah, Kerns Sarah L, Barnett Gillian C, Vega Ana, Kapouranis Thodori, Aguado Barrera Miguel E, Avuzzi Barbara, Azria David, Chang-Claude Jenny, Choudhury Ananya, Coedo Costa Carla, Dunning Alison, Farcy-Jacquet Marie-Pierre, Faivre-Finn Corinne, Gutiérrez-Enríquez Sara, Fuentes-Ríos Olivia, Gómez Caamaño Antonio, Lambrecht Maarten, López Pleguezuelos Carlos, Rancati Tiziana, Rattay Tim, de Ruysscher Dirk, Seibold Petra, Sperk Elena, Talbot Christopher, Webb Adam, Veldeman Liv, Rosenstein Barry S, West Catharine M L
Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
The Christie NHS Foundation Trust, Manchester, United Kingdom.
J Natl Cancer Inst. 2025 May 1;117(5):1018-1026. doi: 10.1093/jnci/djae349.
Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesized that patients with a high polygenic risk score for RA will have an increased risk of radiotherapy toxicity given the involvement of DNA repair.
Primary analysis was performed on 1494 prostate cancer, 483 lung cancer, and 1820 breast cancer patients assessed for development of radiotherapy toxicity in the REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) study. Validation cohorts were available from the Radiogenomics Consortium. All patients had undergone curative-intent radiotherapy and were assessed prospectively for toxicity. Germline genomic data was available for all patients, allowing a polygenic risk score to be calculated using 101 RA risk variants. Polygenic risk score was analyzed as a continuous variable and with a more than 90th percentile cutoff. Associations with acute and late standardized total average toxicity (STAT) scores and individual toxicity endpoints were analyzed in multivariable models with preselected adjustment variables.
Increasing polygenic risk score for RA did not increase the risk of STAT-acute or STAT-late in any cohort. There was an increased risk of late esophagitis in the lung cancer cohort (coefficient = 0.018, P = .01), however this was not validated (P = .79). No individual acute or late toxicity endpoints were statistically significantly associated with polygenic risk score for the prostate or breast cohorts. No statistically significant results were found in the validation cohorts in multivariable models.
Patients with a high genetic risk for RA do not show increased levels of toxicity after radiotherapy suggesting treatment planning does not need to be modified for such patients.
重叠基因与类风湿关节炎（RA）及DNA修复途径有关。因此，我们推测，鉴于DNA修复的参与，RA多基因风险评分高的患者放疗毒性风险会增加。
在 REQUITE（验证放疗毒性的预测模型和生物标志物以减少癌症幸存者的副作用并提高生活质量）研究中，对1494例前列腺癌、483例肺癌和1820例乳腺癌患者进行了初步分析，这些患者接受了放疗毒性评估。验证队列来自放射基因组学联盟。所有患者均接受了根治性放疗，并对毒性进行了前瞻性评估。所有患者都有生殖系基因组数据，从而能够使用101个RA风险变异计算多基因风险评分。多基因风险评分作为连续变量进行分析，并采用第90百分位数以上的临界值。在具有预选调整变量的多变量模型中，分析了与急性和晚期标准化总平均毒性（STAT）评分及个体毒性终点的关联。
在任何队列中，RA多基因风险评分的增加均未增加急性或晚期STAT的风险。肺癌队列中晚期食管炎的风险增加（系数 = 0.018，P = 0.01），然而这并未得到验证（P = 0.79）。前列腺癌或乳腺癌队列中，没有个体急性或晚期毒性终点与多基因风险评分有统计学显著关联。在多变量模型的验证队列中未发现统计学显著结果。
RA遗传风险高的患者放疗后并未表现出更高水平的毒性，这表明对此类患者无需修改治疗计划。
