Background The purpose of this study was to examine the impact of breast cancer therapy on biological aging as measured by expression of genes for cellular senescence (p16INK4a, SenMayo), DNA damage response, and proinflammatory senescence-associated secretory phenotype. Methods This longitudinal, observational study evaluated women diagnosed with breast cancer (stage 0-III) prior to radiation therapy (RT) and/or chemotherapy (CT) and at repeated visits out to 2 years. Peripheral blood mononuclear cell gene expression was assessed using RNA sequencing on quality-verified RNA. Longitudinal data were analyzed using mixed linear models and a zero-inflated 2-part model. Results Women (mean age = 55.5 years) receiving CT with or without RT (n = 73) had higher odds (odds ratio = 2.97, 95% confidence interval = 1.52 to 5.8) of having detectable p16INK4a following treatment compared with RT (n = 76) or surgery alone (n = 37). The proportion of women expressing 16INK4a over the follow-up period increased in all treatment groups (P < .001), with no interaction by treatment. All groups also increased over time in DNA damage response (P < .001), SenMayo (P < .001), and senescence-associated secretory phenotype (P < .001). Groups differed in the pattern of increase over time with statistically significant quadratic time by group differences for CT with or without RT compared with RT alone for DNA damage response (P = .05), SenMayo (P = .006), and the senescence-associated secretory phenotype (P = .02). Conclusions Results revealed activation of genes associated with biological aging in women with breast cancer from diagnosis through early survivorship, including DNA damage response, cell senescence, and the inflammatory secretome. Increases were evident across cancer treatments, although women receiving CT showed sustained increases, whereas RT exhibited slowing at later time points. Overall, findings suggest that women treated for breast cancer are aging within their immune cells.

中文翻译：

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乳腺癌幸存者生物衰老的转录组标志物：一项纵向研究


背景 本研究的目的是检查乳腺癌治疗对生物衰老的影响，通过细胞衰老基因表达 （p16INK4a， SenMayo）、DNA 损伤反应和促炎衰老相关分泌表型来衡量。方法 这项纵向观察性研究评估了在放疗 （RT） 和/或化疗 （CT） 之前以及 2 年内重复就诊时被诊断患有乳腺癌 （0-III 期） 的女性。使用质量验证的 RNA 的 RNA 测序评估外周血单核细胞基因表达。使用混合线性模型和零充气 2 部分模型分析纵向数据。结果 与 RT （n = 76） 或单独手术 （n = 37） 相比，接受 CT 联合或不联合 RT （n = 73） 的女性 （平均年龄 = 55.5 岁） 治疗后可检测到 p16INK4a 的几率更高 （比值比 = 2.97,95% 置信区间 = 1.52 至 5.8）。在所有治疗组中，在随访期间表达 16INK4a 的女性比例均增加 （P < .001），与治疗之间没有相互作用。各组的 DNA 损伤反应 （P < .001）、SenMayo （P < .001） 和衰老相关分泌表型 （P < .001） 也随时间增加。与单独 RT 相比，有或没有 RT 的 CT 在基因损伤反应 （P = .05）、SenMayo （P = .006） 和衰老相关分泌表型 （P = .02） 方面，各组在增加模式上存在差异，各组差异具有统计学意义二次时间。结论 结果揭示了乳腺癌女性从诊断到早期生存过程中与生物衰老相关的基因激活，包括 DNA 损伤反应、细胞衰老和炎性分泌组。 在癌症治疗中，增加是明显的，尽管接受 CT 的女性表现出持续增加，而 RT 在较晚的时间点表现出减慢。总体而言，研究结果表明，接受乳腺癌治疗的女性正在其免疫细胞内衰老。