Carroll Judith E, Crespi Catherine M, Cole Steve, Ganz Patricia A, Petersen Laura, Bower Julienne E
Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
J Natl Cancer Inst. 2025 Feb 1;117(2):312-321. doi: 10.1093/jnci/djae201.
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.
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.
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).
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.
本研究的目的是通过细胞衰老基因（p16INK4a、SenMayo）的表达、DNA损伤反应以及促炎衰老相关分泌表型来检测乳腺癌治疗对生物衰老的影响。
这项纵向观察性研究评估了在放疗（RT）和/或化疗（CT）之前被诊断为乳腺癌（0-III期）的女性，并在长达2年的多次随访中进行评估。使用RNA测序对质量验证后的RNA评估外周血单个核细胞基因表达。使用混合线性模型和零膨胀两部分模型分析纵向数据。
与接受放疗（n = 76）或仅接受手术（n = 37）的女性相比，接受有或无放疗的化疗（n = 73）的女性（平均年龄 = 55.5岁）在治疗后检测到p16INK4a的几率更高（优势比 = 2.97，95%置信区间 = 1.52至5.8）。在所有治疗组中，随访期间表达16INK4a的女性比例均增加（P <.001），且无治疗交互作用。所有组的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。与单独放疗相比，有或无放疗的化疗组在DNA损伤反应（P = 0.05）、SenMayo（P = 0.006）和衰老相关分泌表型（P = 0.02）方面，随时间增加的模式存在差异，具有统计学意义的二次时间×组间差异。
结果显示，从诊断到早期生存阶段，乳腺癌女性中与生物衰老相关的基因被激活，包括DNA损伤反应、细胞衰老和炎症分泌组。在所有癌症治疗中均有明显增加，尽管接受化疗的女性显示持续增加，而放疗在后期时间点则表现出减缓。总体而言，研究结果表明接受乳腺癌治疗的女性在其免疫细胞内正在衰老。
