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Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...

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在非转移性前列腺癌放射治疗后,晚期膀毒性的多基因风险评分.

Manzur Farazi1, Xin Yang1, Carson J Gehl1

  • 1The Medical College of Wisconsin, Milwaukee, Wisconsin.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
|March 3, 2025
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多基因风险评分 (PRS) 可以识别前列腺癌患者在放射治疗后膀毒性风险较高. 这种遗传工具可能有助于个性化治疗,以减少幸存者的副作用.

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科学领域:

  • 辐射瘤学 辐射瘤学
  • 遗传学 遗传学 是一个
  • 泌尿器科 泌尿器科 泌尿器科 泌尿器科

背景情况:

  • 晚期膀毒性是前列腺癌患者接受放射治疗的一个重大问题,影响幸存者的生活质量.
  • 已知的膀毒性风险因素有限,主要集中在辐射剂量和膀体积暴露.
  • 多基因风险评分 (PRS) 提供了一种潜在的方法来识别遗传倾向于发展膀毒性的患者.

研究的目的:

  • 开发和验证多基因风险评分 (PRS) 以预测接受放射治疗的前列腺癌患者晚期膀毒性.
  • 评估PRS与特定的尿路副作用的关联,包括血,尿和频率.
  • 评估PRS在识别可能从个性化治疗策略中受益的患者中的实用性.

主要方法:

  • 使用来自放射遗传学联盟 (N=3,988) 的全基因组关联数据构建了一个PRS.
  • 在REQUITE和URWCI研究 (N=2,034) 中,PRS被前性测试,使用Cox回归分析大量出血 (≥G2) 的时间.
  • 使用英国生物库数据 (N=8,430) 对临床诊断的辐射囊炎进行了外部验证,并对罕见变异进行了基因负担测试.

主要成果:

  • 115种PRS显著相关于血风险增加 (HR=1.22,P=0.009),尿 (HR=1.18,P=0.016),以及尿动频率 (HR=1.14,P=0.036).
  • 在对临床因素进行调整后,PRS最高分位数 (PRShigh) 的患者患出血症的风险增加了两倍以上 (HR=2.12,P=0.002).
  • 在英国生物库 (OR=2.15,P=0.026) 中,PRS在临床诊断的辐射囊炎中表现出类似的预测性能,BOD1L1被确定为潜在的放射敏感性基因.

结论:

  • 开发的PRS有效地识别了在前列腺癌放射治疗后容易发展晚期膀毒性患者.
  • 这种遗传风险评估工具可以为治疗规划提供信息,并可能指导选择需要优化膀节约策略的患者.
  • 实施PRS指导治疗可以减少膀毒性的发生率和影响,改善前列腺癌幸存者的治疗结果.