PCCA 变异 rs16957301 是一种新型 AKI 风险基因型，对接受 ICI 治疗的患者具有特异性：来自我们所有人队列的真实世界证据。

IF 7.6 1区医学 Q1 ONCOLOGY

European Journal of Cancer Pub Date : 2024-11-09 DOI:10.1016/j.ejca.2024.115114

Yanfei Wang , Chenxi Xiong , Weifeng Yu , Minghao Zhou , Tyler Shugg , Fang-Chi Hsu , Michael T. Eadon , Jing Su , Qianqian Song

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引用次数: 0

摘要

简介：免疫检查点抑制剂（ICIs）可增强免疫系统靶向和消灭癌细胞的能力，但也可能引发免疫相关不良事件（irAEs），如急性肾损伤（ICI-AKI），从而使患者管理复杂化。由于对 ICI-AKI 遗传倾向的了解有限，因此需要进行基因组研究以改进治疗策略：利用大规模真实世界数据确定 ICI-AKI 的遗传倾向：通过系统性文献检索，我们发现了 14 个与 ICI-AKI 相关的候选变体。我们利用 "我们所有人 "队列对这些变异进行了候选变异关联研究。为了评估 ICI-AKI 风险，我们建立了一个 ICI 治疗队列和一个普通队列。经性别调整的逻辑回归评估了每个候选基因型对自我报告种族和祖先估计种族的影响。Kaplan-Meier 生存分析评估了遗传对无 AKI 生存的影响：结果：ICI队列（n = 414）显示一年的AKI发病率为23.2%，明显高于普通队列（6.5%，n = 213 282）。PCCA基因中的rs16957301变体（chr13:100324308，T > C）是自述为白人（Beta=0.93，CI：0.32 - 1.54，ORs= 2.53，Bonferroni校正后的P-值=0.047）和祖先估计为欧洲人（Beta=0.94，CI：0.31 - 1.57，ORs= 2.56，Bonferroni校正后的P-值=0.044）的人群中ICI-AKI的重要风险基因型。与参考基因型（TT，7.0 个月，对数秩 P = 0.04）相比，具有 rs16957301 风险基因型（TC/CC）的自我报告白种人发生 AKI 的时间显著提前（3.6 个月）。在祖先估计的欧洲人中也发现了一致的结果。在一般队列中，该变异不存在显著的 AKI 风险（Beta：-0.008-0.035，FDR：0.75-0.99）：我们的研究结果表明，PCCA 中的 rs16957301 可作为白种人的 ICI-AKI 风险标记。还需要进一步的研究来验证这种关联，并探索其他人群的风险。

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PCCA variant rs16957301 is a novel AKI risk genotype-specific for patients who receive ICI treatment: Real-world evidence from all of us cohort

Introduction

Immune checkpoint inhibitors (ICIs) enhance the immune system's ability to target and destroy cancer cells, but can also trigger immune-related adverse events (irAEs), such as acute kidney injury (ICI-AKI), complicating patient management. Limited knowledge of genetic predispositions to ICI-AKI highlights the need for genomic studies to improve therapeutic strategies.

Objective

To identify genetic predispositions for ICI-AKI using large-scale real-world data.

Methods

A systematic literature search led to 14 candidate variants related to irAEs. We performed a candidate variant association study with these variants using the All of Us cohort. An ICI-treated cohort and a general cohort were established to evaluate ICI-AKI risk. Logistic regression, adjusted for sex, evaluated the impact of each candidate genotype, separately for self-reported and ancestry-estimated race. Kaplan-Meier survival analysis assessed genetic effects on AKI-free survival.

Results

The ICI cohort (n = 414) showed a one-year AKI incidence rate of 23.2 %, significantly higher than the general cohort (6.5 %, n = 213,282). The rs16957301 variant (chr13:100324308, T > C) in the PCCA gene was a significant risk genotype for ICI-AKI among self-reported White (Beta=0.93, CI: 0.32 – 1.54, ORs= 2.53, Bonferroni-corrected P-value=0.047) and ancestry estimated Europeans (Beta = 0.94, CI: 0.31 – 1.57, ORs= 2.56, Bonferroni-corrected P-value=0.044). Self-reported White with the rs16957301 risk genotypes (TC/CC) developed AKI significantly earlier (3.6 months) compared to the reference genotype (TT, 7.0 months, log-rank P = 0.04). Consistent results were found in ancestry-estimated Europeans. This variant did not present significant AKI risks in the general cohort (Beta: −0.008–0.035, FDR: 0.75–0.99).

Conclusion

Our findings suggest that rs16957301 in PCCA may serve as an ICI-AKI risk marker in Caucasians. Further studies are needed to validate this association and explore risks in other populations.

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来源期刊

European Journal of Cancer 医学-肿瘤学

CiteScore

11.50

自引率

4.80%

发文量

953

审稿时长

23 days

期刊介绍： The European Journal of Cancer (EJC) serves as a comprehensive platform integrating preclinical, digital, translational, and clinical research across the spectrum of cancer. From epidemiology, carcinogenesis, and biology to groundbreaking innovations in cancer treatment and patient care, the journal covers a wide array of topics. We publish original research, reviews, previews, editorial comments, and correspondence, fostering dialogue and advancement in the fight against cancer. Join us in our mission to drive progress and improve outcomes in cancer research and patient care.