High RRM2 Correlates with Mitochondrial and Immune Responses in the Eosinophilic Subtype of Clear Cell Renal Cell Carcinoma.

IF 4.2 2区 医学 Q2 IMMUNOLOGY
Journal of Inflammation Research Pub Date : 2024-11-02 eCollection Date: 2024-01-01 DOI:10.2147/JIR.S478993
Xinqing Zhu, Abdullah Al-Danakh, Yuli Jian, Mohammed Safi, Sijie Luo, Qiwei Chen, Shujing Wang, Deyong Yang
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引用次数: 0

Abstract

Background: Clear cell renal cell carcinoma (ccRCC), the predominant subtype of RCC, is distinguished by unique biological characteristics and heterogeneity, including eosinophilic and clear subtypes. Notwithstanding progress in therapy, immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs), the prognosis for individuals with metastatic ccRCC remains poor, presumably owing to metabolic alterations leading to mitochondrial dysfunction, which affects treatment response variability.

Methods: We analyzed histological and immunohistochemical data from a cohort at Dalian Medical University's First Affiliated Hospital alongside RNA-sequencing transcriptome data from the TCGA database. Histologically, eosinophilic and clear ccRCC subtypes were evaluated using Kaplan-Meier and Cox proportional hazards models for survival analysis and prognosis. Differential gene expression (DEG) analysis and Gene Set Enrichment Analysis were performed to explore transcriptomic differences and relevant pathways.

Results: The study discovered substantial histological and molecular differences between the eosinophilic and clear cell subtypes of ccRCC. The eosinophilic subtype linked with frequent high-grade tumors (69.05% eosinophil vs 35.35% clear) and a poorer prognosis (HR=2.659, 95% CI:1.437-4.919, P=0.002). DEG analysis revealed distinct expression patterns among subtypes and identified a risk score signature that remained significant even after adjusting for clinical variables (HR=3.967, 95% CI: 1.665-9.449, P=0.002), showing less favorable survival in the high-risk group (P < 0.0001). RRM2 emerged as the most prognostic gene from this risk score, particularly in the eosinophilic subtype, alongside other clinical variables. By IHC, RRM2 shows high IHC score in eosinophilic compared to clear subtype (P=0.019). In addition, highly expressed RRM2 correlates with poor outcomes and is linked to mitochondrial genes, immunological pathways, and ICIs treatment.

Conclusion: These findings show significant differences in prognosis between subtypes. RRM2 was the most prognostic gene from the discovered novel risk score signature associated with subtypes. Future research is essential to validate these insights and their therapeutic implications for ccRCC management.

高 RRM2 与透明细胞肾细胞癌嗜酸性亚型的线粒体和免疫反应有关
背景:透明细胞肾细胞癌(ccRCC)是RCC的主要亚型,具有独特的生物学特征和异质性,包括嗜酸性亚型和透明亚型。尽管在治疗、免疫检查点抑制剂(ICIs)和酪氨酸激酶抑制剂(TKIs)方面取得了进展,但转移性ccRCC患者的预后仍然很差,这可能是由于代谢改变导致线粒体功能障碍,从而影响了治疗反应的可变性:我们分析了大连医科大学附属第一医院队列中的组织学和免疫组化数据,以及TCGA数据库中的RNA测序转录组数据。采用Kaplan-Meier和Cox比例危险度模型对嗜酸性和透明性ccRCC亚型进行了生存分析和预后评估。进行了差异基因表达(DEG)分析和基因组富集分析,以探索转录组差异和相关通路:研究发现,嗜酸性亚型和透明细胞亚型的ccRCC在组织学和分子学上存在很大差异。嗜酸性细胞亚型与高分化肿瘤(嗜酸性细胞占69.05%,透明细胞占35.35%)和较差的预后有关(HR=2.659,95% CI:1.437-4.919,P=0.002)。DEG分析揭示了亚型之间不同的表达模式,并确定了一个风险评分特征,该特征即使在调整临床变量后仍有意义(HR=3.967,95% CI:1.665-9.449,P=0.002),显示高风险组的生存率较低(P <0.0001)。RRM2与其他临床变量一起成为该风险评分中最具预后性的基因,尤其是在嗜酸性粒细胞亚型中。通过 IHC,RRM2 在嗜酸性亚型中的 IHC 得分高于透明亚型(P=0.019)。此外,高表达的RRM2与不良预后相关,并与线粒体基因、免疫途径和ICIs治疗有关:结论:这些研究结果表明,不同亚型的预后存在明显差异。RRM2是已发现的与亚型相关的新型风险评分特征中最具预后性的基因。未来的研究对于验证这些见解及其对ccRCC管理的治疗意义至关重要。
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来源期刊
Journal of Inflammation Research
Journal of Inflammation Research Immunology and Microbiology-Immunology
CiteScore
6.10
自引率
2.20%
发文量
658
审稿时长
16 weeks
期刊介绍: An international, peer-reviewed, open access, online journal that welcomes laboratory and clinical findings on the molecular basis, cell biology and pharmacology of inflammation.
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