Bellal Sarah, Rolley Cyrielle, Richard Jeremy, Bounaix Nolwenn, Le Corre Vincent, Copin Marie-Christine, Blanchet Odile, Bigot Pierre, Procaccio Vincent, Bris Céline
Department of Pathology, Angers University Hospital, Angers, France.
Univ Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, Angers, France.
Pathol Oncol Res. 2025 Jul 23;31:1612172. doi: 10.3389/pore.2025.1612172. eCollection 2025.
Clear cell renal cell carcinoma (ccRCC) is the most common renal malignancy. However, the combined clinical and biological scores commonly used to predict the clinical outcome are imperfect and need improvement. The main goal of our study was to assess the effect of mtDNA genetics on the prognosis of ccRCC patients and to explore morphologic correlation. Mitochondrial DNA copy number (mtDNAcn) variation between tumor and paired matched healthy kidney tissue was assessed by real-time quantitative PCR and expressed as a ratio in 105 patients. According to this median ratio, the cohort was divided into two groups: "LOW" (n = 53) and "HIGH" (n = 52). Cancer-Specific Survival (CSS) and Disease-Free Survival were assessed in each group. The tumor samples were classified into two subtypes (Clear or Eosinophilic cells) according to the cytoplasmic morphology. CSS was significantly reduced in the "HIGH" than in the "LOW" group with respective 5-year survival rates: 78.7% (CI 95: 64.8-95.5) and 95.5% (CI 95 87.1-100.0) (Hazard Ratio: 7.4 (CI 95: 1.9-29.9, ) in multivariate analysis, including pathological classification, tumor size, International Society of Urological Pathology grade, lymphovascular invasion, dedifferentiated pattern, necrosis and adjuvant therapy. Next-generation sequencing of mtDNA was performed on 14 tumors and matched healthy kidney tissue. No hotspot mutation or redundant large deletion was found. None of the variants or large deletions identified had an impact on prognosis. MtDNAcn variation in tumor relative to normal kidney appears as an independent prognostic factor in ccRCC, which was also associated with eosinophilic morphology. MtDNA content could be considered an additional prognostic factor, in combination with other predictive parameters. Furthermore, these results underline the importance of the role of mitochondria in ccRCC and the need for further functional studies to understand the pathophysiological mechanisms better and consider therapies targeting mitochondrial metabolism.
透明细胞肾细胞癌（ccRCC）是最常见的肾脏恶性肿瘤。然而，常用于预测临床结局的综合临床和生物学评分并不完善，需要改进。我们研究的主要目的是评估线粒体DNA（mtDNA）遗传学对ccRCC患者预后的影响，并探索形态学相关性。通过实时定量PCR评估105例患者肿瘤组织与配对的健康肾组织之间的线粒体DNA拷贝数（mtDNAcn）变化，并将其表示为比值。根据该中位数比值，将队列分为两组：“低”组（n = 53）和“高”组（n = 52）。评估每组的癌症特异性生存（CSS）和无病生存情况。根据细胞质形态将肿瘤样本分为两种亚型（透明细胞或嗜酸性细胞）。“高”组的CSS明显低于“低”组，5年生存率分别为：78.7%（95%CI：64.8 - 95.5）和95.5%（95%CI：87.1 - 100.0）（多因素分析中风险比：7.4（95%CI：1.9 - 29.9），包括病理分类、肿瘤大小、国际泌尿病理学会分级、淋巴管浸润、去分化模式、坏死和辅助治疗）。对14例肿瘤组织及其配对的健康肾组织进行了mtDNA的二代测序。未发现热点突变或多余的大片段缺失。所鉴定的变异或大片段缺失均未对预后产生影响。肿瘤相对于正常肾脏的mtDNAcn变化似乎是ccRCC的一个独立预后因素，并且还与嗜酸性形态相关。mtDNA含量可与其他预测参数结合，被视为一个额外的预后因素。此外，这些结果强调了线粒体在ccRCC中的作用的重要性，以及需要进一步进行功能研究以更好地理解病理生理机制并考虑针对线粒体代谢的治疗方法。
