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北京大学学报（医学版） ›› 2026, Vol. 58 ›› Issue (3): 631-640. doi: 10.19723/j.issn.1671-167X.2026.03.025

• 论著 • 上一篇    下一篇

预后不良的肾细胞癌伴淋巴结转移的分子特征

舒帆1,2,*, 葛力源1,*, 邓汉彰1,3, 殷昊明1, 欧俊永1, 邓绍晖1, 郝一昌1, 陆敏4,5, 张展奕1, 段佩辰1, 张树栋1,*()   

  1. 1. 北京大学第三医院泌尿外科, 北京 100191
    2. 昆明医科大学第二附属医院泌尿外科, 昆明 650101
    3. 北京协和医院生物标志物研究平台, 北京 100730
    4. 北京大学第三医院病理科, 北京 100191
    5. 北京大学基础医学院病理学系, 北京 100191
  • 收稿日期:2024-07-10 出版日期:2026-06-18 发布日期:2026-01-07
  • 通讯作者: 张树栋
  • 作者简介:

    * These authors contributed equally to this work

  • 基金资助:
    国家自然科学基金(82273389); 北京市自然科学基金(7232212)

Molecular characteristics for poor prognosis related renal cell carcinoma with lymph metastases

Fan SHU1,2, Liyuan GE1, Hanzhang DENG1,3, Haoming YIN1, Junyong OU1, Shaohui DENG1, Yichang HAO1, Min LU4,5, Zhanyi ZHANG1, Peichen DUAN1, Shudong ZHANG1,*()   

  1. 1. Department of Urology, Peking University Third Hospital, Beijing 100191, China
    2. Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
    3. Center for Biomarker Discovery and Validation, National Infrastructures for Translation Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing 100730, China
    4. Department of Pathology, Peking University Third Hospital, Beijing 100191, China
    5. Department of Pathology, Peking University School of Basic Medical Sciences, Beijing 100191, China
  • Received:2024-07-10 Online:2026-06-18 Published:2026-01-07
  • Contact: Shudong ZHANG
  • Supported by:
    the National Natural Science Foundation of China(82273389); the Natural Science Foundation of Beijing(7232212)

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摘要：

目的: 通过下一代测序(next-generation sequencing，NGS)技术分析肾细胞癌(简称肾癌)淋巴结转移的基因突变谱，发现与预后不良相关的分子特征，为肾癌机制的研究以及治疗提供新的思路。方法: 对31例淋巴结转移的肾癌和21例非转移性肾癌患者的临床资料进行回顾性分析，同时从病理科调取肿瘤原发灶、淋巴结转移灶、远处转移灶的石蜡包埋组织共81例，使用NGS技术检测患者的基因突变谱，术后随访分析淋巴结转移与患者预后的关系。结果: 与非转移性肾癌相比，淋巴结转移肾癌在肿瘤大小(P=0.006)、世界卫生组织(World Health Organization，WHO)/国际泌尿病理协会(International Society of Urological Pathology, ISUP)分级(P=0.002)、T分期(P=0.003)、合并癌栓(P=0.025)上差异有统计学意义。最常见的突变基因是肿瘤抑制基因VHL (38%)、PBRM1 (22%)和IGF2R (20%)，且拷贝数变异与肿瘤转移相关，部分突变特征与已知的突变模式高度相似。淋巴结转移组和非转移组患者的突变频率存在差异，转移组大多数基因的突变频率较高，然而Reactome通路富集分析未在两组共有的富集途径上显示出差异有统计学意义。同一患者的肿瘤原发灶和转移灶之间有很强的一致性，基因组学指标[如纯度、倍性、加权基因组完整性指数(weighted-genomic integrity index, WGII)和肿瘤内异质性(intra-tumor heterogeneity, ITH)]及克隆、亚克隆组成分析进一步支持了这种一致性。无转移组的总生存率较高(P=0.041)，且特定基因突变(如IGF2R、JUN、EPHA5和FH)与较差的预后相关。淋巴结可能起到“转移池”的作用，促进肾癌的远处转移。结论: 多基因NGS同时评估了多个相关标记物，揭示了淋巴结转移肾癌患者的基因改变谱，基于NGS的分子分析可以帮助临床医生评估患者的预后，并发现新的机制及治疗靶点。

关键词: 肾细胞癌, 淋巴转移, 高通量核苷酸序列分析, DNA突变分析, 预后

Abstract:

Objective: Next-generation sequencing (NGS) technology was used to analyze the gene mutation profile of lymph node metastases in renal cell carcinoma, and the molecular characteristics associated with poor prognosis were found, providing new ideas for mechanism research and treatment. Methods: Retrospective clinical data collection was conducted on 31 patients with lymphoid metastatic renal cell carcinoma and 21 patients with non-metastatic renal cell carcinoma. A total of 81 formalin-fixed paraffin-embedded tissue samples were retrieved from the Department of Pathology, including primary tumor, lymph node metastasis, and distant metastasis samples. The gene mutation profiles of the patients were examined using next-generation sequencing technology. The patients were followed up to analyze the correlation between lymph node metastasis and patient prognosis. Results: The lymph node metastasis group showed differences in tumor size (P=0.006), World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade (P=0.002), T stage (P=0.003) and tumor thrombus (P=0.025) compared with non-metastatic renal cell carcinoma. The most commonly mutated genes in our cohort were the tumor suppressor genes VHL (38%), PBRM1 (22%), and SETD2 (20%). More-over, copy number variations were associated with tumor metastasis, and some mutation features were highly similar to known mutation patterns. There was a difference in mutation frequency between the patients in the metastasis group and samples in the non-metastasis group. The mutation frequency of most genes in the metastasis group was higher, however, Reactome pathway enrichment analysis did not show statistically significant differences in the shared enriched pathways between the two groups. There was a strong degree of concordance between the tumor' s primary and metastatic foci in the same patient, and genomic indicators [such as purity, ploidy, weighted-genomic integrity index (WGII), and intra-tumor heterogeneity (ITH)] as well as clonal and subclonal composition analysis further supported this consistency. The overall survival (OS) was higher in the patients without metastases (P=0.041), and specific gene mutations (such as IGF2R, JUN, EPHA5, and FH) were associated with poorer prognosis. To facilitate distant metastasis, lymph nodes might function as a "metastatic pool". Conclusion: The multigene NGS evaluates multiple relevant markers simultaneously, revealing several genetic alterations in the patients with lymphatic metastatic renal cell carcinorma. NGS-based molecular analysis can assist clinicians in assessing a patient' s prognosis and identifying novel, potentially therapeutic mechanisms.

Key words: Renal cell carcinoma, Lymphatic metastasis, High-throughput nucleotide Sequencing, DNA mutational analysis, Prognosis

中图分类号: 

  • R737.11

表1

淋巴结转移性肾细胞癌组和非转移组患者的人口统计学和临床基线特征"

Variable Overall Metastatic group Non-metastatic group P value
Number of patients 52 31 21
Gender, n (%) >0.999
  Female 19 (36.5) 11 (35.5) 8 (38.1)
  Male 33 (63.5) 20 (64.5) 13 (61.9)
T stage, n (%) 0.003
  Tx 2 (3.8) 2 (6.5) 0 (0)
  T0 2 (3.8) 0 (0) 2 (9.5)
  T1 14 (26.9) 3 (9.7) 11 (52.4)
  T2 2 (3.8) 1 (3.2) 1 (4.8)
  T3 29 (55.8) 22 (71.0) 7 (33.3)
  T4 3 (5.8) 3 (9.7) 0 (0)
Smoking, n (%) 0.325
  No 35 (67.3) 23 (74.2) 12 (57.1)
  Yes 17 (32.7) 8 (25.8) 9 (42.9)
Drinking, n (%) 0.415
  No 39 (75.0) 25 (80.6) 14 (66.7)
  Yes 13 (25.0) 6 (19.4) 7 (33.3)
Hypertension, n (%) 0.367
  No 27 (51.9) 14 (45.2) 13 (61.9)
  Yes 25 (48.1) 17 (54.8) 8 (38.1)
Pathological type, n (%) 0.293
  ccRCC 34 (65.4) 18 (58.1) 16 (76.2)
  nccRCC 18 (34.6) 13 (41.9) 5 (23.8)
WHO/ISUP grade, n (%) 0.002
  1 1 (1.9) 1 (3.2) 0 (0)
  2 17 (32.7) 3 (9.7) 14 (66.7)
  3 22 (42.3) 18 (58.1) 4 (19.0)
  4 12 (23.1) 9 (29.0) 3 (14.3)
Tumor thrombus, n (%) 0.025
  No 34 (65.4) 16 (51.6) 18 (85.7)
  Yes 18 (34.6) 15 (48.4) 3 (14.3)
Age/years, M (P25, P75) 53.50 (43.00, 63.25) 53.00 (46.00, 63.50) 58.00 (43.00, 61.00) 0.867
Tumor size/cm, M (P25, P75) 6.70 (4.42, 9.93) 8.20 (5.85, 10.60) 4.60 (2.60, 6.50) 0.006
BMI/(kg/m2), M (P25, P75) 24.44 (21.96, 26.09) 24.44 (20.92, 26.02) 24.42 (23.51, 26.12) 0.396
Hemoglobin/(g/L), M (P25, P75) 133.50 (112.00, 150.25) 128.00 (112.00, 137.00) 151.00 (132.00, 162.00) 0.002
BUN/(mmol/L), M (P25, P75) 5.25 (4.38, 6.00) 5.55 (4.80, 6.25) 4.80 (4.00, 5.70) 0.097
Creatinine/(μmol/L), M (P25, P75) 80.50 (71.25, 102.25) 84.00 (71.00, 116.50) 78.00 (72.00, 85.00) 0.138

图1

所有肾细胞癌样本的基因突变谱"

图2

转移性与非转移性肾细胞癌体细胞突变的基因图谱"

图3

转移性肾细胞癌原发灶和转移灶的差异突变模式"

图4

肾细胞癌原发灶和转移灶之间的克隆进化特征"

图5

肾细胞癌淋巴结转移与预后的关联分析"

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