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Journal of Peking University (Health Sciences) ›› 2026, Vol. 58 ›› Issue (3): 631-640. doi: 10.19723/j.issn.1671-167X.2026.03.025

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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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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

CLC Number: 

  • R737.11

Table 1

Demographic and clinical characteristics between lymphoid metastatic renal cell carcinoma group and non-metastatic group"

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

Figure 1

Molecular profile of all renal cell carcinoma samples A, whole exome sequencing revealed the somatic mutations that were most frequent in our cohort. Patients are displayed individually in the columns (grey squares), with colored squares denoting the presence of somatic mutations. B, the copy number variants (CNVs) that are prevalent in this cohort. M, metastatic group; NM, non-metastatic group."

Figure 2

The genomic landscape of somatic mutations in renal cell carcinoma with or without lymphoid metastasis A, oncoprint illustrations of somatic alterations in nonmetastatic RCC by gene frequency; B, oncoprint illustrations of somatic alterations in metastatic RCC by gene frequency; C, the top 20 differential CNV between metastatic and nonmetastatic ccRCC patients; D, KEGG analysis of mutated genes with different prevalence in the nonmetastatic group; E, KEGG analysis of mutated genes with different prevalence in the metastatic group. RPSC signaling pathway: signaling pathways regulating pluripotency of stem cells. RCC, renal cell carcinoma; ccRCC, clear cell renal cell carcinoma; CNV, copy number variants; Padj, adjusted P value; KEGG, Kyoto Encyclopedia of Genes and Genomes."

Figure 3

Discordance of mutation patterns between primary and metastatic renal cell carcinoma A, oncoprint illustrations of somatic alterations in metastasis by gene frequency. B-E, four box plots summarizing: purity, ploidy, weighted-genomic integrity index (WGII), and intra-tumor heterogeneity (ITH). Values are compared between primary and metastatic tumors, and the P value is at the top of the plot. F, composition of clonal and subclonal arms alterations in the primary and metastatic tumors. G, composition of clonal and subclonal somatic alterations in the primary and metastatic tumors."

Figure 4

Characterization of metastasizing clones between primary and metastatic renal cell carcinoma A, illustration of the method used to categorize tumor clones. B, shared and private mutations among the paired primary and metastatic samples. Every column represents a patient and the height of the column depicts the percentage of mutations in that pair. C, the selection of alterations between primary tumor and metastasis, the bar chart demonstrates the percentage of mutation clonal genes. D, the selection of alterations between primary tumor and metastasis, the bar chart demonstrates the percentage of arm-level clone."

Figure 5

Correlation analysis between lymph node metastasis and prognosis in renal cell carcinoma A, Kaplan-Meier curve showing the overall survival (OS) to time of death compared by lymphatic metastasis via the Log-rank test. Patients lost to follow-up were censored from analysis and are represented by the tick marks on the curves. B, the frequency of genes with different prevalence between different prognostic groups. Group 1 represented the population in which an outcome event (death) occurred during follow-up. Group 2 represented the patients who were still alive at the last follow-up. C-D, lymph nodes act as a "metastatic pool" to support distant metastasis of the tumor. C, molecular evolution in a typical renal cell carcinoma patient with both lymph node and bone metastases, and the number of mutations determines the length of the corresponding branch and trunk. D, venn diagram illustrated the overlap and independently mutated genes between the primary tumor, lymph node and bone metastases."

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