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Purpose <p>Patients with clear cell renal cell carcinoma (ccRCC) often develop lung metastases (LuM) years after curative surgery. The choice of treatment measures and timing for ccRCC-LuM is still controversial. The cause for differential responses of primary ccRCC and LuM to anti-angiogenesis (AA) treatment remains unknown.</p> Methods <p>In a longitudinal cohort study, clinical data of 44 ccRCC-LuM patients (2012–2024) was collected to clarify differential responses of primary ccRCC and LuM to AA treatment. In another profiling cohort, whole-exome and bulk RNA sequencings were performed using primary ccRCC and LuM samples from 8 ccRCC-LuM patients (2013–2020) to unravel potential mechanisms.</p> Results <p>Of 52 participants, 12 (23%) were women and the mean (SD) age was 57.6 (8.7) years. The local disease control rate of LuM lesions was significantly lower than that of primary ccRCC lesions (77% <i>vs.</i> 95%). LuM foci had a poorer local progression-free survival (9[95%CI: 6–12] months <i>vs.</i> 33[95%CI: 17–49] months). Mutation and expression differences between primary ccRCC and LuM for enzymes associated with methylation were striking. The primary ccRCC might be good at performing epithelial-mesenchymal transition while LuM focuses on the secretion of surfactant proteins as a shield from drugs. The molecular spectrum of locally advanced cases showed punctuated evolution, suggesting the possibility of rapid progression.</p> Conclusions <p>We reported the possible mechanisms of ccRCC-LuM formation and resistance to AA therapy, which might result from a series of methylation cascades. Timely surveillance and local treatment are crucial to ccRCC-LuM behaving as solitary or oligo-metastasis.</p>

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Multiomics characterization of lung metastasis formation and resistance to anti-angiogenesis therapy in renal cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • Kandi Xu,
  • Wenhao Lin,
  • Lishu Zhao,
  • Hao Wang,
  • Xinyue Liu,
  • Yujin Liu,
  • Li Ye,
  • Wengang Zhang,
  • Zhimin Chen,
  • Xuyang Chen,
  • Yujie Li,
  • Qianqian Zhang,
  • Wencheng Zhao,
  • Lu Chen,
  • Yayi He

摘要

Purpose

Patients with clear cell renal cell carcinoma (ccRCC) often develop lung metastases (LuM) years after curative surgery. The choice of treatment measures and timing for ccRCC-LuM is still controversial. The cause for differential responses of primary ccRCC and LuM to anti-angiogenesis (AA) treatment remains unknown.

Methods

In a longitudinal cohort study, clinical data of 44 ccRCC-LuM patients (2012–2024) was collected to clarify differential responses of primary ccRCC and LuM to AA treatment. In another profiling cohort, whole-exome and bulk RNA sequencings were performed using primary ccRCC and LuM samples from 8 ccRCC-LuM patients (2013–2020) to unravel potential mechanisms.

Results

Of 52 participants, 12 (23%) were women and the mean (SD) age was 57.6 (8.7) years. The local disease control rate of LuM lesions was significantly lower than that of primary ccRCC lesions (77% vs. 95%). LuM foci had a poorer local progression-free survival (9[95%CI: 6–12] months vs. 33[95%CI: 17–49] months). Mutation and expression differences between primary ccRCC and LuM for enzymes associated with methylation were striking. The primary ccRCC might be good at performing epithelial-mesenchymal transition while LuM focuses on the secretion of surfactant proteins as a shield from drugs. The molecular spectrum of locally advanced cases showed punctuated evolution, suggesting the possibility of rapid progression.

Conclusions

We reported the possible mechanisms of ccRCC-LuM formation and resistance to AA therapy, which might result from a series of methylation cascades. Timely surveillance and local treatment are crucial to ccRCC-LuM behaving as solitary or oligo-metastasis.