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Differences in Mutations Across Tumour Sizes in Clear-Cell Renal Cell Carcinoma - Beyond the Abstract

Renal cell carcinomas (RCC) behave indolently up to sizes that would be alarming in other cancers.1 In no other malignancy does tumor size, in the magnitude of centimeters, inform risk stratification and decisions regarding observation, as it does in RCC. This drove our curiosity in mutational differences between large and small clear cell RCCs (ccRCCs).2 Does the difference in behavior between large and small tumors reflect underlying genomic differences? Do tumors acquire aggressive mutations as they grow larger?

We examined 1,039 ccRCCs from three large genomic cohorts (TRACERx, TCGA, CAGEKID) to examine the distribution of key mutations across tumor size.3-5 We focused on mutations VHL, PBRM1, SETD2, BAP1, and CDKN2A loss. SETD2, BAP1, and CDKN2A loss were all considered “aggressive” changes as they have been associated with worse outcomes in prior studies.

We found that aggressive mutations were 2-3 times more common in larger tumors (>7 cm) compared to smaller ones (≤4 cm) across cohorts. Meanwhile, indolent mutations, PBRM1 and VHL, which are thought to occur earlier in tumor evolution, as shown in TRACERx - were roughly equally prevalent across tumor sizes.6 Though rarer in smaller tumors, we found that aggressive mutations (CDKN2A loss and SETD2) were associated with worse outcomes (invasive disease, metastasis at presentation, recurrence after resection, and worse overall survival) in tumors ≤7 cm while controlling for size.

While our study does not answer whether tumors acquire aggressive mutations as they grow larger or whether tumors with aggressive mutations grow faster, we hypothesize both play a role. Our findings suggest that aggressive mutations acquired during tumor growth and evolution could drive the different behavior of large ccRCCs compared to small ccRCCs. Whether identifying these mutations could improve patient risk stratification and inform decisions around resection and adjuvant treatment warrants further investigation.

Written by: Steven Monda, Department of Urology, University of Michigan, Ann Arbor, MI,

References:

  1. Monda SM, Lui HT, Pratsinis MA, et al: The Metastatic Risk of Renal Cell Carcinoma by Primary Tumor Size and Subtype, Elsevier, 2023, pp 137
  2. Monda SM, Carney BW, May AM, et al: Differences in mutations across tumour sizes in clear‐cell renal cell carcinoma. BJU International, 2024
  3. Turajlic S, Xu H, Litchfield K, et al: Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal, Elsevier, 2018, pp 581
  4. Vasudev NS, Scelo G, Glennon KI, et al: Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma, Clin Cancer Res, 2023, pp 1220-1231
  5. Ricketts CJ, De Cubas AA, Fan H, et al: The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma, Elsevier B.V., 2018, pp 313-326.e5
  6. Turajlic S, Xu H, Litchfield K, et al: Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal, Cell Press, 2018, pp 595-610.e11
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