Normal urothelium harbors extensive mutations, with large regions overtaken by mutant clones.

  • Major Finding: Normal urothelium harbors extensive mutations, with large regions overtaken by mutant clones.

  • Concept: Chromatin-remodeling gene mutations were common, as were mutations reflecting specific-mutagen exposure.

  • Impact: This work identifies another normal tissue in which clonal expansion of cells harboring somatic mutations is common.

Somatic mutations derived primarily from DNA-replication errors and exposure to mutagens naturally accumulate over time and have implications for cancer development and evolution. Complementary studies by Li, Du, Chen, Xu, Lin, and colleagues and Lawson and colleagues investigated somatic mutations in normal urothelial cells. Li, Du, Chen, Xu, Lin, and colleagues focused on healthy urothelial cells [morphologically normal urothelium (MNU)] and diseased urothelial samples from microdissected bladder and ureter urothelium of 120 patients with urothelial-cell cancer (UCC) from China, whereas Lawson and colleagues studied MNU samples from 15 patients (including more than 2,000 microbiopsies) with UCC and 5 organ donor patients without cancer from Europe. Li, Du, Chen, Xu, Lin, and colleagues found that 37% of MNU samples from patients with UCC had mutations in at least one putative bladder cancer driver gene. TP53 was the most commonly mutated gene in UCC samples but was mutated in only 4% of MNU samples. MNU mutations frequently affected genes such as KMT2D and KDM6A, which encode proteins involved in chromatin remodeling. Mutagenesis patterns indicative of exposure to aristolochic acid, a component of many herbs traditionally used in East Asia, were common in MNU in this study population; notably, single clones associated with AA-induced mutagenesis could expand to cover several square centimeters of urothelium. In agreement with Li, Du, Chen, Xu, Lin, and colleagues, Lawson and colleagues observed positive selection for UCC-associated mutations in chromatin-remodeling genes in MNU, whereas mutations in some other genes strongly associated with UCC, such as TP53, were largely absent. Mutational burdens and mutational signatures varied substantially across donors and even from clone to clone within samples from each donor, possibly reflecting the wide variety and extent of possible mutagenic exposures. Unlike in the work of Li, Du, Chen, Xu, Lin, and colleagues, evidence of AA-induced mutagenesis was not found, likely reflecting the low use of herbs traditionally used in East Asia in this European study population; however, many MNU samples in both studies showed signs of APOBEC cytidine deaminase–induced mutagenesis, a common feature of UCC. Together, the results of these two studies highlight the fact that MNU harbors noteworthy clonal expansion that often does not lead to tumorigenesis, raising further questions about what triggers malignant transformation in UCC.

Li R, Du Y, Chen Z, Xu D, Lin T, Jin S, et al. Macroscopic somatic clonal expansion in morphologically normal human urothelium. Science 2020;370:82–9.

Lawson ARJ, Abascal F, Coorens THH, Hooks Y, O'Neill L, Latimer C, et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 2020;370:75–82.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.