Musangile Fidele Y, Matsuzaki Ibu, Iwamoto Ryuta, Sagan Kanako, Nishikawa Mizuki, Mikasa Yurina, Takahashi Yuichi, Higashine Ryoma, Kojima Fumiyoshi, Hara Isao, Murata Shin-Ichi
Department of Human Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
Department of Urology, Wakayama Medical University, Wakayama, Japan.
Virchows Arch. 2025 Apr;486(4):729-737. doi: 10.1007/s00428-024-03901-w. Epub 2024 Aug 21.
Recent research in urothelial carcinoma (UC) has focused on coding mutations, leaving the significance of non-coding mutations unexplored. This study aims to evaluate non-coding DNA mutation frequencies compared to coding regions in normal urothelium and flat lesions, exploring their implications for tumor biology. Using targeted next-generation sequencing with UC-related gene panel, we analyzed non-coding and coding DNA mutation frequencies across 119 samples of flat urothelium encompassing various lesion types. Mutation patterns were examined based on the presence of associated flat or papillary tumors, and we investigated the correlation between mutation rates in target genes and genetic mutations within genomic regions. Intronic mutations (IMs) displayed variability across lesions, with normal urothelium (NU) exhibiting the highest frequency (43%) and urothelial carcinoma in situ (CIS) the lowest (9%). We observed similar sets of frequently mutated genes in both intronic and exonic regions, distinct from promoter region mutations. Although IMs paralleled exonic mutations in NU, reactive atypia, and atypia of unknown significance (AUS), they were less prevalent in dysplasia (DYS) and CIS. In contrast to CIS-associated AUS and DYS lesions, AUS-DYS lesions associated with papillary tumors exclusively exhibited recurrent intronic mutations involving FGFR3 and ERCC2, aligning with mutation patterns seen in exonic regions. ERCC2 intronic mutations correlated with the mutation rates of the gene panel. Our findings suggest that intronic mutations significantly contribute to tumor heterogeneity in urothelial lesions and may potentially be linked to genomic instability, warranting further investigation.
近期关于尿路上皮癌（UC）的研究主要集中在编码突变上，而非编码突变的意义尚未得到探索。本研究旨在评估正常尿路上皮和平坦病变中与编码区相比的非编码DNA突变频率，探讨其对肿瘤生物学的影响。通过使用与UC相关的基因panel进行靶向二代测序，我们分析了119个包含各种病变类型的扁平尿路上皮样本中的非编码和编码DNA突变频率。根据相关扁平或乳头状肿瘤的存在情况检查突变模式，并研究目标基因突变率与基因组区域内基因突变之间的相关性。内含子突变（IMs）在不同病变中表现出变异性，正常尿路上皮（NU）的频率最高（43%），原位尿路上皮癌（CIS）最低（9%）。我们在内含子和外显子区域观察到相似的一组频繁突变基因，与启动子区域突变不同。尽管IMs在NU、反应性异型增生和意义不明的异型增生（AUS）中与外显子突变相似，但在发育异常（DYS）和CIS中不太常见。与CIS相关的AUS和DYS病变不同，与乳头状肿瘤相关的AUS-DYS病变仅表现出涉及FGFR3和ERCC2的复发性内含子突变，与外显子区域的突变模式一致。ERCC2内含子突变与基因panel的突变率相关。我们的研究结果表明，内含子突变显著促成尿路上皮病变中的肿瘤异质性，并且可能与基因组不稳定相关，值得进一步研究。
