Bdioui Ahlem, Akkari Mariem, Krifa Maroua, Souiden Yosra, Sleimane Ethmane, Mokni Wafa, Lazrek Nada Ben, Mestiri Sarra, Hmissa Sihem, Missaoui Nabiha
Research Laboratory Lr21es03, Oncogenesis and Tumor Progression, Medicine Faculty of Sousse, University of Sousse, Sousse, Tunisia.
Pathology Department, Sahloul University Hospital, Sousse, Tunisia.
J Egypt Natl Canc Inst. 2025 May 26;37(1):22. doi: 10.1186/s43046-025-00279-x.
Microsatellite instability (MSI) and deficiency in the human mismatch repair (MMR) system are critical drivers of genomic instability in various cancers. Tumors exhibiting MSI and MMR deficiency (dMMR) have prognostic implications and are associated with differential responses to immune checkpoint inhibitors. Given their key roles in tumorigenesis, investigating MMR protein expression and MSI in urothelial cancer of the bladder is essential to improve therapeutic strategies and deepen understanding of its molecular features. This study aimed to assess MMR protein expression and MSI in primary urothelial carcinoma of the bladder and to evaluate their associations with clinicopathological characteristics.
A total of 49 primary urothelial carcinomas were analyzed for MMR expression using immunohistochemistry, and dMMR tumors underwent further analysis for MSI status using the markers of the Bethesda panel (BAT25, BAT26, D2S123, D5S346, and D17S250). The MMR expression and MSI findings were associated with clinicopathological parameters.
dMMR was identified in two high-grade urothelial carcinomas (4.1%), while the remaining cases demonstrated proficient MMR. Both dMMR tumors showed impaired immunoreactivity, with one tumor displaying a simultaneous loss of the MLH1/PMS2 heterodimer and the other showing isolated MSH6 loss. MSI analysis revealed instability in BAT26 in the MLH1/PMS2-deficient tumor and at D17S250 in the MSH6-deficient tumor. Both tumors exhibited low-level MSI (MSI-L). No relevant associations were found between MMR/MSI status and clinicopathological features (p > 0.05).
The identification of MSI-L and MMR deficiency in only two samples underscores the rarity of MSI in urothelial carcinoma among Tunisian patients. These findings emphasize the need for larger, multi-center studies to elucidate the MSI/dMMR molecular and clinical implications in bladder carcinoma.
微卫星不稳定性（MSI）和人类错配修复（MMR）系统缺陷是多种癌症基因组不稳定的关键驱动因素。表现出MSI和MMR缺陷（dMMR）的肿瘤具有预后意义，并与对免疫检查点抑制剂的不同反应相关。鉴于它们在肿瘤发生中的关键作用，研究膀胱尿路上皮癌中的MMR蛋白表达和MSI对于改善治疗策略和加深对其分子特征的理解至关重要。本研究旨在评估原发性膀胱尿路上皮癌中MMR蛋白表达和MSI，并评估它们与临床病理特征的相关性。
使用免疫组织化学分析了49例原发性膀胱尿路上皮癌的MMR表达，dMMR肿瘤使用贝塞斯达面板（BAT25、BAT26、D2S123、D5S346和D17S250）的标志物进一步分析MSI状态。MMR表达和MSI结果与临床病理参数相关。
在2例高级别尿路上皮癌（4.1%）中鉴定出dMMR，其余病例显示MMR功能正常。两个dMMR肿瘤均显示免疫反应性受损，一个肿瘤同时缺失MLH1/PMS2异二聚体，另一个显示单独的MSH6缺失。MSI分析显示，MLH1/PMS2缺陷肿瘤中的BAT26不稳定，MSH6缺陷肿瘤中的D17S250不稳定。两个肿瘤均表现为低水平MSI（MSI-L）。未发现MMR/MSI状态与临床病理特征之间存在相关关联（p>0.05）。
仅在两个样本中鉴定出MSI-L和MMR缺陷，凸显了突尼斯患者膀胱尿路上皮癌中MSI的罕见性。这些发现强调需要进行更大规模的多中心研究，以阐明MSI/dMMR在膀胱癌中的分子和临床意义。
