Ren Xin-Yu, Song Yu, Wang Jing, Chen Long-Yun, Pang Jun-Yi, Zhou Liang-Rui, Shen Song-Jie, Cao Xi, Wang Yu-Xin, Shao Miao-Miao, Liang Zhi-Yong, Sun Qiang, Wu Huan-Wen
Department of Pathology, State Key Laboratory of Complex Severe and Rare Diseases, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Front Oncol. 2021 Mar 4;11:570623. doi: 10.3389/fonc.2021.570623. eCollection 2021.
To investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters.
We retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed.
The median age of the cohort was 49 years (range: 24-90 years) with a median follow-up period of 68 months (range: 1-170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival.
The incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.
研究三阴性乳腺癌（TNBC）中错配修复（MMR）和微卫星不稳定性（MSI）的状况，并探讨MMR/MSI状态与临床病理参数之间的相关性。
我们回顾性收集了440例TNBC患者的组织样本并构建组织芯片。采用免疫组织化学（IHC）检测MLH1、MSH2、MSH6和PMS2的蛋白表达。我们还使用MSI聚合酶链反应（PCR）检测分析了195例患者样本。分析MSI状态与临床病理参数及预后之间的相关性。
该队列患者的中位年龄为49岁（范围：24 - 90岁），中位随访期为68个月（范围：1 - 170个月）。除1例通过IHC鉴定为错配修复缺陷（dMMR）的样本外，所有样本的MLH1、MSH2、MSH6和PMS2均呈阳性，该样本MSH2缺失但MSH6表达完整。MSI PCR显示无高频微卫星不稳定（MSI-H）病例，而分别有14例（7.2%）和181例（92.8%）样本显示低频微卫星不稳定和微卫星稳定。如MSI PCR所示，dMMR样本存在低频不稳定性，且从二代测序观察到肿瘤中可能存在缺失。未检测到MMR或MSI状态与临床病理参数、程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）表达或生存之间的相关性。
TNBC中dMMR/MSI-H的发生率极低，可能会遇到罕见的MSI PCR/MMR IHC结果不一致的情况。此外，MMR/MSI状态的预后价值可能有限。有必要进一步研究探索TNBC的其他预测性免疫治疗生物标志物。
