Huang Jinglin, Xu Liang, Cai Yacheng, Tan Xiaoli, Lin Hanjie, Chen Zhiting, Wang Chao, Deng Weihao, Fu Xinhui
Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China.
BMC Cancer. 2025 Jul 1;25(1):1103. doi: 10.1186/s12885-025-14484-3.
Microsatellite instability (MSI) status guides immunotherapy and Lynch syndrome (LS) screening. Given the 5-10% discordance rate between mismatch repair immunohistochemistry (MMR-IHC) and Microsatellite instability polymerase chain reaction (MSI-PCR), true high microsatellite instability (MSI-H) cases in proficient mismatch repair (pMMR) colorectal cancer (CRC) may miss critical interventions. This study investigates molecular pathological characteristics between concordant and discordant groups assessed by these two methods, aiming to reduce the risk of misdiagnosing MSI-H and LS.
The MMR-IHC and MSI-PCR were conducted respectively in 2910 CRC patients. Sanger sequencing identified the mutation status of KRAS, BRAF, and PIK3CA genes, and next-generation sequencing (NGS) detected LS-related genes. We compared the molecular pathological features between the pMMR&MSS and pMMR&MSI-H groups, as well as between the dMMR&MSI-H and dMMR&MSS groups. Eleven screening strategies for pMMR&MSI-H were formulated for pMMR patients.
The consistency rate between the two methods was 96.8% (2816/2910), with a discordance rate of 3.2% (94/2910), comprising 43 cases in the pMMR&MSI-H group and 51 cases in the dMMR&MSS group. Germline mutations in LS-associated genes were detected in 36.4% (4/11) of the pMMR&MSI-H group but were absent in all 9 dMMR&MSS cases. Compared with the pMMR&MSS consistent group, the pMMR&MSI-H inconsistent group showed higher prevalence in patients with right colon (55.8% vs.20.3%), well-differentiated (18.8% vs.8.4%), and PIK3CA exon 20 (E20) mutations (30.0% vs.8.7%). Compared with the dMMR&MSI-H consistent group, the dMMR&MSS inconsistent group was more common in patients with rectum (49.0% vs. 15.2%), stage IV patients (23.5% vs. 8.3%), and PIK3CA E20 wild-type (97.8% vs. 82.4%). The strategy of supplemental MSI-PCR detection for the right colon pMMR patients could identify 55.8% (24/43) of pMMR&MSI-H patients. Adding the detection of patients with PIK3CA E20 mutation based on the right colon can increase the PMMR&MSI-H detection rate to 65.1% (28/43).
We recommend supplemental MSI-PCR testing for pMMR CRC patients with right colon OR PIK3CA E20 mutation. For those with MSI-H results, subsequent NGS should be performed to identify germline mutations in LS-associated genes.
微卫星不稳定性（MSI）状态指导免疫治疗和林奇综合征（LS）筛查。鉴于错配修复免疫组化（MMR-IHC）与微卫星不稳定性聚合酶链反应（MSI-PCR）之间存在5%-10%的不一致率，错配修复功能正常（pMMR）的结直肠癌（CRC）中真正的高度微卫星不稳定（MSI-H）病例可能会错过关键干预措施。本研究调查了通过这两种方法评估的一致组和不一致组之间的分子病理特征，旨在降低MSI-H和LS误诊风险。
对2910例CRC患者分别进行MMR-IHC和MSI-PCR检测。桑格测序确定KRAS、BRAF和PIK3CA基因的突变状态，二代测序（NGS）检测LS相关基因。我们比较了pMMR&MSS组和pMMR&MSI-H组之间以及dMMR&MSI-H组和dMMR&MSS组之间的分子病理特征。为pMMR患者制定了11种针对pMMR&MSI-H的筛查策略。
两种方法的一致率为96.8%（2816/2910），不一致率为3.2%（94/2910），其中pMMR&MSI-H组43例，dMMR&MSS组51例。pMMR&MSI-H组中36.4%（4/11）检测到LS相关基因的胚系突变，而9例dMMR&MSS病例均未检测到。与pMMR&MSS一致组相比，pMMR&MSI-H不一致组在右半结肠癌患者（55.8%对20.3%）、高分化（18.8%对8.4%）和PIK3CA外显子20（E2）突变患者（30.0%对8.7%）中的患病率更高。与dMMR&MSI-H一致组相比，dMMR&MSS不一致组在直肠癌患者（49.0%对15.2%）、IV期患者（23.5%对8.3%）和PIK3CA E20野生型患者（97.8%对82.4%）中更常见。对右半结肠pMMR患者进行补充MSI-PCR检测的策略可识别55.8%（24/43）的pMMR&MSI-H患者。在右半结肠基础上增加对PIK3CA E2突变患者的检测，可将PMMR&MSI-H检测率提高到65.1%（28/43）。
我们建议对右半结肠癌或PIK3CA E2突变的pMMR CRC患者进行补充MSI-PCR检测。对于MSI-H结果的患者，应进行后续NGS以识别LS相关基因的胚系突变。
