Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
J Cancer Res Clin Oncol. 2023 Jul;149(7):3423-3434. doi: 10.1007/s00432-022-04261-1. Epub 2022 Aug 8.
To better understand the clinicopathological characteristics and molecular alterations in different intratumoral components of colorectal cancer (CRC) with heterogeneity of mismatch repair (MMR) protein expression and microsatellite instability (MSI) status.
The histopathological features, MSI status, and other molecular alterations were analyzed in separately microdissected intratumoral regions and matched metastatic lymph nodes in four cases with intratumoral heterogenous MMR expression screened from 500 CRC patients, using PCR-based MSI testing, MLH1 promoter methylation, and targeted next-generation sequencing (NGS).
High microsatellite instability (MSI-H) was identified in MLH1/PMS2-deficient regions in Cases 1 to 3 and in MSH2/MSH6-deficient regions in Case 4, while microsatellite stability (MSS) was detected in all the intratumoral regions and metastatic lymph nodes with proficient MMR expression (pMMR). Intratumoral heterogeneity of MLH1 promoter methylation and/or other common driving gene mutations of CRC, such as KRAS and PIK3CA mutations, was identified in all four CRCs. Further, three cases (75%) showed heterogeneous histomorphological features in intratumoral components and metastatic lymph nodes (Cases 1, 2, and 4), and the corresponding metastatic lymph nodes showed moderate differentiation with MSS/pMMR (Cases 2 and 3).
Intratumoral heterogeneous MSI status is highly correlated with intratumoral histomorphological heterogeneity, which is also an important clue for the intratumoral heterogeneity of drive gene mutations in CRC. Thus, it is essential to detect MMR protein expression and other gene mutations in metastases before treatment, especially for CRCs with intratumoral heterogenous MMR protein expression or heterogenous histomorphological features.
更好地理解结直肠癌（CRC）中不同肿瘤内成分的临床病理特征和分子改变，这些肿瘤内成分的错配修复（MMR）蛋白表达和微卫星不稳定性（MSI）状态存在异质性。
从 500 例 CRC 患者中筛选出 4 例存在肿瘤内 MMR 表达异质性的病例，通过聚合酶链反应（PCR）-MSI 检测、MLH1 启动子甲基化和靶向下一代测序（NGS），对其分别微切割的肿瘤内区域和匹配的转移性淋巴结进行组织病理学特征、MSI 状态和其他分子改变分析。
在病例 1 至 3 中，在 MLH1/PMS2 缺陷区域中检测到高微卫星不稳定性（MSI-H），在病例 4 中，在 MSH2/MSH6 缺陷区域中检测到高微卫星不稳定性（MSI-H），而在所有具有 MMR 表达功能的肿瘤内区域和转移性淋巴结中均检测到微卫星稳定性（MSS）。在所有 4 例 CRC 中均发现 MLH1 启动子甲基化和/或 CRC 常见驱动基因突变（如 KRAS 和 PIK3CA 突变）的肿瘤内异质性。此外，3 例（75%）肿瘤内成分和转移性淋巴结的肿瘤形态学特征存在异质性（病例 1、2 和 4），相应的转移性淋巴结显示出中等分化，具有 MSS/pMMR（病例 2 和 3）。
肿瘤内异质性 MSI 状态与肿瘤内形态学异质性高度相关，这也是 CRC 中驱动基因突变肿瘤内异质性的重要线索。因此，在治疗前检测转移灶中的 MMR 蛋白表达和其他基因突变非常重要，特别是对于肿瘤内 MMR 蛋白表达或异质性形态学特征存在异质性的 CRC 患者。
