Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Immunol. 2023 Jan 9;13:974793. doi: 10.3389/fimmu.2022.974793. eCollection 2022.
Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study.
Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively.
BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy.
Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.
靶向改变，如 BRAFV600E 突变和 NTRK 融合，在微卫星不稳定高（MSI-H）结直肠癌（CRC）中富集。具有靶向改变的 MSI-H（MSI-H 改变）可能为靶向治疗和免疫治疗提供独特的机会。我们在本研究中系统评估了 MSI-H 改变和无靶向改变的 MSI-H（MSI-Hwt）CRC 患者的分子特征和免疫相关特征。
在 1938 例连续入组的 CRC 患者中，纳入了 126 例 MSI-H 状态（6.50%）的患者进行回顾性研究。分别通过下一代测序（NGS）和基因表达谱分析（GEP）检测基因组和转录组数据。
BRAFV600E、NTRK1 和 FGFR2 突变是 MSI-H CRC 患者最常见的靶向改变。MSI-H 改变表型与年龄较大（p<0.001）、右侧（p=0.024）和女性（p=0.036）显著相关。MSI-H 改变组中未发现林奇综合征（LS）患者。MSI-H 改变和 wt 亚组的肿瘤突变负担（TMB）和肿瘤新生抗原负担（TNB）相当（p<0.05）。随后，转录组研究分析进一步表明，MSI-H 改变的 CRC 患者与免疫活性肿瘤微环境相关，具有更高水平的 Teff IFN-γ、CYT 和 MERCK 18 特征，以及更低水平的 IPRES 基因特征、EMT 和 TGFβ特征。此外，病例研究支持携带靶向改变的 MSI-H CRC 患者也可能从免疫治疗中获得长期无疾病生存获益。
我们的研究初步揭示了 MSI-H 改变作为一种新的 MSI-H CRC 患者亚型，具有独特的分子特征和免疫活性肿瘤微环境。鉴于免疫检查点抑制剂（ICIs）治疗的可及性，我们的结果可能为具有靶向改变的 MSI-H CRC 患者的免疫治疗提供临床证据。
