Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 100142 Beijing, China.
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, 510260 Guangzhou, Guangdong, China.
Discov Med. 2024 Jul;36(186):1477-1485. doi: 10.24976/Discov.Med.202436186.137.
Metastatic colorectal cancer (mCRC) is increasingly characterized by myriad genomic alterations beyond the well-known factors such as , , and microsatellite instability (MSI). Novel genomic changes, including amplifications, mutations, and gene fusions, are now recognized as potential targets for precision therapy. This study aims to explore the genomic landscape of a Chinese cohort with mCRC to identify potentially targetable genetic alterations for personalized treatment strategies.
A total of 500 mCRC patients in China were enrolled, based on which genomic profiling was performed using capture-based targeted sequencing across a panel of 520 genes on tumor tissues to identify prevalent genomic alterations. The mutations were analyzed by optimized proprietary algorithms. MSI and mismatch repair deficiency status were analyzed using the read-count-distribution approach. Besides, the overall survival (OS) related to these molecular changes was estimated.
The cohort's genomic profiling revealed mutations in 78%, in 60%, and in 47% of the patients. MSI-High status was confirmed in 5.8% of cases via a next-generation sequencing (NGS)-based algorithm. / amplifications were found in 12% (60/500) of patients, with potential therapeutic implications for those without concurrent mutations. A subset of patients (1.2%; 6/500) showed fusions and DNA damage response (DDR) gene mutations (except ) that could be targeted therapeutically. The (G12C) variant was detected in 14 patients (2.8%), and 61 (12.2%) had a mutation. Notably, survival analysis showed no significant differences in OS between mutant loci and mutations ( = 0.436). However, mutations were associated with a poorer prognosis than wild-type and non- mutations (16.3 months vs. 29.5 and 31.1 months, respectively; < 0.001).
This study validates the feasibility of using NGS to detect prognostic and therapeutically actionable genetic variants in Chinese mCRC patients, contributing to understanding the genomic variation within this population and highlighting the potential for personalized medicine in managing mCRC.
转移性结直肠癌（mCRC）的特征越来越多地表现为除了众所周知的因素（如 KRAS、NRAS 和微卫星不稳定性（MSI））以外的众多基因组改变。新型基因组改变，包括扩增、突变和基因融合，现在被认为是精准治疗的潜在靶点。本研究旨在探索中国 mCRC 患者的基因组图谱，以确定潜在的可靶向遗传改变，制定个体化治疗策略。
共纳入中国 500 例 mCRC 患者，对其肿瘤组织进行基于捕获的靶向测序，对 520 个基因进行基因组分析，以确定常见的基因组改变。使用优化的专有算法分析突变。使用读长分布方法分析 MSI 和错配修复缺陷状态。此外，还估计了这些分子变化与总生存期（OS）的关系。
该队列的基因组分析显示，78%的患者存在 突变，60%的患者存在 突变，47%的患者存在 突变。通过基于下一代测序（NGS）的算法，有 5.8%的病例证实 MSI-High 状态。在 12%（60/500）的患者中发现了 /扩增，这对于没有同时存在 突变的患者可能具有治疗意义。一部分患者（1.2%；6/500）存在融合和 DNA 损伤反应（DDR）基因突变（除 外），可以进行靶向治疗。在 14 例患者（2.8%）中检测到 （G12C）变体，61 例（12.2%）患者存在 突变。值得注意的是，生存分析显示 OS 无显著差异在 突变部位和 突变之间（ = 0.436）。然而，与 野生型和非 突变相比， 突变与较差的预后相关（16.3 个月与 29.5 和 31.1 个月相比， ＜0.001）。
本研究验证了使用 NGS 在中国 mCRC 患者中检测预后和治疗性可操作遗传变异的可行性，有助于了解该人群的基因组变异，并突出了在管理 mCRC 中应用个体化医学的潜力。
