Huang Yi-Hsuan, Lin Peng-Chan, Su Wu-Chou, Chan Ren-Hao, Chen Po-Chuan, Lin Bo-Wen, Shen Meng-Ru, Chen Shang-Hung, Yeh Yu-Min
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan.
Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan.
Diagnostics (Basel). 2021 Dec 8;11(12):2308. doi: 10.3390/diagnostics11122308.
Systemic characterization of genomic alterations into signaling pathways helps to understand the molecular pathogenies of colorectal cancer; however, their clinical implications remain unclear. Here, 128 patients with metastatic colorectal cancer (mCRC) receiving targeted next generation sequencing were retrospectively enrolled to analyze the impact of altered oncogenic pathways on clinical outcome. The datasets from Memorial Sloan Kettering Cancer Center were used for validation. In 123 patients with non-MSI-high tumor, the most common mutated gene was (84.6%), followed by (78.0%), (49.6%), and (22.8%). When mutated genes were allocated into signaling pathways defined as The Cancer Genome Atlas Pan-Cancer Analysis Project, alterations of cell cycle, Wnt, p53, RTK-RAS, PI3K, TGF-β, Notch, and Myc pathways were identified in 88%, 87%, 85%, 75%, 28%, 26%, 17%, and 10% of mCRC tissues, respectively. The survival analyses revealed that Myc and TGF-β pathway alterations were associated with a shorter overall survival (OS) (hazard ratio [HR]: 2.412; 95% confidence interval [CI]: 1.139-5.109; = 0.018 and HR: 2.754; 95% CI: 1.044-7.265; = 0.033, respectively). The negative prognostic impact of altered TGF-β pathway was maintained in patients receiving an anti-EGFR antibody. The OS of patients with mCRC carrying and mutation was shorter than those with either or mutation (HR: 4.981, 95% CI: 0.296-83.92; = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.
对基因组改变进行信号通路的系统表征有助于理解结直肠癌的分子发病机制；然而，它们的临床意义仍不明确。在此，回顾性纳入了128例接受靶向二代测序的转移性结直肠癌（mCRC）患者，以分析致癌通路改变对临床结局的影响。使用纪念斯隆凯特琳癌症中心的数据集进行验证。在123例非微卫星高度不稳定（MSI-H）肿瘤患者中，最常见的突变基因是（84.6%），其次是（78.0%）、（49.6%）和（22.8%）。当将突变基因分配到定义为癌症基因组图谱泛癌分析项目的信号通路中时，在88%、87%、85%、75%、28%、26%、17%和10%的mCRC组织中分别鉴定出细胞周期、Wnt、p53、RTK-RAS、PI3K、TGF-β、Notch和Myc通路的改变。生存分析显示，Myc和TGF-β通路改变与较短的总生存期（OS）相关（风险比[HR]：2.412；95%置信区间[CI]：1.139 - 5.109；P = 0.018和HR：2.754；95% CI：1.044 - 7.265；P = 0.033）。在接受抗表皮生长因子受体（EGFR）抗体治疗的患者中，TGF-β通路改变的负面预后影响仍然存在。携带和突变的mCRC患者的OS短于携带或突变的患者（HR：4.981，95% CI：0.296 - 83.92；P = 0.02）。这些发现具有临床意义，如预后预测、治疗指导和分子靶向治疗的开发。
