Abstract
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 TP53 (84.6%), followed by APC (78.0%), KRAS (49.6%), and SMAD4 (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; p = 0.018 and HR: 2.754; 95% CI: 1.044–7.265; p = 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 MYC and BRAF mutation was shorter than those with either MYC or BRAF mutation (HR: 4.981, 95% CI: 0.296–83.92; p = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.
Highlights
Colorectal cancer is one of the most common cancer worldwide with approximately 1.2 million new cases annually [1]
Oncogenic pathway-associated clinical impact needs to be determined in metastatic colorectal cancer (mCRC). This present study aimed to evaluate the genomic alterations of oncogenic pathways and their clinical implications in Taiwanese patients with mCRC
The Microsatellite instability (MSI) status analysis was examined in all 128 patients using the PCR-based technique; the MSI status using the next-generation sequencing (NGS)-based analyses was evaluated in 108 patients
Summary
Colorectal cancer is one of the most common cancer worldwide with approximately 1.2 million new cases annually [1]. Despite the introduction of early screening strategies, 35% of patients are diagnosed with distant metastasis at initial presentation [2]. 10–40% of patients experience disease metastasis after curative surgery [3]. Complete resection of metastatic lesions combined with systemic treatments provide prolonged survival and cure opportunity; metastatic colorectal cancer (mCRC) continued as a challenging public concern [4,5,6]. The 5-year survival rate of patients with mCRC remains less than 15% [2]. A comprehensive understanding of molecular biology is important in the development of effective therapeutic strategies for mCRC
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