Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer
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...
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MDPI AG
2021-12-01
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| Series: | Diagnostics |
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| Online Access: | https://www.mdpi.com/2075-4418/11/12/2308 |
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| author | Yi-Hsuan Huang Peng-Chan Lin Wu-Chou Su Ren-Hao Chan Po-Chuan Chen Bo-Wen Lin Meng-Ru Shen Shang-Hung Chen Yu-Min Yeh |
| author_facet | Yi-Hsuan Huang Peng-Chan Lin Wu-Chou Su Ren-Hao Chan Po-Chuan Chen Bo-Wen Lin Meng-Ru Shen Shang-Hung Chen Yu-Min Yeh |
| author_sort | Yi-Hsuan Huang |
| collection | DOAJ |
| description | 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 <i>TP53</i> (84.6%), followed by <i>APC</i> (78.0%), <i>KRAS</i> (49.6%), and <i>SMAD4</i> (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; <i>p</i> = 0.018 and HR: 2.754; 95% CI: 1.044–7.265; <i>p</i> = 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 <i>MYC</i> and <i>BRAF</i> mutation was shorter than those with either <i>MYC</i> or <i>BRAF</i> mutation (HR: 4.981, 95% CI: 0.296–83.92; <i>p</i> = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development. |
| first_indexed | 2024-03-10T04:19:03Z |
| format | Article |
| id | doaj.art-863a47956ac14fecb86fd85274c3d470 |
| institution | Directory Open Access Journal |
| issn | 2075-4418 |
| language | English |
| last_indexed | 2024-03-10T04:19:03Z |
| publishDate | 2021-12-01 |
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| series | Diagnostics |
| spelling | doaj.art-863a47956ac14fecb86fd85274c3d4702023-11-23T07:54:18ZengMDPI AGDiagnostics2075-44182021-12-011112230810.3390/diagnostics11122308Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal CancerYi-Hsuan Huang0Peng-Chan Lin1Wu-Chou Su2Ren-Hao Chan3Po-Chuan Chen4Bo-Wen Lin5Meng-Ru Shen6Shang-Hung Chen7Yu-Min Yeh8Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDepartment of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDepartment of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDivision of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDivision of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDivision of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDepartment of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDepartment of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanDepartment of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, TaiwanSystemic 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 <i>TP53</i> (84.6%), followed by <i>APC</i> (78.0%), <i>KRAS</i> (49.6%), and <i>SMAD4</i> (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; <i>p</i> = 0.018 and HR: 2.754; 95% CI: 1.044–7.265; <i>p</i> = 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 <i>MYC</i> and <i>BRAF</i> mutation was shorter than those with either <i>MYC</i> or <i>BRAF</i> mutation (HR: 4.981, 95% CI: 0.296–83.92; <i>p</i> = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.https://www.mdpi.com/2075-4418/11/12/2308metastatic colorectal cancernext-generation sequencinggenomic profilingoncogenic signaling pathways |
| spellingShingle | Yi-Hsuan Huang Peng-Chan Lin Wu-Chou Su Ren-Hao Chan Po-Chuan Chen Bo-Wen Lin Meng-Ru Shen Shang-Hung Chen Yu-Min Yeh Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer Diagnostics metastatic colorectal cancer next-generation sequencing genomic profiling oncogenic signaling pathways |
| title | Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer |
| title_full | Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer |
| title_fullStr | Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer |
| title_full_unstemmed | Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer |
| title_short | Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer |
| title_sort | association between altered oncogenic signaling pathways and overall survival of patients with metastatic colorectal cancer |
| topic | metastatic colorectal cancer next-generation sequencing genomic profiling oncogenic signaling pathways |
| url | https://www.mdpi.com/2075-4418/11/12/2308 |
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