Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer

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.

Keywords: genomic profiling; metastatic colorectal cancer; next-generation sequencing; oncogenic signaling pathways.

Figure 1

Tumor mutation burden in Taiwanese patients with mCRC. (A) TMB in each of 113 evaluated tumor tissues using the targeted-NGS technique. The dashed line indicated 10 mutations/mb. TMB in mCRC with distinct primary location (B), and MSI-H presentation (C) was shown and compared using the Mann Whitney U test. The horizontal line denoted the median, the upper and lower bottom of the box indicated the 25th and 75th percentile, and the whiskers marked the 5th and 95th percentiles. * represented p < 0.05.

Figure 2

Genetic alterations of Taiwanese patients with non-MSI-H mCRC. (A) Frequencies of genetic alterations (>3%) were identified in non-MSI-H mCRC. (B) The frequencies, types, and co-occurrences of mutated genes in major oncogenic pathways.

Figure 3

Alterations of signaling pathways in Taiwanese mCRC. Genomic alterations of the RTK-RAS (A), Wnt (B), PI3K (C), Myc (D), and TGF-β pathway (E). The color intensity represented the alteration frequency of pathway members. An arrow indicated an activation; a bar at the end of an edge indicated an inhibitory interaction.

Figure 4

The survival impact of altered signaling pathways. The Kaplan-Meier curves of overall survival in patients with mCRC with and without altered RTK-RAS (A), Wnt (B), TGF-β (C), and Myc pathway (D) were shown and compared using a log-rank test.

Figure 5

The correlation between altered signaling pathways and survival of patients with mCRC receiving disparate first-line treatment. The Kaplan-Meier survival curves of patients with and without genomic alterations of TGF-β pathway receiving FOLFIRI regimen (A), an anti-EGFR antibody (B), and bevacizumab (C) as first-line treatment. The association between the altered Myc pathway and survivals of patients receiving FOLFIRI (D), an anti-EGFR antibody (E), and bevacizumab (F) as first-line treatment were compared using a log-rank test, as well as the altered TGF-β pathway.