Published online May 28, 2019. doi: 10.3748/wjg.v25.i20.2489
Peer-review started: February 6, 2019
First decision: March 14, 2019
Revised: March 27, 2019
Accepted: April 19, 2019
Article in press: April 20, 2019
Published online: May 28, 2019
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer deaths worldwide. It has been reported that many clinicopathological factors may contribute to the prognostic prediction of cancer patients except tumor-node-metastasis stage, including lymphovascular invasion (LVI). LVI is suggested to be an early and critical step in lymph node metastasis and systemic dissemination of cancer cells. However, the prognostic value and genetic mechanisms of LVI in CRC have not been well investigated so far.
LVI is a common histopathological finding in cancers and is considered to be an important step in cancer progression toward metastasis, but its genetic mechanisms in CRC have yet to be fully understood. Our study may offer new insight into the biology of LVI and provide valuable information for better management of CRC.
The objective of this study was to investigate the prognostic value of LVI in CRC and identify the genomic alterations associated with LVI using array-based comparative genomic hybridization (CGH).
We performed a retrospective analysis in a population of 1219 CRC patients to evaluate the presence of LVI, as well as its relationship with classical clinicopathological parameters and patient’s outcome. Kaplan-Meier method and Cox regression model were used for overall survival analysis. We also analyzed the genomic profiles of 47 CRC samples using CGH to identify the genomic alterations associated with LVI. A decision tree model classifier was applied to the CGH data to identify special DNA copy number alterations (DCNAs) for differentiating CRCs with and without LVI. We further performed functional enrichment and protein-protein interaction network analyses to explore the potential molecular mechanisms of LVI in CRC.
Of the 1219 CRC patients included in the retrospective analysis, 150 (12.3%) cases presented with LVI. The comparison of clinicopathological characteristics between CRCs with and without LVI found that the presence of LVI was significantly with higher histological grade and advanced tumor stage (both P < 0.001). Survival analysis showed that LVI was an independent predictor for overall survival in CRC, with a hazard ratio of 1.77 (95% confidence interval: 1.40-2.25, P < 0.001). Based on the CGH data of 47 CRC samples, 184 DCNAs (105 gains and 79 losses) were found to exhibit a significant difference in the frequencies between LVI and non-LVI groups (P < 0.05), and the majority were located at 22q, 17q, 10q, and 6q. We further performed decision tree analysis and constructed a classifier that could distinguish CRCs with LVI from those without it at an accuracy of 95.7% by examining seven special DCNAs. Functional enrichment analyses showed that the genomic alterations related to LVI were correlated with immune response and inflammation. Additionally, we constructed a protein-protein interaction network and screened out some key genes, such as EP300, STAT3, SIRT1, and RPS6KB1, which were involved in epithelial-mesenchymal transition, active angiogenesis or matrix remodeling.
The present study identified that LVI was significantly associated with features of aggressive tumors and reduced survival in CRC, and its development might correlate with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling.
Our study preliminarily explored the genetic alterations associated with LVI in CRC, which might offer novel targets for the treatment and prevention of cancer dissemination. Further studies are required to confirm our findings and to clarify the precise mechanism involved in LVI.