Abstract
The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers. We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC. We identified 71 genes of 1289 cancer-related genes of which the expression correlated with tumor stages. Of the 71 genes, 47 significantly differed between the Tumor-Node-Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of ESCC, whereas adhesion molecules and extracellular matrix-related molecules possibly promoting invasiveness increased in the later stages. For lymph node metastasis, we identified 44 genes with predictive values, which included cell adhesion molecules and cell membrane receptors showing higher expression in node-positive cases and cell cycle regulators and intracellular signaling molecules showing higher expression in node-negative cases. The ensemble classifiers trained with the selected features predicted tumor stage and lymph node metastasis in the 18 validation cases with respective accuracies of 94.4% and 88.9%. This demonstrated the reproducibility and predictive value of the identified features. We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.
Highlights
Esophageal cancer shows the poorest prognosis among the malignant tumors of the digestive tract
Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of esophageal squamous cell carcinoma (ESCC), whereas adhesion molecules and extracel
By using a generalized linear model-based regression analysis that allowed us to extract information on features relevant to discrete graded categories, we identified genes of which the expression was altered in association with tumor progression
Summary
Esophageal cancer shows the poorest prognosis among the malignant tumors of the digestive tract. In an effort to better understand this disease and predict its clinical outcome, numerous molecular markers for tumor progression and prognosis, e.g., STMY3 [5], interleukin 6 [6], C1orf10 [7], and EC45 [8], and for lymph node metastasis, e.g., caveolin-1 [9], EphA2 [10], FAK [11], cystain B [12], and MMP-12 [13], have been identified This limited information, is not enough to clarify the carcinogenesis, tumor progression, and invasiveness of esophageal cancer; just as in the allegory about the five blind men and the elephant, the complete picture of the pathophysiology of the disease remains elusive. We identified genes of which the expressions were associated with lymph node metastasis by a feature-subset selection algorithm: this algorithm enabled us to optimize the statistical explanatory
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