Background: With improvements in next-generation DNA sequencing technology, lower cost is needed to collect genetic data. More machine learning techniques can be used to help with cancer analysis and diagnosis.

Methods: We developed an ensemble machine learning system named performance-weighted-voting model for cancer type classification in 6,249 samples across 14 cancer types. Our ensemble system consists of five weak classifiers (logistic regression, SVM, random forest, XGBoost and neural networks). We first used cross-validation to get the predicted results for the five classifiers. The weights of the five weak classifiers can be obtained based on their predictive performance by solving linear regression functions. The final predicted probability of the performance-weighted-voting model for a cancer type can be determined by the summation of each classifier’s weight multiplied by its predicted probability.

Results: Using the somatic mutation count of each gene as the input feature, the overall accuracy of the performance-weighted-voting model reached 71.46%, which was significantly higher than the five weak classifiers and two other ensemble models: the hard-voting model and the soft-voting model. In addition, by analyzing the predictive pattern of the performance-weighted-voting model, we found that in most cancer types, higher tumor mutational burden can improve overall accuracy.

Conclusion: This study has important clinical significance for identifying the origin of cancer, especially for those where the primary cannot be determined. In addition, our model presents a good strategy for using ensemble systems for cancer type classification.