A Neural Network Framework for Predicting the Tissue-of-Origin of 15 Common Cancer Types Based on RNA-Seq Data

Sequencing-based identification of tumor tissue-of-origin (TOO) is critical for patients with cancer of unknown primary lesions. Even if the TOO of a tumor can be diagnosed by clinicopathological observation, reevaluations by computational methods can help avoid misdiagnosis. In this study, we developed a neural network (NN) framework using the expression of a 150-gene panel to infer the tumor TOO for 15 common solid tumor cancer types, including lung, breast, liver, colorectal, gastroesophageal, ovarian, cervical, endometrial, pancreatic, bladder, head and neck, thyroid, prostate, kidney, and brain cancers. To begin with, we downloaded the RNA-Seq data of 7,460 primary tumor samples across the above mentioned 15 cancer types, with each type of cancer having between 142 and 1,052 samples, from the cancer genome atlas. Then, we performed feature selection by the Pearson correlation method and performed a 150-gene panel analysis; the genes were significantly enriched in the GO:2001242 Regulation of intrinsic apoptotic signaling pathway and the GO:0009755 Hormone-mediated signaling pathway and other similar functions. Next, we developed a novel NN model using the 150 genes to predict tumor TOO for the 15 cancer types. The average prediction sensitivity and precision of the framework are 93.36 and 94.07%, respectively, for the 7,460 tumor samples based on the 10-fold cross-validation; however, the prediction sensitivity and precision for a few specific cancers, like prostate cancer, reached 100%. We also tested the trained model on a 20-sample independent dataset with metastatic tumor, and achieved an 80% accuracy. In summary, we present here a highly accurate method to infer tumor TOO, which has potential clinical implementation.