Circumvent the uncertainty in the applications of transcriptional signatures to tumor tissues sampled from different tumor sites

// Jun Cheng 1 , You Guo 1, 2 , Qiao Gao 3 , Hongdong Li 1 , Haidan Yan 1 , Mengyao Li 1 , Hao Cai 1 , Weicheng Zheng 1 , Xiangyu Li 1 , Weizhong Jiang 3 , Zheng Guo 1 1 Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350001, China 2 Department of Preventive Medicine, School of Basic Medicine Sciences, Gannan Medical University, Ganzhou, 341000, China 3 Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China Correspondence to: Zheng Guo, email: guoz@ems.hrbmu.edu.cn Weizhong Jiang, email: jiangwz362100@163.com Keywords: the proportions of tumor epithelial cell, gene pairs, REOs-based signature, stromal cells, microdissected samples Received: November 25, 2016     Accepted: January 30, 2017     Published: February 27, 2017 ABSTRACT The expression measurements of thousands of genes are correlated with the proportions of tumor epithelial cell (PTEC) in clinical samples. Thus, for a tumor diagnostic or prognostic signature based on a summarization of expression levels of the signature genes, the risk score for a patient may dependent on the tumor tissues sampled from different tumor sites with diverse PTEC for the same patient. Here, we proposed that the within-samples relative expression orderings (REOs) based gene pairs signatures should be insensitive to PTEC variations. Firstly, by analysis of paired tumor epithelial cell and stromal cell microdissected samples from 27 cancer patients, we showed that above 80% of gene pairs had consistent REOs between the two cells, indicating these REOs would be independent of PTEC in cancer tissues. Then, by simulating tumor tissues with different PTEC using each of the 27 paired samples, we showed that about 90% REOs of gene pairs in tumor epithelial cells were maintained in tumor samples even when PTEC decreased to 30%. Especially, the REOs of gene pairs with larger expression differences in tumor epithelial cells tend to be more robust against PTEC variations. Finally, as a case study, we developed a gene pair signature which could robustly distinguish colorectal cancer tissues with various PTEC from normal tissues. We concluded that the REOs-based signatures were robust against PTEC variations.