Selection Of Transcriptional Signatures Applicable To Tumor Tissues Sampled From Different Tumor Sites

The clinical tumor tissues are usually composed of tumor epithelial cells and stromal cells which have different gene expression patterns.The infiltration difference of tumor stromal cells,sampled from different tumor sites,which would affect or confuse the gene expressions for tumor epithelial cells.In the study,based on the expression data of colon and breast cancer and the corresponding tumor cell information of the tissues from the TCGA(The Cancer Genome Atlas)database,the expression measurements of 2271 and 2309 genes significantly correlated with proportions of tumor epithelial cell(PTEC,Spearman correlation analysis,FDR<10%)were detected,respectively.And they are significantly consistent between positive correlations with up-regulations and negative correlations with down-regulations in tumor epithelial cells compared with tumor stromal cells.So it is speculated that the correlation between the PTEC and the expression measurements of thousands of genes is caused by the difference of expression patterns between two cells.For the tumor diagnostic or prognostic signatures based on a summarization of expression levels of the signature genes,the risk score for a patient may depend on the tumor tissues sampled from different tumor sites with diverse PTEC and could result in the uncertainly prognostic and diagnostic results for the same patient.Therefore,it is currently urgent to solve the problem that to select the signatures are robust against the variations of the tumor epithelial cell in clinical tumor tissues.For the problem,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 included breast cancer and colorectal cancer,we showed that above 80% of gene pairs had consistent REOs between thetwo 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.In conclusion,the REOs-based signatures are high robustness against the variations of the tumor cells proportion and have the huge potential for the clinical transformation.