Gender-specific dysregulations of nondifferentially expressed biomarkers of metastatic colon cancer.

Colon cancer is a common cancer type in both sexes and its mortality rate increases at the metastatic stage. Most studies exclude nondifferentially expressed genes from biomarker analysis of metastatic colon cancers. The motivation of this study is to find the latent associations of the nondifferentially expressed genes with metastatic colon cancers and to evaluate the gender specificity of such associations. This study formulates the expression level prediction of a gene as a regression model trained for primary colon cancers. The difference between a gene's predicted and original expression levels in a testing sample is defined as its mqTrans value (model-based quantitative measure of transcription regulation), which quantitatively measures the change of the gene's transcription regulation in this testing sample. We use the mqTrans analysis to detect the messenger RNA (mRNA) genes with nondifferential expression on their original expression levels but differentially expressed mqTrans values between primary and metastatic colon cancers. These genes are referred to as dark biomarkers of metastatic colon cancer. All dark biomarker genes were verified by two transcriptome profiling technologies, RNA-seq and microarray. The mqTrans analysis of a mixed cohort of both sexes could not recover gender-specific dark biomarkers. Most dark biomarkers overlap with long non-coding RNAs (lncRNAs), and these lncRNAs might have contributed their transcripts to calculating the dark biomarkers' expression levels. Therefore, mqTrans analysis serves as a complementary approach to identify dark biomarkers generally ignored by conventional studies, and it is essential to separate the female and male samples into two analysis experiments. The dataset and mqTrans analysis code are available at https://figshare.com/articles/dataset/22250536.