Weighted Frequent Gene Co-expression Network Mining to Identify Genes Involved in Genome Stability

Gene co-expression network analysis is an effective method for predicting gene functions and disease biomarkers. However, few studies have systematically identified co-expressed genes involved in the molecular origin and development of various types of tumors. In this study, we used a network mining algorithm to identify tightly connected gene co-expression networks that are frequently present in microarray datasets from 33 types of cancer which were derived from 16 organs/tissues. We compared the results with networks found in multiple normal tissue types and discovered 18 tightly connected frequent networks in cancers, with highly enriched functions on cancer-related activities. Most networks identified also formed physically interacting networks. In contrast, only 6 networks were found in normal tissues, which were highly enriched for housekeeping functions. The largest cancer network contained many genes with genome stability maintenance functions. We tested 13 selected genes from this network for their involvement in genome maintenance using two cell-based assays. Among them, 10 were shown to be involved in either homology-directed DNA repair or centrosome duplication control including the well- known cancer marker MKI67. Our results suggest that the commonly recognized characteristics of cancers are supported by highly coordinated transcriptomic activities. This study also demonstrated that the co-expression network directed approach provides a powerful tool for understanding cancer physiology, predicting new gene functions, as well as providing new target candidates for cancer therapeutics. Proteins interact with each other in a network manner to precisely regulate complicated physiological functions of life. Diseases such as cancer may occur if the network regulations go wrong. In cancer research, network mining has been utilized to identify biomarkers, predict therapeutic targets, and discover new mechanisms for cancer development. Among these applications, the search for genes with similar expression patterns (co-expression) over different samples is particularly successful. However, few network mining approaches were systematically applied to different types of cancers to extract common cancer features. We carried out a systematic study to identify frequently co-expressed gene networks in multiple cancers and compared them with the gene networks found in multiple normal tissues. We found dramatic differences between networks from the two sources, with gene networks in cancer corresponding to specific traits of cancer. Specifically, the largest gene network in cancer contains many genes with cell cycle control and DNA stability functions. We thus predicted that a set of poorly studied genes in this network share similar functions and validated that most of these genes are involved in DNA break repair or proper cell division. To the best of our knowledge, this is the largest scale of such a study.