Network perturbation by recurrent regulatory variants in cancer.
Cancer driving genes have been identified as recurrently affected by variants that alter protein-coding sequences. However, a majority of cancer variants arise in noncoding regions, and some of them are thought to play a critical role through transcriptional perturbation. Here we identified putative transcriptional driver genes based on combinatorial variant recurrence in cis-regulatory regions. The identified genes showed high connectivity in the cancer type-specific transcription regulatory network, with high outdegree and many downstream genes, highlighting their causative role during tumorigenesis. In the protein interactome, the identified transcriptional drivers were not as highly connected as coding driver genes but appeared to form a network module centered on the coding drivers. The coding and regulatory variants associated via these interactions between the coding and transcriptional drivers showed exclusive and complementary occurrence patterns across tumor samples. Transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.
Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
Kiwon
K
Jang
Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
Kwoneel
K
Kim
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Ara
A
Cho
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Insuk
I
Lee
Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
Jung Kyoon
JK
Choi
D000818:Animals; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
D009363:Neoplasm Proteins