Cancer type‐dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types

Molecular Systems Biology

Solip Park¹ 

[1] EMBL-CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain

关键词: cancer;    epistasis;    evolution;    genetic interaction networks;    tissue specificity;   

DOI  :  10.15252/msb.20156102

来源: Wiley

【 摘 要 】

Abstract

Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re-wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another.

Synopsis

Analysis of genetic interactions using data from > 3,000 tumors shows that co-occurrence and mutual exclusivity between cancer driver alterations change extensively in different cancer types, thus indicating plasticity of epistasis across cell types.

• Co-occurrence and mutual exclusivity interactions between cancer driver alterations are identified across > 3,000 human tumors.
• These differences in genetic interactions indicate how genomic alterations co-operate or act redundantly to driver cancer changes in different cancer types.
• This plasticity of epistasis across cell types has important implications for cancer therapy, genetic architecture and evolution.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.