Journal Article

Widespread genetic epistasis among cancer genes

White, Kevin P., McNerney, Megan E., Fu, Audrey Q., Wang, Xiaoyue

2014

Overview

Quantitative genetic epistasis has been hypothesized to be an important factor in the development and progression of complex diseases. Cancers in particular are driven by the accumulation of mutations that may act epistatically during the course of the disease. However, as cancer mutations are uncovered at an unprecedented rate, determining which combinations of genetic alterations interact to produce cancer phenotypes remains a challenge. Here we show that by using combinatorial RNAi screening in cell culture, dense and often previously undetermined interactions among cancer genes were revealed by assessing gene pairs that are frequently co-altered in primary breast cancers. These interacting gene pairs are significantly associated with survival time when co-altered in patients, indicating that genetic interaction mapping may be leveraged to improve risk assessment. As many of these interacting gene pairs involve known drug targets, personalized treatment regimens may be improved by overlaying genetic interactions with mutational profiling. Cancer can result from mutations in more than one gene and these multiple mutated genes are often functionally dependent on each other; this interaction is known as epistasis. Here, the authors use a combinatorial RNAi screen to identify epistatic genes that are mutated in breast cancer and reveal large numbers of previously unreported gene interactions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/89 / 14/1 / 14/63 / 38/90 / 38/91 / 631/208/2490/1472 / 631/208/68 / 631/67/1347 / Breast Neoplasms - genetics / Cell Line, Tumor / Epistasis, Genetic - genetics / Female / Genes, Neoplasm - genetics / Humanities and Social Sciences / Humans / multidisciplinary / Mutation / Phenotype / Risk assessment / RNA - genetics / RNA Interference / Science / Science (multidisciplinary)