Copy Number Networks to Guide Combinatorial Therapy of Cancer and Proliferative Disorders

Abstract

Interaction networks can be charted by seeking gene pairs that are amplified and/or deleted in tandem, even when located at a distance on the genome. Our experience with radiation hybrid (RH) panels, a library of cell clones that have been used for genetic mapping, have shown this tool can pinpoint statistically significant patterns of co-inherited gene pairs. In fact, we were able to identify gene pairs specifically associated with the mechanism of cell survival at single gene resolution. Further, the RH network can be used to provide single gene specificity for cancer networks constructed from correlated copy number alterations (CNAs). In a survival network for glioblastoma, we found that the epidermal growth factor receptor (EGFR) oncogene interacted with 46 genes. Of these genes, ten (22%) happened to be targets for existing drugs. Here, we highlight the potential of CNA networks to guide combinatorial drug treatment in cancer, autoimmunity and atherosclerosis.

Complementary human gene interaction maps from radiation hybrids and CRISPRi

“…The relatively non-toxic effects of increased gene copy number in the RH approach allows mapping of interactions for all genes and is reflected in the fact that retention of donor DNA is uniform across the entire genome. 1,4,7,[16][17][18][19] In contrast, the essential genes in the CRISPRi study were chosen for their moderate growth phenotype. The selection was necessary because interactions are difficult to assess when loss of one gene partner abolishes cell growth.…”

Cost-Effective Mapping of Genetic Interactions in Mammalian Cells

“…We previously used publicly available RH data to construct a genetic interaction map for mammalian cells (Lin et al, 2010 ; Lin and Smith, 2015 ). We reasoned that significant co-inheritance of marker pairs separated from each other in the human genome would disclose genetic interactions promoting cell survival.…”

Cost-effective mapping of genetic interactions in mammalian cells

“…We previously used publicly available RH data to construct a genetic interaction map for mammalian cells (Lin et al 2010;Lin, Smith 2015). We reasoned that significant co-inheritance of marker pairs separated from each other in the human genome would disclose genetic interactions promoting cell survival.…”