Oncogenes create a unique landscape of fragile sites

Abstract

Recurrent genomic instability in cancer is attributed to positive selection and/or the sensitivity of specific genomic regions to breakage. Among these regions are fragile sites (FSs), genomic regions sensitive to replication stress conditions induced by the DNA polymerase inhibitor aphidicolin. However, the basis for the majority of cancer genomic instability hotspots remains unclear. Aberrant oncogene expression induces replication stress, leading to DNA breaks and genomic instability. Here we map the cytogenetic locations of oncogene-induced FSs and show that in the same cells, each oncogene creates a unique fragility landscape that only partially overlaps with aphidicolin-induced FSs. Oncogene-induced FSs colocalize with cancer breakpoints and large genes, similar to aphidicolin-induced FSs. The observed plasticity in the fragility landscape of the same cell type following oncogene expression highlights an additional level of complexity in the molecular basis for recurrent fragility in cancer.

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

“…This genome fragility induced by oncogene overexpression generated chromosomal breakages in regions which do not show sensitivity to aphidicolin-induced replication stress in the same cells, and does not induce fragility in known aphidicolin-sensitive fragile loci. Thus, the expression of fragile sites is highly dynamic, and the type of replication stress may affect the variety and frequency of fragile sites expressed [Miron et al, 2015]. Given the extensive fragile site activation observed following oncogene activation, further research will be needed to determine the biological function of the genes located at these fragile loci and to determine if and how they might contribute to the progression of cancer.…”

“…We have reviewed data that support a model for FHIT loss in the initial stages of cancer development, while others have reported that activation of additional fragile sites and loss of their respective gene products can occur following oncogene activation. The Kerem laboratory [Miron et al, 2015] recently reported activation of previously documented and novel fragile sites following induction of specific oncogenes in culture. Activating mutations in Ras or overexpression of cyclin E led to extensive chromosome fragmentation in normal human fibroblast cells, creating a unique fragility landscape specific for each oncogene.…”

Chromosome Imbalances in Cancer: Molecular Cytogenetics Meets Genomics

“…Thus, this study, in agreement with the cell type-specific activity of CFS [Murano et al, 1989;Le Tallec et al, 2011Hosseini et al, 2013], further confirms that the conventional CFS maps based on aphidicolin exposure cannot be predictive of the cancer response. More importantly, the results provided by Miron et al [2015] offer a biological explanation for the novel fragility regions described [Bignell et al, 2010], which could represent cancer-specific signatures.…”

“…These studies prompted to verify whether oncogene overexpression can trigger chromosome instability in a site-specific manner [Miron et al, 2015]. Interestingly, cancer cells displayed a different (and specific) profile of breaks when different oncogenes were overexpressed and, furthermore, these sites were only partially overlapping with known CFS.…”

To break or not to break – context matters

“…3 Therefore, we were intrigued to investigate whether oncogene expression induces FSs and, if so, to define the repertoire of oncogene-induced FSs and compare it to that of aphidicolin-induced FSs. 8 Cyclin E and Harvey rat sarcoma viral oncogene homolog (HRAS) are both known cellular oncogenes. Overexpression of cyclin E or activating mutations in HRAS such as G12V are found in many human cancers.…”