Abstract
The oncogenic role of common fragile sites (CFS), focal and pervasive gaps in the cancer genome arising from replicative stress, remains controversial. Exploiting the TCGA dataset, we found that in most CFS the genes residing within the associated focal deletions are down-regulated, including proteins involved in tumour immune recognition. In a subset of CFS, however, the residing genes are surprisingly overexpressed. Within the most frequent CFS in this group, FRA4F, which is deleted in up to 18% of cancer cases and harbours the CCSER1 gene, we identified a region which includes an intronic, antisense pseudogene, TMSB4XP8. TMSB4XP8 focal ablation or transcriptional silencing elicits the overexpression of CCSER1, through a cis-acting mechanism. CCSER1 overexpression increases proliferation and triggers centrosome amplifications, multinuclearity, and aberrant mitoses. Accordingly, FRA4F is associated in patient samples to mitotic genes deregulation and genomic instability. As a result, cells overexpressing CCSER1 become sensitive to the treatment with aurora kinase inhibitors. Our findings point to a novel tumourigenic mechanism where focal deletions increase the expression of a new class of "dormant" oncogenes.
Highlights
The cancer genome presents widespread focal deletions (FDs)
A large subset of these FDs occurs at common fragile sites (CFS), chromosomal loci which are prone to breaks elicited by replicative stress (Hazan et al, 2016; Glover et al, 2017)
In the attempt to shed light on the role of CFS in oncogenesis, we have exploited the The Cancer Genome Atlas (TCGA) dataset to interrogate the relationship between the FDs occurring at CFS and the expression of the protein coding genes within the CFS boundaries
Summary
The cancer genome presents widespread focal deletions (FDs). Whereas a minority of FDs inactivates tumour suppressors, the impact of most FDs remains unknown (Bignell et al, 2010; Chen & Weiss, 2014). CFS are pervasive throughout the cancer genome, as they are frequently present in cancers originating from several tissues, present a remarkable cell type specificity (Beroukhim et al, 2010; Bignell et al, 2010; Zack et al, 2013). Despite their widespread occurrence, their oncogenic role remains controversial (Bignell et al, 2010; Rajaram et al, 2013; Hazan et al, 2016; Glover et al, 2017). Whereas few tumour suppressor genes including FHIT, WWOX and more recently PARK2 have been linked to CSFs, a clear role in oncogenesis for the vast majority of genes associated with CFS remains unknown
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