Abstract
One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we’ve addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.
Highlights
In human cancer it is generally the case that highly recurrent point mutations, such as those occurring in KRAS or TP53, contribute to the selective advantage of tumor cells
Validation of MACROD2 as a Common Fragile Site Gene To test whether our classification could successfully predict new common fragile site gene genes, we examined whether induction of replicative stress in a colon cancer cell line can generate deletions in MACROD2 or A2BP1, which, together with the known common fragile site gene gene FHIT, are the three genes most frequently affected by focal deletions in colon cancer
We initiated this study to reconcile two disparate findings: the absence of tumor suppressor candidates from two loci frequently affected by focal deletions, and the ability of focal deletions to enrich for tumor suppressors in a functional screen
Summary
In human cancer it is generally the case that highly recurrent point mutations, such as those occurring in KRAS or TP53, contribute to the selective advantage of tumor cells. The case is less clear with DNA copy number alterations, where some frequent alterations such as amplification of the ERBB2/HER2 locus clearly provide a selective advantage, whereas others like the frequent deletions of DNA at the telomeric ends of chromosomes likely do not This means that alteration frequency alone is not sufficient to determine whether or not a given DNA copy number alteration directly impacts oncogenicity. Nowhere has this been more difficult to tease out than for candidate tumor suppressor genes located within common fragile sites. Other studies have made observations that do not support a tumor suppressor role for these genes, including the inability to detect inactivating point mutations [6,7] and the frequent failure of deletions to affect underlying RNA or protein expression [7,8], both of which are common features of other tumor suppressor genes
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