Chromatin maintenance and cancer

It is now well established that cancer is a collection of mostly genetic diseases. They progress through the accumulation of alterations, such as point mutations in genes that affect mechanisms, often known as the hallmarks of cancer which ultimately confer the altered cell some advantageous properties with respect to neighboring ‘normal’ cells. Decades of intense research on the molecular biology of cancer have delineated many of such hallmarks. Nevertheless, some others have only begun to appear with the advent of large Cancer Genomics initiatives, such as The Cancer Genome Atlas and the International Cancer Genome Consortium.

One of these novel hallmarks has to do with the alteration of general mechanisms of chromatin regulation and maintenance. It is now clear that these mechanisms become altered in one way or another across many tumor types, and that their alteration in principle could lead to the de-regulation of several cellular functions that promote tumorigenesis. With this in mind, we have examined the mutations that occur in chromatin regulatory factors (CRFs) across 4623 tumor samples representing 31 cancer genome re-sequencing projects from 13 anatomical sites. The results of this study have just been published in Genome Biology.

 

I want to highlight here the main findings of our study.

• CRFs are overrepresented amongst driver genes. From IntOGen-mutations, we obtained the list of putative driver genes across 4623 tumor samples. While 34 out of 183 CRFs (manually compiled from the literature) probably act as drivers in these tumors, the total number of drivers found in them amounts to 348 within 22696 human genes. This underlines the relevance of CRFs’ alteration in tumorigenesis in all tumor types with data in IntOGen-mutations.
  

  Word cloud of the 34 CRFs identified as candidate drivers across the 4623 tumors from 13 sites. The size of the word indicates the mutation frequency across all tumors.

• Multi-proetin complexes rather than individual CRFs drive carcinogenesis in these tumors. Several complexes of CRFs that act together exhibit both a clear bias towards the accumulation of high-impact mutations and a pattern of mutual exclusivity in the genes where those mutations occur within the samples of a tumor type.

• The outcome of CRFs’ mutations is possibly the de-regulation of the expression of broad genesets. The pattern of mutations of two CRFs across almost 1000 cancer cell lines correlates with the de-regulation of genes marked by H3K27me3, H3K9ac, as well as late replicating genes.
• The approach can be applied to other sets of drivers. For the first time –thanks to the IntOGen-mutations web discovery tool— it is possible to assess the likely involvement of groups of genes in tumorigenesis across more than 4500 samples. The process is straightforward and may shed light on the relevance of other cellular mechanisms, genesets or pathways in tumorigenesis (watch the video tutorial below to learn how to get information for a set of genes in IntOGen-mutations).

 

 

 

You can explore our results through the IntOGen-mutations web discovery tool and through Gitools interactive heatmaps. So, browse away!

 

Article:

Gonzalez-Perez A#, Jene-Sanz A# & Lopez-Bigas N. The mutational landscape of chromatin regulatory factors across 4623 tumor samples. Genome Biology 2013, 14:r106

# Equal contribution