This is the 3rd-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.
Here I report a case in Zodiac related to TP53, the master tumor suppressor.
A recent study published in NATURE (Liu et al., 2015) demonstrates genomic deletion of TP53 frequently encompasses essential neighboring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. The authors anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing common genomic alterations.
By searching TP53 and POLR2A in Zodiac (www.compgenome.org/zodiac) landing page, it can be seen that
the two genes have a strong green edge (see figure above) connecting “CN-CN” in a network reported in Zodiac. This means that the two genes’ copy numbers are strongly and positively correlated based on TCGA data as well, confirming (computationally) the finding in the Nature paper based on Zodiac results.
Typing TP53 alone in the Zodiac search bar gives all the statistically significant genetic interactions to TP53 (see here) and the figure below for a screen shot.
Clicking on the entry shows “3179” (CN — CN) in the above Table of “Number of interactions by platforms” (in your browser, not in this post) will display the top 20 genes having significant positive and negative copy number interactions (e.g., co-deletions or co-amplifications) with TP53. The top 20 genes with positive interactions are shown below.
Moving mouse on the gene name will retrieve NCBI gene summary and display the summary on the screen. Glancing over the 20 genes, first, the reported POLR2A gene in the Nature paper did not make to the top 20. It was ranked as the 40th top gene with strongest CN-CN interaction with TP53 in Zodiac (results not shown). Glancing over the top 20 genes, Olfactory receptors (OR) have 4 genes in this list, showing a strong copy number co-variation pattern between OR family and TP53. OR genes are known to be important, highlighted by the 2004 Nobel Prize for its discovery. Also, OR2AT4 is believed in a recent study (Nature commentary here) to become a drug target in dermatology. Zodiac seems to suggests other OR genes be related to TP53. Potentially more ground work in wet labs can be pursued to test the effects of these genes in cell lines and mouse models. Another interesting gene in this list is “TNFSF12”, the 19th top gene. There has been ample research on TWEAK, the protein encoded by TNFSF12, on its role on apoptosis and angiogenesis. A full list of CN-CN interactions in Zodiac can be find here. The most significant genes are listed at the bottom. I hope this list will help researchers to find more drug targets that related to the master tumor suppressor, TP53.