Previously, we examined transcripts that are and are not perturbed in cancer. This was done by comparing all cases where transcripts were up or down-regulated in cancer tissue against the entirety of non-cancer studies (that involve some sort of perturbation) in our database. Using this large non-cancer dataset, we can derive some very significant P-values, which we like. We did, however, mention some weaknesses with this approach and suggested a different approach for a future post. Here's the future post.
This time, we grabbed 160 studies that involved comparison of cancer tissue to adjacent, healthy tissue and looked for genes that were never/rarely upregulated or downregulated in cancer tissue. There are also weaknesses in this approach. The relatively small dataset means we won't see extreme P-values. Also, since every gene is perturbed in cancer in this dataset, in one direction or the other, we can't search for genes that are rarely perturbed at all (in both directions), as we did before. Finally, note that we only examine solid tissue cancers here, where a comparison between diseased and healthy tissue can be made.
Jumping into it, what are the genes that are rarely downregulated in cancer? TOP2A leads the list, being upregulated in 52 studies, and downregulated in only 2. The P-value here is about 10^-14. Next up is COL1A1, which was upregulated 41 times, and never downregulated. ASPM, CTHRC1, MMP11, SPP1, CENPF, CDH3, CDKN3, and NEK2 follow.
This list of genes rarely downregulated in cancer (dbase ID 146502203, available on our next database update) corresponds nicely to genes that are most commonly up-regulated in cancer in the broader approach we used in our initial post: P = 10^-230. We also constructed a list of genes that were NEVER seen to be downregulated in the cancer vs adjacent studies we have on hand (dbase ID 146503205). Naturally, this list overlaps quite strongly with genes rarely downregulated in cancer (which includes the "nevers").
We'll examine possible treatment approaches that would downregulate the above genes in a future post. For now, we'll point out that well-known cancer treatments are prominent as downregulaters: cdk4/6 inhibitors, bromodomain inhibitors, mek1/2 inhibitors, etc.
How about genes that are rarely upregulated in cancer (dbase ID 146503204)? Here, ADH1B leads the way, downregulated in 52 studies and upregulated in only 2 (which, coincidentally, is the exact opposite of the pattern we see with TOP2A). Next, we see ASPA, DPT, CFD, CXCL12, MT1M, ABCA8, FAM107A, ADH1C, and C7. ASPA is the first gene to never be upregulated in cancer, having 40 examples of downregulation without a single case of upregulation. Again, we also have a strongly overlapping list of genes that are never upregulated in cancer (146504206). And again, these new lists correspond very strongly (P<10^-200) to lists constructed using the broader approach.
Briefly, what are the treatments that might upregulate genes that are rarely upregulated in cancer? MAPK and tyrosine kinase inhibitors are seen, as well as BMP2 treatment, and IL17A antagonists.
Are there "natural" or "lifestyle" approaches that might tend to downregulate genes upregulated in cancer? We'll look at that in the future. Initially, we're both relieved and disappointed that well-known cancer treatments come to the fore when we try, bioinformatically, to reverse cancer trends. Such a result strongly validates our approach, no? On the other hand, we'd be happy to see some less obvious approaches emerge. As we've mentioned before, treating the primary cancer may promote metastasis, while treating the metastasis may enhance primary cancer growth. Eyeballing the data, abetting metastasis seems to be more of a concern when upregulating genes that are downregulated in cancer (e.g. with MAPK inhibitors), rather than downregulating the upregulated genes.
We also generated a more obscure list (146504207). This time, we wanted to find genes that were seen to be upregulated in some studies, and downregulated in others. We required that no such genes be altered (up or down) with a P-value < .05, and that the gene be seen in at least 16 studies. AKR1B10 is the winner here, upregulated in 13 studies and downregulated in 14. IGFBP3, ANXA3, NNMT, AZGP1, TACSTD2, CXCL2, DACH1, NEBL and TDO2 follow. When we run this list, consisting of a mere 30 members, against all the lists in our database, nothing of significance emerges. Despite the weak significances, it does appear that studies involving drug resistance percolated to the top, and a quick Google search indeed reveals studies where some of the above genes are implicated in resistance. For example, AKR1B10 induces resistance to daunorubicin in at least one study. In addition to relevance to resistance, one could speculate that cancer types or cancer subsets could hinge on these sorts of genes: if IGFBP3 is upregulated, it might be worthwhile to downregulate it, and vice-versa.
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