COSMIC and HSMD for cancer drug discovery

To browse COSMIC you can simply navigate to the main page and search for a gene, cancer type, mutation, etc in the search box. To illustrate we will explore the results for a single gene. Type BRAF in the search interface and hit enter. 

If you select the BRAF result, COSMIC returns a detailed page that provides: gene summaries, links to other COSMIC resources (e.g., Census genes, Hallmark genes, etc), external links, drug resistance, tissue distribution, genome browser view, mutation distribution, variants, and references. 

First, let’s look at the Overview section. Along the top of this section there are several useful icons. The ‘Census gene’ icon tells us that BRAF is a known cancer gene according to the Gene Census (see below). The next three icons tell us that it is also an ‘Expert curated gene’, that mouse insertional mutagenesis experiments support that BRAF is a cancer gene, and finally that BRAF is a ‘Cancer Hallmark’ gene. After these icons are many more details about BRAF including coordinates, synonyms, link to COSMIC-3D (see below), and more.

Next, let’s examine the Gene view. The histogram of mutation (substitution) frequency shows a very dramatic “hotspot” of mutations at position 600 (e.g., p.V600E). Mouse over this part of the histogram to see details. This is a very well-known driver mutation in multiple types of cancer.

Finally, navigate to the ‘Tissue distribution’ section. Sort the table by ‘Point mutations’ -> ‘% Mutated’. Notice that cancers of the thyroid and skin (e.g., melanoma) are by far the most consistently mutated at the BRAF gene locus (note NS means not specified). A subset of samples also display copy number variation (CNV) gains and up-regulated expression. In general certain predominanly mutated genes tend to be associated with cancers of certain origins. However, there are many exceptions to this statement and some genes (e.g., TP53) are widely mutated in many different cancer types.