The Five Most Mutated Genes in Cancers – [A 2017 ICGC Perspective]

The International Cancer Genome Consortium (ICGC) has a portal that currently (May 2017) hosts data from 70 cancer projects spanned across 16 countries.

Here are a few descriptors of the data (as of current):

– 19,305 donors
– 31 tumor types in 21 primary tumor sites
– data types include: simple somatic mutations (SSM), structural somatic mutations, copy number somatic mutations (CNSM), sequence and array based gene expression data, methylation data, protein expression data, etc.

This is big data because it comprises of ~163,000 files in ~1.2 PB (petabytes), which is the equivalent of 1,200 terabytes or 1,200,000 gigabytes. A lot of A,C,T,G sequences…

The portal is a great platform in of itself, in that you can do advanced searches and ‘onsite’ data analyses, genome browsing, and much more. So, if you like numbers (like me), you can literally spend countless hours trying to make sense of this ever growing ocean of data.

The purpose of this post is not to go deep though; I may do that in later posts. Here, I’m only going to talk about the top 5 mutated genes with high impact (simple somatic mutations) across all cancers from 10,648 donors.

The Five Most Mutated Genes

The chart represents the distribution of mutations by impact and less by the numbers, which is why it is sensical to observe the several fold impact of the mutations in TP53 compared to the subsequent ones.

  1. TP53 (tumor protein p53)

Located on chromosome 17, this gene codes for a protein involved in cellular stress response, thereby regulating the expression of subsequent genes to induce DNA repair, apoptosis (programmed cell death), senescence, and cell cycle arrest, to name a few.

In the ICGC data there are currently 3,211 donors affected by a multitude (1,213) of mutations in the TP53 gene.

You can assume that depending on the mutation type and effect, the expression and the function of p53 can be more or less affected.

Cancers are characterized by abnormal cell proliferation. Dysfunctional p53 and an inability to prevent proliferation can promote such proliferation. It is of important note that there are many other factors with key roles in cell development: p53 is but one of them.

In the current ICGC data, TP53 mutations are the most prevalent in tumors at the following sites: ovary, lung, esophagus, rectum, pancreas, colon, and brain.

  1. LRP1B (LDL receptor-related protein 1B)

Located on chromosome 2, this gene codes for an LDL receptor, which is implicated in a multitude of processes of normal cell function.

In the ICGC data, there are currently 3,386 donors affected by 52,858 mutations in this gene. It is important to observe that there is not only way to affect the expression of a certain gene and the structure and function of the protein it codes for (given that we’re talking about a protein coding gene).

In the ICGC data, LRP1B mutations are the most prevalent in tumors at the following sites: skin, blood, esophagus, ovary, prostate, liver, kidney, breast, pancreas, and lung.

  1. BRAF (v-raf murine sarcoma viral oncogene homolog B)

Located on chromosome 7, this gene codes for a serine/threonine kinase, involved in the regulation of MAP kinase/ERKs signaling pathway, which affects the way cells divide and differentiate. According to the ICGC:

Mutations in this gene are associated with cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.

Mutations in this gene have also been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.” [source]

In the ICGC data, there are 1,503 donors affected by 1,699 mutations in this gene, and these mutations are the most prevalent at the following sites: skin, head and neck, and esophagus.

  1. RYR2 (ryanodine receptor 2)

Located on chromosome 1, this gene encodes a cardiac ryanodine receptor, which is part of a calcium channel responsible for supplying calcium to cardiac muscle. A malfunctioning/non-functional protein, as a result of a mutated gene, will impact normal cardiac function.

In the ICGC data, there are 3,148 donors affected by 15,840 mutations in this gene, and these mutations are the most prevalent at the following sites: esophagus, skin, ovary, breast, liver, blood, prostate, pancreas, kidney, and lung.

  1. KMT2C (lysine (K)-specific methyltransferase 2C)

Located on chromosome 7, this gene codes for a protein involved in histone methylation.

In the ICGC data, there are 2,050 donors affected by 4,266 mutations in this gene, and these mutations are the most prevalent at the following sites: skin, lung, liver, prostate, blood, breast, and kidney.


One question that may arise out of these observations is:

How come mutations in a gene that encodes a protein responsible for a very specific function in a specific tissue/site/cell can lead to the development of cancers at other sites?

The faulty nature of our nuclear replicative machinery allows for random replication errors (mutations). The default error rate is very small, in the range of 1 in 10 million to 1 in 100 million [source], but given that human DNA appears to replicate at rate of ~50 nucleotides per second [source] and given the very large number of cells in a body and even in a specific tissue, errors are likely to occur.

And when repair factors and enzymes are themselves dysfunctional, this can lead to abnormal and uncontrolled proliferation. Pair that with other endogenous and exogenous factors that may impact the body’s capacity to handle the problem, and you have an environment that allows for tumor formation.

Getting back to the main question, in later stages of tumor progression, progenitor cells escape tumor primary site and migrate to different sites that favor subsequent tumor development. Metastasis is a very complex process that is beyond the scope of this post.

My main assumption, to answer the question, is that site-specific dysfunctional proteins and cells that cannot be eliminated/terminated because of incapable repair machinery, and other factors, can lead to development and migration of tumors to other sites.

Whether or not this is correct is not the point…

What’s more important is our ability to mitigate these issues that grow from such mutations. And my hope is that we’ll be able to identify and attack the problem as close as possible to its initiation, using methods of biology and technology, such as: immunotherapy, genome engineering, and other very targeted, extremely specific interventions.

Images: Adapted from/Courtesy of ICGC: 1 and 2.

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