The Complex biology of cancer mutations

How does a normal cell transform into a cancerous cell? The transformation is complex. The transition takes place over time with cells manifesting several signature phenotypic and genotypic alterations. In a normal cell, cell division is facilitated by several interacting genes through defined signal transduction pathways. In addition, mechanisms that control or regulate cell division also exist. The intricately maintained balance between cell proliferation and suppression sustain the normal functioning of cells.

Cancer cells, however, are typified by an imbalance between these two functions. In addition, over the course of cancer development, several characteristics are acquired by cancer cells. The typically understood characteristics, classified as major hallmarks of cancer, are: sustained proliferation, evading growth suppressors, activating invasion and metastasis, enabling immortality, inducing angiogenesis, resisting cell death, reprogramming of energy metabolism and evading destruction by the immune system.1 Such a display of complex characteristics involves accumulation of several alterations in genes (mutations). Understanding these mutations provide opportunities to develop novel ways to tackle the disease.

Germline versus somatic mutations

Genetic alterations that occur in germ cells (egg or sperm) are called germline mutations and are directly inherited by the progeny. Mutations occurring in any other cells of the body outside of germ cells are defined as somatic mutations and are not inherited by subsequent generations. Mutations occurring in developing somatic cells can give rise to populations of cells carrying the mutation. Depending on whether they occur in genes involved in growth and proliferation (oncogenes) or in growth suppression (tumor suppressor genes), they can exert diametrically opposite effects, but both favoring unchecked development of cancer cells.

Activating and deactivating mutations

Cell growth is affected by the activation of cell surface receptors (such as receptor tyrosine kinases (RTK)), which in turn activates a series of phosphorylation events ultimately resulting in the expression of proteins, such as RAFMEK, and ERK, which are responsible for growth, development and survival.2 Mutations in these signal transduction genes can trigger development of different types of cancer.

For example, three different types of mutations in the RAF gene (KRASNRAS and HRAS) lead to development of lung cancer, skin cancer or bladder cancer.3 Mutations in RAF gene result in the constitutive activation of the RAF-MEK-ERK signal transduction pathway leading to uncontrolled cell division and growth. These are called activating mutations and they lead to a gain of function for the protein.

Conversely, other types of mutations, namely inactivating mutations, could result in loss of function of proteins, leading to an entirely different outcome. For example, the tumor suppressor gene TP53 has anti-proliferative functions and is involved in shutting down stressed or damaged cells. It is responsible for deciding the fate of damaged or stressed cells. It decides if a damaged DNA fragment has to be repaired or the cell should be sent through an apoptotic pathway for preventing the damaged cells from posing a danger to normal cells, thus providing a cellular brake on cancer development. Deactivating mutations that result in a loss of function of TP53 render this brake nonfunctional, thus making cells vulnerable for cancer development and metastasis.4

The four major classes of cancer mutations

From single base pair alterations to complete chromosomal rearrangements, a range of genetic alterations result in cancer. The four major and significant ones are described below.

Single nucleotide variant

Mutations in a single nucleotide (SNVs) are point mutations that cause missense or nonsense amino acid substitutions. SNVs could be activating mutations causing cancer or could be silent mutations (without causing any perceptible effects). 

For example, a single nucleotide mutation resulting in substitution from valine to glutamic acid at codon 600 (V600E) in the BRAF gene accounts for about 90% of the BRAF mutation type in melanoma.5 Using inhibitors of BRAF mutants and employing companion diagnostics approaches that include testing for BRAF mutations and determining the appropriate treatment plans are some of the options available for melanoma. Inhibitors of BRAF mutants, such as vemurafenib and debrafenib, have been developed for targeting melanoma.6

Another SNV of significance is an amino acid substitution in exon 21 of leucine to arginine (L858R) in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). This single mutation can make a difference in the efficacy of drugs used in advanced non-small cell lung cancer (NSCLC), such as gefitinib, erlotinib and afatinib.7

Copy number variant

Sometimes chromosomal rearrangements can cause a change in copy number leading to either loss or gain of function. Segments of chromosomes can be deleted or duplicated or inverted, all of which could lead to alterations in copy numbers of genes, resulting in differential expression of those genes. Such copy number variations have been implicated in cancer nt. For example, in a study using individuals derived from four different HIV populations and from different methods of acquisition of the virus, a clear difference in copy number of the CC chemokine ligand 3-like 1 (CCL3L1) gene has been observed. Based on the copy number the risk for individuals developing HIV infection could be determined.8

Translocations and fusions

Chromosomal translocations occur when a segment of a chromosome is transferred to a different part of the same chromosome or to an entirely different chromosome. With chromosomal translocations, shuffling of genes take place, usually resulting in differential expression. Sometimes, portions of different genes join together, resulting in what are called gene fusions or fusion genes.

An example of this is the Philadelphia chromosome, made of a fusion between breakpoint cluster region gene (BCR) and Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene, found in more than 95% of chronic myeloid leukemia.9 Similarly, fusion between the anaplastic lymphoma kinase (ALK) and the echinoderm microtubule-associated protein-like 4 (EML4) gene is seen also seen in NSCLC.10


Insertions and deletions (indels) of nucleotides are frameshift mutations, resulting in changes in amino acid sequences that lead to differential expression. Depending on how the shift occurs, the mutation could introduce a stop codon prematurely, resulting in truncated proteins. Along with SNVs, indels are the most commonly observed somatic mutations.11 Commonly mutated genes across different cancer types have been shown to be SNVs and indels.12

Driver and passenger mutations

During the course of establishing themselves, cancer cells exploit all resources in their environment to their advantage and acquire several new mutations. Of these, a few mutations, called the driver mutations, occur in oncogenes and tumor suppressor genes and facilitate tumor growth and proliferation. The adaptive significance provided by these driver mutations is crucial for cancer progression.13

An example is the 790M mutation of the EGFR tyrosine kinase (TK) inhibitor in NSCLC. During EGFR TK therapy, some cancer cells develop resistance to drugs through the acquisition of the 790M driver mutation.14 Detection of this mutation is important to provide alternative treatment options. Several mutations occur alongside driver mutations, but these, so called passenger mutations, do not confer any direct advantages or modify tumor growth rates.15


Cancer is a complex disease. Cancer cells acquire several mutations over the period of their existence. Cancer development and progression is conferred by processes akin to a Darwinian evolution. These involve continuous acquisition of genetic variation due to randomly occurring mutations and selection of genetically advantageous variations by natural selection in the tumor environment. This selection eliminates those that are deleterious for cancer growth and selects those that have accumulated enough beneficial variations that enable the cancer cells to thrive.

This constantly evolving nature of cancer cells emphasizes the need for constant monitoring of cancer, even after detection and during treatment. Non-invasive approaches such as liquid biopsy, where mutations can be detected from blood samples, enable residual disease detection, disease progression monitoring and comprehensive genomic profiling.



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