Genetics of Cancer

The incidences of cancer started shooting up in the year 1991. Since a decade the cancer cases increased by a factor of three. There is simply no complete cure to this dreadful condition. It involves changes in the genome leading to uncontrolled cellular proliferation, transformation, invasion, metastasis, apoptosis suppression, and angiogenesis. The environmental factors such as chemicals, radiations, viruses, microbes, and hormones cause cancer. Apart from the above reasons, there are more factors involved. The cell follows a cyclical pattern of division involving different phases. It includes the G1, S, G2, and the M phases respectively. The transition of one phase from the other involves checkpoints. The CDK/cyclin complexes mainly control the cell cycle. The checkpoints determine the damaged DNA. They also help in checking the problems in the cell cycle machinery. Hence, they play a crucial role in permitting normal cells to continue. Problems in the cell cycle checkpoints trigger cancerous conditions. Certain viruses such as retroviruses cause cancer. They increase the oncogenic products. Also, for the normal cells, apoptosis plays a crucial role. The cancer cells do not undergo apoptosis.

Image 1: Cancer cells and normal cells

Cell cycle and cancer:

A cell cycle involves six main checkpoints such as the restriction point, the G1/S DNA damage checkpoint, the S phase DNA damage checkpoint, G2/M checkpoint, centrosome duplication checkpoint, and mitotic checkpoint. The restriction point occurs between the mid to late G1 phase. This point ensures the cell to enter into the S phase after receiving the appropriate signals. The G1/S damage checkpoint occurs at the G1 phase transition. It senses the DNA damage. The S phase DNA damage checkpoint arrests the cell cycle in the later part. It detects the DNA damage or an incomplete replication of DNA. The G2/M checkpoint also detects the damaged DNA. The centrosome duplication checkpoint detects the defects in the centrosome duplication process. This checkpoint also detects centrosome segregation defects. The mitotic checkpoint occurs in the M phase. It checks the formation of mitotic spindles.

The CDK/cyclin complexes control the cell cycle. The cyclin-dependent kinases belong to the class of kinases. The cyclins are known as the regulatory subunits. The CDKs are known as catalytic subunits. The cell cycle checkpoints involve a genetic control. The genes participating in the multiple cell cycle checkpoints are known as gatekeeper genes. These genes prevent the cell cycle progression until the damaged DNA gets repaired.

Phases of the cell cycle	Cyclin-CDK complexes
G1 phase	Cyclin D, CDK-4 Cyclin D, CDK-6
Late G1 phase	Cyclin E, CDK-2
S phase	Cyclin A, CDK-2
G2 phase	Cyclin A, cdc 2
M phase	Cyclin B, cdc 2

Table: All phases of the cell cycle and the associated cyclin-CDK complexes

1.     G1 Phase:

Alterations in the signaling pathways associated with the cyclin-dependent kinases lead to the uncontrolled cell proliferation. Retinoblastoma involves tumor in the retina. It occurs in childhood. The gene responsible for getting mutated and causing the disease is known as the RB gene. It is present on the q arm of the thirteenth chromosome. Deletion or inactivation of both the copies of the RB gene leads to retinoblastoma. The cell loses the protein product pRb.

This phase requires a regulatory protein. It is known as pRb. It gets phosphorylated by cyclin/CDK complex. The pRb binds to the E2F transcription factor and prevents the cell’s entry into the S phase. After the phosphorylation of pRb, it gets inactivated and releases the E2F. Now the cell safely enters the S phase. However, in the retinoblastoma, the cell loses the pRb protein due to RB gene mutation. Hence, the cell enters into the S phase without checking any damaged DNA. Thus, it leads to an unrestrained tumor formation.

2.     G1/S checkpoint:

The tumor suppressor gene known as TP53 gene plays a crucial role in cell cycle arrest and DNA repair. This checkpoint gets invoked due to dsDNA breaks and damage. The product of the TP53 gene is a protein. It is known as p53. It helps in arresting the cell cycle in the G1 phase or the G1/S phase. After the repair of the DNA, the cycle resumes back. However, failure to get repaired leads to apoptosis or cell death. It occurs in the normal cells where p53 gets activated. In the cancer cells, the p53 is not present. Hence, there is no cell cycle arrest and repair of damaged DNA. Thus, the cells form tumors.

3.     G2/M checkpoint:

It is a DNA damage checkpoint. It helps in progressing the cell from the G2 phase to mitosis phase. It maintains the cdc2/ cyclin B1 in an inactive state. The protein p53 also plays a crucial role here.

Image 2: Cell cycle

Cellular proliferation:

Signal transduction involves extracellular growth factors. They regulate cell growth and differentiation. The genes encoding the growth factors or the growth factor receptors may get mutated. Hence, they lead to oncogenic properties. A gene encodes for the signal transducing protein. It is known as ras gene. The transcription factor gets encoded by another gene. It is known as the Myc gene. Mutations in both the genes also cause cancer.

Genes, Viruses, and Cancer:

Cancer involves mutations in three main gene classes. They include proto-oncogenes, tumor suppressor genes, and mutator genes. The products of proto-oncogenes stimulate cell proliferation. The mutant ones are known as oncogenes. They are the active forms of cancer genes. The oncogenes stimulate unregulated cellular proliferation. The RNA viruses also replicate via DNA intermediate. These viruses are known as retroviruses. Upon the retroviral infection, the RNA genome of the viral particle synthesizes a kind of cDNA. It is known as proviral DNA. The viruses also have oncogenes. They are known as viral oncogenes. When they occur in the host cell, these genes are known as cellular oncogenes. The host DNA sequences homologous to that of the virus are known as proto-oncogenes. These genes get activated to oncogenes. Three main methods do this. The first method involves increasing the amount of proto-oncogene product. The second method involves mutations in the coding sequences. Chromosomal translocation also leads to activation of oncogenes.

Apoptosis and Cancer:

The cell death or apoptosis gets triggered in the case of unrepaired damaged DNA or any other unwanted cellular conditions. The failure of the checkpoints in stopping the cell cycle progression also triggers cancer. Cancer also occurs due to the activation of anti-apoptotic genes such as Bcl_2. Thus, many such factors contribute to cancer. 

References:
[1] Human Genetics, 3/e, Gangane
[2] Molecular Genetics of Cancer, John Cowell
[3] The Genetics of Cancer: Genes Associated with Cancer Invasion, Metastasis, Gajanan V. Sherbet, M. S. Lakshmi
[4] API Textbook of Medicine, Ninth Edition, Two Volume Set, Y P Munjal, Surendra K Sharma

© Copyright, 2018 All Rights Reserved.