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The genetic basis of cancer

Introduction

Cancer is a group of diseases and is basically classified by the type of tissue it originates. All of the complex organisms are made of a higher number of cells. Cells are the fundamental unit of them in their structure and also in functions. Most of the body cells of an adult are specialized for specific functions. They are called differentiated cells. They are in a nondividing state. For instance, nerve cells of adults are specialized with functional, structural and biochemical properties and never divide. But some tissues consist of a special type of cells that are called “stem cells” which are not differentiated and can divide and turn into the differentiated state by getting specific structural, functional and biochemical properties. For instances: epidermal stem cells of the skin can divide and form differentiated skin cell that is contributed in wound healing and renewing the layers of the skin; blood-forming stem cells that can differentiate into any kind of blood cells forming new blood cells for blood tissue; stem cells in the liver can divide and differentiate replacing the damaged cells in the liver. Epidermal stem cells and blood-forming stem cells divide continuously. However, stem cells in the liver need an extracellular signal to begin the division ensuring that cell division occurs only when the liver is damaged. Thus, there are three types of cells: continuously dividing cells, seldom dividing cells and non-dividing cells. Cell proliferation(Increasing the number of cells in a tissue), cell growth and cell differentiation of tissue must be tightly regulated to ensure that tissue retains appropriate structure and functions. This is regulated by a significant number of genes. The fundamental process of cancer is the rapid and abnormal cell division. Non-dividing cells cannot divide and therefore non-dividing cells never become cancerous but the other two types of cells mentioned above can become cancerous if their cell division controlling mechanisms become defective. Excessive cell proliferation occurs in any cancer. A tumour which is an abnormal cell growth is developed in most cancers except blood cancers. The tumour enlarges by rapidly multiplying its cells and then starts to spread nearby tissues, causing local spread. A tumour that can invade nearby tissues is called a malignant tumour. In the advanced stages of cancer, the cancer cells get the ability to spread all over the body by travelling through blood vessels and lymph vessels to distant locations. This is called metastasis. Local spread or metastatic spread in an organ that is crucial for the body functions can cause death if it is uncontrolled.

Cell division ( commons.wikimedia.org )

Genetic alterations and cancer

All somatic cells of an organism include all genes of the genome(an organism’s complete set of DNA, containing all of its genes). However, only an appropriate definite set of genes are expressed in a specific cell type. Gene contains hereditary information as a code that is written using the base sequence of the DNA molecule. Gene is expressed by encoding protein by which makes effects in cell functions by directly involving metabolic pathways. Gene expression results in a functional or structural change in the host organism. Gene expression should occur in the proper place(in the appropriate cell), at the proper time and in the appropriate procedure. However, cancer cells do not have a proper expression of genes. Cancer is called a fundamentally genetic disease because cancer arises as a result of defects in genes. Mainly these defects are mutations that affect DNA base sequence of genes and sometimes these may be caused as a result of some processes such as DNA methylation which is a process by which changes the gene expression manner without changing the sequence of bases. Genetic alterations can occur during the lifetime as a result of exposure to certain environmental factors or inherit from parents. A normal cell needs multiple changes in structural, functional and biochemical properties to become malignant. These changes arise as results of multiple genetic alterations.

Alterations in expression of tumour suppressor genes and proto-oncogenes

proto-oncogenes​ and ​tumour suppressor genes​ work together to regulate the rate of cell division. In the process of the cell division proto-oncogenes act as the accelerator and tumour suppressor genes act as the brake. Rate of cell division increases by proto-oncogenes and decreases by tumour suppressor genes. When a proto-oncogene is mutated, it is called an ​oncogene​. Oncogenes are hyperactive than non-mutated proto-oncogenes. These oncogenes produce hyperactive stimulatory factors by which abnormally stimulate cell division. One copy of the mutant allele is sufficient to induce excessive cell proliferation as it produces abnormal factors which can overstimulate cell division. Therefore this is a dominant-acting mutation. Tumour suppressor genes produce factors by which inhibit cell division. Alleles of mutant tumour suppressor genes can not produce factors which can properly inhibit cell division or can not express properly. However, if the gene has a non-mutant allele, it can produce inhibiting factors that can inhibit cell division in a normal manner and may be able to inhibit cell division properly. Therefore, in most cases, both of the alleles must be mutated to induce excessive cell proliferation. Therefore this is a recessive-acting mutation.

Defects in the regulation of the cell cycle

The cell cycle is the key point in cancer progression. In the process Cell cycle, cells undergo growth and division. Any cell passes a cell cycle when it divides. After a cell division, the next cell division is taken only if that division is necessary and the structure and functions of the cell are healthy. If another division is not necessary, the cell undergoes a rest period. Also, if the structure and/or functions of the cell have defects, either it should undergo a rest period until it is repaired or should be destroyed to avoid the reproduction of daughter cells with the same genetic deficiency. In normal cells, the cell cycle is tightly regulated by the processes that are called “checkpoints”. Checkpoints examine whether the components of the cell are in a proper state and DNA have been replicated without damage to carry out a successful cell division. If not, checkpoints do not let the cell to pass specific stages in the cell division. Checkpoints let the cell approach its particular stages of the cell cycle only at the appropriate time and only with appropriate cell components. If the genes which encode functional proteins of these checkpoints become mutated, they can not encode those functional proteins properly. Due to the absence of the relevant functional proteins, checkpoints do not perform properly. As a result, the stages of the cell cycle can happen inappropriately without the normal controls that regulate cell proliferation.

Consequences of defective DNA repair system

Any somatic cell has a DNA repair system. During the life of a cell, its DNA can be damaged by its normal metabolic activities and by some environmental factors such as radiation. It happens oftentimes. The DNA repair system of a cell is responsible to repair such damages and maintain the prescribed base sequence of the DNA molecules. However, if some of the genes which encode functional proteins of the DNA repair system are mutated, some mechanisms of the DNA repair system can fail to function properly. Therefore some DNA damages can not be repaired including certain damaged genes that contribute to cancer. It may open a path to malignancy. Defects of the DNA repair system can induce more frequent mutations lessening the ability of DNA repair. Therefore the progression rate of cancer can be increased by a defective DNA repair system.

Involvement of telomeres and telomerase activity

Telomeres are another aspect that can be crucial in tumour development. Telomeres are parts of a chromosome and are made by repeating the same short sequence of base pairs over and over again. The DNA part of a telomere is continuous with the DNA molecule of its host chromatid(chromosome is made of two chromatids). Telomeres are located on both ends of chromatids. Telomeres do not encode proteins but act like caps forming protection to both ends of chromatids. They allow the chromosomes to be well organized in the nucleus, avoid nucleotides lose in genes located at ends during replication and allow chromosomes to have a proper replication. A specific type of enzyme that is called telomerase is needed to express for avoiding nucleotides lose in telomeres during replication. In the absence of telomerase, several numbers of nucleotides located at the end of the telomere are lost in replication. However, in most somatic cells, telomerase enzyme activities are absent. Due to the absence of telomerase enzymes, telomere parts of chromosomes are not able to multiply with their original full length. This means some DNA part of telomere is lost at every multiplication of chromosomes. In another way, telomeres of the daughter cell are shorter than telomeres of the parent cell. Consequently, telomere lengths are shortened generation to generation. After a cell passes a definite number of cell divisions, its telomere lengths become a critical value and after passing that value the cell becomes unable to divide any more times. Cancer cells must be divided up to a very high number of times to produce a large amount of excess cell proliferation. If telomere lengths of cancer cells become shorter within a limited series of cell divisions, the ability of multiplication becomes limited to a relatively lesser number of times, bringing a challenge to the tumour development process. In cancer progression cancer cells overcome this challenge by activating telomerase enzymes. Telomerase enzymes are activated in cancer cells by certain gene mutations. As a result, cancer cells become capable of dividing an unlimited number of times, creating a large tumour.

Formation of new blood vessal into the tumour

Angiogenesis and cancer
nuevos vasos sanguíneos(Spanish) = New blood vessels
células normales and células cancerosas(Spanish) = Normal cells and cancer cells

Except for blood cancers, a tumour occurs in all of the other types of cancers. Tumour cells require oxygen and nutrition as normal cells, even at much higher rates. Therefore blood vessels should be grown well into the tumour. Growth of new blood vessels into tissue is called “angiogenesis”. Angiogenesis is controlled in normal cells by the inhibitors and stimulators. If the genes which encode components of these inhibitors and stimulators become mutated, it can induce overexpression of stimulators and underexpression of inhibitors. As a result, angiogenesis occurs at a much higher rate than normal. Therefore, this kind of mutation lets the tumour grow a lot of new blood vessels into it. When the tumour becomes rich in blood vessels it can get oxygen and nutrition at a higher rate as sufficient to higher-rated-metabolic activities of tumour cells.

Relationship between microRNA and oncogenes

Also, defects involved in microRNAs can support the growth of cancer. MicroRNAs(miRNAs) are small RNA molecules which can regulate gene expressions by pairing with complementary sequences of mRNA. Researchers have found that some kind of miRNA can control the expression of some oncogenes. Therefore without the proper regulation that is induced by miRNA, oncogenes can express properly without any interruption. Abnormal low levels of miRNA can help the tumour cells to divide rapidly. However, scientists have found higher levels of some types of miRNAs are involved in promoting some types of metastasis cancers. Therefore genes which encode the proteins associated with the formation of miRNAs may be involved in cancer progression.

Metastasis

In most cancer cases, metastasis is responsible for causing death. In advanced stages of cancer, broken away tumour cells of the primary tumour can form secondary tumours in distant locations in the body by travelling through blood vessels and lymphatic vessels to those locations. Those secondary tumours are like branches of the primary tumour. They can arise in lymph nodes or in any other distant organ. To complete the metastasis process, certain primary tumour cells should be able to complete multiple steps of the metastasis process. These steps: detachment from the primary tumour, entry into the bloodstream(=Intravasation), survival in the circulation, exit from capillary beds into the parenchyma (main functional portion) of an organ(=Extravasation), adoption to the new environment, colonization in the organ. However, a normal somatic cell or even most of the cells in the primary tumour can’t complete these all steps and a set of specific genetic alterations are needed to get the ability to complete the metastasis process. Primary tumour cells must obtain these genetic mutations along with other mutations that are required to form malignancy. Scientists have suggested certain gene mutations that contribute to cancer. Genes that achieved these mutations are called metastasis genes. They can be divided into these major types: metastasis initiation genes, metastasis progression genes and metastasis virulence genes. Metastasis initiation gene activities help malignant cells to begin the metastasis process by allowing them to carry out sub-processes such as detachment, motility of cells into the vessels, intravasation, etc. Metastasis progression gene activities contribute to colonization(growth of a clone of cells) of secondary tumours in specific target organs​. Metastasis virulence gene activities provide a selective growth advantage to malignant cells in the secondary site giving them an aggressiveness and are crucial for malignant cells to survive in secondary environments. However, the nature of metastasis is not fully understood yet.

Contribution between viral infections and cancer risk

Viruses can rearrange and mutate host genes. They can convert proto-oncogenes to oncogenes and overexpress proto-oncogenes. Therefore some of the viral infections may give the rise to cancer. Retroviruses are the major kind of cancer-causing viruses.

Heritable genetic conditions that can increase cancer risk

In most cases, cancer is not caused by hereditary genetic factors. However, there are some hereditary genetic conditions by which increase cancer risk directly. For instance, If some person inherits a mutant allele of a tumour suppressor gene, that person has a higher chance of developing cancer as the normal allele of that gene is more likely to mutate at least in a few somatic cells. Also, some genetic predispositions to various conditions that can be involved in cancer progression can enhance the effects of environmental factors. For instance, genes which encode receptors that bind potential carcinogens can increase the cancer risk by strengthening the effects of carcinogens; Also, if someone has a genetic condition which increases the chance of addiction to smoking(smoking gains the cancer risk), that condition may contribute to causing that person a lung cancer by addicting him to smoke. Also, cancer can be induced by some inflammatory diseases(diseases that induce an autoimmune response in which the immune system mistakenly attacks its host’s own body cells) which may sometimes be inherited. An example is IBD (Inflammatory bowel disease) by which gains the risk of developing colorectal cancer.

Path to malignancy – How does a normal cell turn into a cancerous cell?

In this article, major types of mutations which are involved in cancer progression have been mentioned. A normal cell needs multiple gene mutations to become a malignant cell. Cells get those mutations one by one during the cancer progression period as this way; If a cell exists alive with a genetic mutation by which increases the cell proliferation rate abnormally, the cell can make a clone of cells that consist of the same mutation. As a result of the rapid divide rate of these mutant cells, they are more advantageous in proliferating in the tissue than other normal cells. Therefore, the percentage of the number of mutant cells in the tissue becomes higher than normal cells. Then one cell of the cells with a single mutation maybe got another mutation by which increases the divide rate. Now, this cell has two mutations and it can make a clone of cells that consist of these similar mutations. Then the cells that have two mutations become more dominant in proliferation in the tissue than any other cells that consist of either one or no mutations. In a similar manner cells in this clone maybe got more mutations also and the percentage of the number of such cells is gained also. As this way, this clone of cells may evaluate to a malignant tumour and then to metastasis stage by acquiring required mutations. However, the occurrence of mutations may quit after only a few mutations and further mutations that can lead to developing a malignant tumour may not occur in some cases leading to developing a non-cancerous tumour (benign tumour) that may not be more dangerous than a malignant tumour.

This genetic changing process can be understood using the progression of colorectal cancer. In colorectal cancer progression, normal tumour suppressor gene APC(a kind of tumour suppressor gene) becomes mutated in a normal cell that lines the colon or rectal. As a result, the cell divides rapidly and a small growth of cells occurs and then it turns into a precancerous tumour. Secondly, in some of the tumour cells, a proto-oncogene is turned into an oncogene. As a result, such cells spread more rapidly and the tumour turns into an adenoma, a non-cancerous tumour. Then some of the cells in this adenoma lose gene proper activity of T53, the major tumour suppressor gene. After this genetic change, those cells become malignant and such malignant cells spread more rapidly in the tumour making a malignant tumour. At last, genetic changes that contribute to metastasis occur in some of the cells of this malignant tumour and as a result, metastatic cancer occurs making secondary tumours in some lymph nodes and in some other organs. In this example, major genetic changes are mentioned and other additional genetic changes should also occur.

Drivers and passengers

During the cancer progression, multiple mutations can arise. These are divided into two types: Drivers and passengers. Drivers are directly involved in the development of cancer and organize major events of the cancer progression. Only this type of mutation was brought to account in this article. Cancer cells have defective DNA repair systems, defective tumour suppressor genes and their cell cycle checkpoints do not work properly. As a result, they may develop and exist with more mutations. Some of these mutations may not help to feed cancer and may occur randomly during cancer progression. Such mutations are called passengers. This type of mutation does not promote cancer growth. However, they may lead to making abnormalities in certain body functions. Also, extra effort is needed to distinguish driver mutations from the collection of both types of mutations. Therefore, the existence of passengers often makes it hard to discover what the drivers are. With the effects of both types of mutations, cancer cells become more varied in structure and functions compared to normal cells.

Conclusion

Excessive cell proliferation occurs in any cancer. This can lead to unnecessary cell growth that is called a tumour. Development of cancer begins from a genetic mutation that can induce rapid cell multiplication. A cell needs multiple mutations to become malignant. These mutations occur in certain tumour cells in multiple steps. tumour evolve towards the malignancy by increasing the percentage of several cells that obtained much more driver mutations. Excessive cell growth may not always become a malignant tumour and it may exist as a benign tumour. A malignant tumour can invade nearby tissues and also it can spread all over the body by sending broken away metastatic cancer cells through blood vessels and lymph vessels. Inherited effects may be involved in developing cancer in various ways. All mutations that develop during cancer progression may not have made active effects that contributed to the development of cancer and these mutations randomly occur as a result of some defects of the cell functions. Some viruses may be able to induce cancer.

References

01.Genetics- A conceptual approach – Benjamin A. Pierce – chapter: 23
02.Masood A. Shammas-Telomeres, lifestyle, cancer, and ageing- [​PMC free article​] 03.Leigh-Ann MacFarlane and Paul R. Murphy-MicroRNA: Biogenesis, Function and         Role in Cancer- [​PMC free article​]
04.Nimrat Chatterjee and Graham C. Walker-Mechanisms of DNA damage, repair           and mutagenesis- [​PMC free article​]
05.Kevin J. Barnum and Matthew J. O’Connell-Cell Cycle Regulation by Checkpoints- [​       PMC free article​]
06. BREAST CANCER METASTASIS: MARKERS AND MODELS – Britta Weigelt, Johannes        L. Peterse and Laura J. van ’t Veer – Nature reviews | cancer – volume 5 | august          2005 [Google Scholar]

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දුලාජ් නදිෂ්ක රාමනායක

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