The Genetic Causes of Cancer
By Ayesha Khanna & Jurgen Kaljuvee

Cancer means different things to people: for some of us, it is the painful memory of a loved one who experienced it; for others, it is a personal journey of trial and recovery; still for others, it is a flashback from something they saw on a television series. If you haven’t studied molecular biology and genetics, you’re most likely to associate cancer with types of cancer – leukemia, breast cancer; symptoms – tumors, fatigue; and treatment - radiation, chemotherapy, and transplants. But what cancer really is an adverse alteration in our DNA, the blueprint for the growth and functioning of the body. This article discusses the genetic causes of cancer, and how good genes can become the enemies within when roused by rogue viruses, random mutations or carcinogens.

WHAT IS CANCER?
Cancer is very simply the uncontrolled proliferation of undfifferentiated cells. All cancer cells share three main characteristics in common:

1. Uncontrolled proliferation. Normal cells have a carefully regulated lifecycle: they live for a certain time period, they divide resulting in more cells exactly like themselves, and then they die. Cancer cell multiplication cannot be regulated on the other hand and they do not respond to the usual signals regulating the cell cycle.
2. Cancer cells are undifferentiated. Usually cells (except for stem cells) in a human body is specialized or differentiated to use biological vocabulary. Cancer cells, however, have lost their normal function, such as processing toxins in liver cells or intake oxygen in lung cells, and their only purpose is to keep more copies of themselves.
3. Cancer cells are immortal. They will divide and live forever provided they have sufficient nutrition around. In living bodys (in vivo) they will die of course with their carrier but in a laboratory (in vitro) they can be sustained forever like so called HeLa cells. The woman who was the unfortunate host of these cervical cancer cells – Henrietta Lacks – died already in 1951 but her cells are still being cultivated in various labs worldwide to perform various cancer experiments.

In every kind of cancer, and there are over 200 kinds of cancer that affect human beings, the root cause lies in the fact that the normal functioning of the cell is affected or that the blueprint of instructions of cell functioning is vitiated. For example, in the case of leukemia, white blood cells in the bone marrow begin to proliferate; and, in the case of breast cancer, cells divide relentlessly and billions of them eventually comprise a tumor.

To understand the issue with cancerous cells, let’s compare the characteristics of normal cells with cancerous cells.

Looking at cancer at this molecular level as the problem of the breakdown of DNA is an inside-out way of understanding cancer. It abstracts away from the specifics of each cancer type and creates a framework or model with which to analyze all types of cancer.

THE BLUEPRINT
Think of the DNA for the human body as equivalent to the blueprint that an architect draws for a building; if someone spills coffee on the blueprint and its lines look different, the construction workers that build from it will create the wrong structure. Similarly, if any of the instructions that are encoded in the DNA are vitiated, the proteins and other molecules that are created from these instructions as building blocks for the organism will behave erratically.

Specific instructions on the regulation of cell growth are encoded in parts of the DNA, or sections of the blueprint, known as genes. Genes contain the information that is used to build proteins, the primary building blocks of the organism, and other molecules that are necessary for the growth and functioning of the organism. Six to eight families of genes, when altered, are often seen mutated in cancerous cell. The main ones are oncogenes, tumor suppressor genes and DNA repair genes. The first two are responsible for regulating the growth of cells, while the third is responsible for fixing any errors that may arise in genes such as the first two.

Oncogenes normally encourage cell growth, but when mutated or over-expressed [this means that they are firing off more signals than they would do normally], they can flood cells with signals to keep on dividing.

Tumor-Suppressor Genes normally regulate and restrain cell growth; if they are switched ‘off’, the cells will divide uncontrollably.

When the tumor suppressor gene, also called the p53 gene, is mutated, the cell’s ability to self-destruct is also compromised. Cells commit suicide when the repair mechanisms don’t work, and they realize that they have become renegade; in these cases, suicide is the healthy option. However, in cancer cells, the genes that are responsible for this function are mutated, and therefore cancer cells continue to live with impunity.

In addition, it appears that the mutation of this gene, along with other genes possibly, is responsible for metastasis [the spread of cancer from location to another] and angiogenesis [the creation of blood capillaries around the cancerous tumor which feeds the cancerous cells]. Metastasis is the ultimate cause of death in the vast majority of cancer patients. Cancer growth is restricted to less than 1 million cells in the absence of new blood vessels. Tumor growth is therefore angiogenesis-dependent.

Mutations in p53 are detected in more than 50% of all human cancers e.g. lung, breast, brain, bladder.

DNA Repair Genes, which correct mistakes in the genes when the cell divides, can fail to function probably and thereby let mistakes accumulate over thousands and thousands of cells.

Genes That Maintain Telomeres, are genes that maintain the telomere length when the cell divides. Normal cells lose a portion of their chromosome tips (telomeres) with each cell division. This establishes a limit to the number of times they can divide before the chromosomes become too short and in this way limits the life span of any cell lineage. This is, in essence, a built-in biological clock that affects all normal cells in our body. Telomere shortening can be avoided by telomerase, an enzyme that protects the telomeres from shortening. Normal cells do not contain telomerase; it is found only in two cell types: sperm cells and cancer cells. Telomerase is really the secret behind cancer’s eternal youth.

GENE MUTATIONS
Genes may mutate because of two main reasons:
• Point mutations: also known as Single Nucleotide Polymorphisms (SNPs). These can occur for a wide range of reasons including exposure to various chemicals, viruses and radiation.
• Translocations: during mitosis (or cell division), parts of the DNA from one chromosome can jump onto another chromosome, thereby altering up the genetic code for a gene. If the gene happens to be one of those responsible for regulating cell growth, then this can lead to the cell becoming cancerous.

TREATING CANCER
This article has tried to build a logical framework for understanding the causes of cancer. Common treatments of cancer aim at destroying the cancerous cells themselves. These treatments include: removing the cancerous cells - this is possible if the tumor can surgically be removed from the body; destroying the cancer cells - this is possible with a cocktail of chemotherapy and radiation; replacing the organ which has been infected by the cancerous cells - this is possible with transplants such as liver and bone marrow transplants.

Many of the treatments for cancer have been affective, especially if the cancer is in the early stages and has not spread, or if the mutation of the genes has not become ‘aggressive’. The latter happens when some cancerous cells reappear after having survived a session of chemotherapy and have become resistant to the chemical cocktail injected to destroy them. With the discovery that the root of cancer lies in gene mutation, scientists have been working on fixing the genes themselves through what is known as gene therapy, a fairly new treatment where the genes, instead of the cell, are targeted.

VIRAL VECTORS & GENE THERAPY
Viruses infect an organism by attacking the DNA of the cells of the host organism. A virus will insert its DNA into the DNA of the cell, thereby rendering it hostage to the virus. The infected cell then reproduces itself, in effect spreading the viral DNA each time it divides. Viruses, therefore, provide an ideal mechanism for reaching the DNA of a cell and if they could be manipulated to go and insert correct genes, instead of their own DNA, this would be one way of fixing the mutated DNA of a cancerous cell. The DNA of the virus is replaced by the gene needed to repair the human cell and inserted into the body. Once the corrected gene has been transplanted in the cell, each time the cell divides, it will be a normal cell instead of a cancerous cell. These virus vehicles are known as viral vectors and are a crucial part of gene therapy.

Gene therapy has been used with significant success in clinical trials and it is expected that this will eventually be the most effective, and probably the least painful way, of curing cancer.

CONCLUSION
The cause of all cancers ultimately lies in a series of mutations that occurs in key genes responsible for the lifecycle of a cell, and its ability to repair its own blueprint. Given the horror that cancer brings to the lives of humans, a great deal of attention is being paid to better and permanent ways of curing the disease. Gene therapy offers one direct, effective and promising treatment of this disease.