Abnormal Genes and cancer
PKGhatak,MD
A Gene is a small part of a Chromosome and contains code for a specific cell function. At times, more than one gene can influence the same cell function. Chemically, the genes are Deoxyribose Nucleic Acids (DNA). There are four different nucleic acids - they are known as A, T, G & C. AT and GC always appear in pairs and are called Base Pairs. The three of these base pairs make a word of the coded instruction. A gene, on average, contains 17,000 Base Pairs and may contain as many as several million. Human chromosomes carry 3.2 billion base pairs and only 25,000 genes are known to code proteins. We have 23 pairs of chromosomes and we inherit one strand of the chromosome from each parent.
Believe it or not, every cell of our body has a defined time of existence: there is a time to be born, a time to achieve maturity, time to die and be replaced by a new cell. Different cell lines have different lifespans e.g., white blood cells live 5 days; red blood cells live 120 days and so on. Deaths of cells are programmed into the genes. If and when programmed cell death fails in one cell, this cell continues to live and multiply. This is the beginning of tumor growth and ultimately ends up in cancer formation.
In an individual, the cells are dividing regularly throughout life. During cell division, the chromosomes duplicate themselves and then separate and move to new cells. This is the critical time when things can go wrong. Errors may appear in the spelling of coded words (Mutation), words may be dropped (Deletion), or attached to a different place (Translocation). The cells of an older person have divided many more times than a younger one and the elderly population is at higher risk of acquiring abnormal genes (Somatic Mutation). It explains the reason for the increased cancer rate in old age. Increasing concentrations of cancer causing chemicals in the environment, food additives, hormones, pesticides, cigarettes, ultraviolet rays of the sun, microwaves, x-rays, and virus infections, etc. either individually or collectively are constantly influencing the normal cell division at this critical juncture. Any minor or major dislocation of this process will lead to somatic mutations. Derailed repair of DNA is an additional cause of mutation.
To guard against these mishaps and to find defective genes, other genes are endowed with surveillance functions and are called Tumor- Suppressor Genes. However, there is no guarantee that mutation will not happen to these very tumor-suppressor genes. And when it happens, it is transmitted to the next generation of children.
A class of genes has the role of a caretaker function called Caretaker Genes. It looks after the entire population of chromosomes. The deficiency of these genes increases the rate of mutation in all genes. Another class of genes, called the Gatekeeper Gene, restrains the growth of individual cells and promotes cell differentiation.
A specific group of cells in our body is constantly keeping a vigil for such mutant cells (Surveillance cells). Once they detect a mutant cell they mark it with a protein, and Killer cells then move in and promptly remove these mutant cells from the body.
Somatic mutation or inherited defective gene/chromosome is the immediate cause of cancer. The development of cancer, however, is a failed multi-step process. A mutant cell has a growth advantage over its neighbors but it must escape from the surveillance cells before it can divide again. When mutant cells have gone through 5 to 10 generations of cumulative mutations then mutant cells have a chance to establish as a Malignant Phenotype (potential to cause cancer in this individual).
Oncogenes.
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These are cancer causing genes. They were first discovered in certain retrovirus induced cancer in chickens. Similar genes (homologous genes) are also present in human cells. But they are very tightly controlled by tumor-suppressors and caretaker genes. To escape the scrutiny of tumor-suppressed-genes and caretaker-genes the oncogenes have to mutate first. There are 3 such mechanisms.
1. Translocation: A piece of a chromosome containing specific genes breaks away from its normal location and attaches to a different chromosome e.g. In chronic myelogenous leukemia. a piece of chromosome 9 is grafted to chromosome 22. This abnormality is better known as the Philadelphia chromosome of CML.
2. DNA Amplification: A certain part of base pairs of a gene appears repeatedly over and over again. This is often seen in Sarcoma and aggressive breast cancer.
3. Point mutation: One base pair mutation appears in several gene locations; often present in pancreatic cancer and colon cancer.
When one copy of mutated oncogenes overrides the effect of its other normal copy and the disease is manifested in the person carrying the mutated genes. This mode of inheritance is known as Autosomal Dominant Inheritance. When one copy of the mutated gene does not cause cancer but needs both copies of genes to be mutated then this type of inheritance is called the Autosomal Recessive Mode of transmission. One mutated copy is usually inherited; the other may be due to somatic mutation.
Hereditary cancer.
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Every normal person has many mutated genes and these mutations are generally harmless. Somatic mutations of genes, for the most part, are not transmitted to the next generation. The hereditary cause of cancer is not more than 5 to 10 % of all cancers. Only about 100 hereditary cancers are known. We read in the newspaper about the finding of a new gene for particular cancer. It does not mean that the gene itself is the cause of cancer. The abnormal gene should be considered as one of the risk factors.
Genes are named according to their functions or association with a specific disease.
To specify the location of genetic mutations on chromosomes, numbers and letters are used like astronomers assign letters and numbers to designate points of light in the dark night sky. To give an example: a 11q 13.1 number signifies chromosome # 11, q is the long arm of this chromosome and 13.1 is the band location. Bands are detected when chromosomes are stained with dyes for microscopic examination. (p stands for the short arm of chromosomes and q for the long arm).
Here are some of the well known hereditary cancers: -
1. Hereditary Adenomatous Polyposis Colon Cancer: The disease is due to APC gene mutation, located on 5q21, a dominant mode of inheritance. Patients develop multiple colon polyps, some or many of them eventually turn cancerous.
2. Hereditary Non-adenomatous Colon Cancer: Also known as Lynch syndrome due to MHS2, MHL1, PMS2 gene mutations, located on any of these positions – 3p21.3, 7p12.2p16, a dominant mode of inheritance.
3. Multiple Endocrine Neoplasia 2a - MEN 2a: Due to RET gene mutation, located on 10q11.2. Patients have medullary thyroid cancer, pheochromocytoma and parathyroid overactivity.
4. Hereditary Breast/ Ovarian Cancer 1: Due to oncogene mutation of BRCA1gene, located on 17q21; dominant mode of inheritance. Carrier of BRCA1gene has an 80% risk of breast cancer and 60% risk of ovarian cancer; and has some increased risk of colon, pancreatic, and uterine cancers.
5. Hereditary Breast/Ovarian Cancer 2: Due to oncogene mutation of the BRCA2 gene, located on 13q12.3, a dominant mode of inheritance. Female carriers in addition to the risk of breast and ovarian cancers also are at risk of cancer of the colon, stomach, gallbladder, bile duct, and melanoma. Male members have a risk of breast, colon, and prostate cancers.
5. Hereditary Prostate Cancer: Due to mutation of oncogene HPC1, location 1q24-25, a dominant mode of inheritance. Carriers of this mutation develop cancer in age 30s - 40s, this cancer is aggressive in nature.
6. Cancers due to Oncogene Translocation:
Cancers of blood cell lines and lymphatic tissues are strongly associated with such defects. Examples are- Chronic myelogenous leukemia, Mantle cell lymphoma, Follicular lymphoma, Ewing’s tumor, T-cell leukemia, Burkett’s lymphoma.
Cells carry out functions according to instructions coded in the genes like applications run on computer software programs. When software programs are corrupted by hackers or computer viruses, they create havoc. Similar processes are at work in cells having cancer enhancing mutations.
Every day scientists and researchers are adding more knowledge in genetics and cancer research, and progress in recent years has been astounding. Your interest in this subject will encourage more research.
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