Cancer Genetic

Definition:

cancer (malignant tumor) is defined as the abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells (in any tissue or organ of the body), which have the tendency to spread & grow in other parts of the body.

Causes & Prevention of Cancer :

Most of the human cancers are caused by certain:
1. chemical.
2.physical
3.biological agents.

The process by which normal cell convert to cancer cell is called malignant transformation.
collectively known as carcinogens.

Role of Heredity:

Familial retinoblastoma, familial adenomatous polyposis, multiple endocrine neoplasia syndrome and hereditary breast & ovarian cancer syndromes.
Members of these families have one or more activated oncogenes in their inherited genome. Therefore fewer additional mutations are required in these persons for the cancer to development.
In most cancers genetic mutations are not inherited and arise in a somatic cells during adulthood as a result of exposure to environmental carcinogens.

In mutations (inherited and acquired) commonly involved three types:
1.Tumor suppressor genes
2.Oncogenes
3.genes involved in DNA repair mechanism.

Tumor suppressor genes:

Retinoblastoma 13 (13q14)

Rb is a tumor suppressor gene. Common in children. Both eyes can be affected. Inherited as an autosomal dominant trait. The gene is located in the proximal long arm of chromosome 13(13q14), where the functional protein of this gene is not absent.

p53

Mutation of the tumor suppressor gene p53 which is located in 17q causes cancer of:
1.Colon cancer
2.Lung cancer
3.Breast cancer
4.Brain cancer
5.Hepatocellular carcinoma
6.Chronic myeloid leukemia in blast crisis.

The most important tumour suppressor genes known so far is:
p53 gene that suppresses uncontrolled proliferation of cells as well as triggers apoptosis (Mutations in p53 gene are seen in about 50 per cent cases of human cancers.
Rb gene (associated with Retinoblastoma and osteo-sarcoma).

Ret gene (associated with Endocrine cancer);
WT-1 (associated with Wilm's tumour);
NF-1 (associated with Neurofibromatosis type-1);
NF-2 (associated with Neurofibromatosis type-2);
APC and DCC (associated with the colon cancer).

Oncogenes:

Cellular oncogenes (c-onc) can be activated to cause cancer as a result of chromosomal rearrangement, e.g. in CML where Ph chromosome can be seen in the malignant bone marrow cells. As a result of this reciprocal translocation of the ABL gene to BCR gene, as a result a novel protein is produced which is said to be the cause of malignancy.


Genes involved in DNA repair mechanisms:

DNA repair mechanisms exist to correct DNA damage due to environmental; mutagens and accidental base misincorporation at the time of DNA replication. Inherited defects in either system can lead to cancer. Example is xerodermal pigmentosum which is an autosomal recessive disorder in DNA repair mechanism after exposure to ultraviolet light.

Cloning, Polymerase Chain Reaction (PCR)

http://www.dnalc.org/ddnalc/resources/animations.html

Cell cycle

The cell cycle, is the series of events that take place in a eukaryotic cell leading to its replication.

The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase (collectively known as interphase) and M phaseActivation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

1- M phase

The relatively brief M phase consists of nuclear division (karyokinesis) and cytoplasmic division (cytokinesis). In plants and algae, cytokinesis is accompanied by the formation of a new cell wall. The M phase has been broken down into several distinct phases, sequentially known as prophase, prometaphase, metaphase, anaphase and telophase leading to cytokinesis.

2- Interphase

After M phase, the daughter cells each begin interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

a. G1 phase
The first phase within interphase, from the end of the previous M phase till the beginning of DNA synthesis is called G1 (G indicating gap or growth). During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.

b. S phase
The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled.

c. G2 phase
The cell then enters the G2phase, which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.

Referances:-

homepage.mac.com/enognog/checkpoint.htm

http://en.wikipedia.org/wiki/Cell_cycle

Breast cancer

For those who are working in breast cancer project, go to this web site:
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=genetics&rid=cmed6.section.30813#30819

Mendel’s Principles of Inheritance

Inherited traits are transmitted by genes which occur in alternate forms called alleles

• Principle of Dominance - when 2 forms of the same gene are present the dominant allele is expressed
• Principle of Segregation - in meiosis two alleles separate so that each gamete receives only one form of the gene
• Principle of Independent Assortment - each trait is inherited independent of other traits (chance)
  

Mendel laws

Gregor Mendel studied the garden pea height, flower color, seed coat color, and seed shape over many generations. He chose 1 or 2 traits per generation to watch acrossed plants with different traits and learned that offspring usually had dominate trait.

No matter what trait he selected for the second generation would show traits at a ratio of 3 to 1 (3 dominat

Mendel found that the inheritance of traits was not due to blending but instead specific traits or units of inheritance were passed from generation to generation we call those units of inheritance genes.

Non-genetic sex-determination systems

Many other sex-determination systems exist. In some species of reptiles, including alligators, some turtles, and the tuatara, sex is determined by the temperature at which the egg is incubated. Other species, such as some snails, practice sex change: adults start out male, then become female. In tropical clown fish, the dominant individual in a group becomes female while the other ones are male.
Some species have no sex-determination system. Earthworms and some snails hermaphrodites; a few species of lizard, fish, and insect are all female and reproduce by parthenogenesis.
In some arthropods, sex is determined by infection, as when Bacteria of the genus Wolbachia alter their sexuality; some species consist entirely of ZZ individuals, with sex determined by the presence of Wolbachia.

Reference:

http://en.wikipedia.org/wiki/Sex-determination_system

Sex-determination system

Most sexual organisms have two sexes. Sex determination in animals, is often accompanied by chromosomal differences. In other cases, sex is determined by environmental variables (such as temperature).
XX/XY sex chromosomes
In the XY sex-determination system, females have two of the same kind of sex chromosome (XX), while males have two distinct sex chromosomes (XY). Some species (including humans) have a gene SRY on the Y chromosome that determines maleness; others (such as the fruit fly) use the presence of two X chromosomes to determine femaleness.
ZW sex chromosomes
The ZW sex-determination system is found in birds and some insects and other organisms. The ZW sex-determination system is reversed compared to the XY system: females have two different kinds of chromosomes (ZW), and males have two of the same kind of chromosomes (ZZ).
Haplodiploidy
Haplodiploidy is found in insects belonging to Hymenoptera, such as ants and bees. Unfertilized eggs develop into haploid individuals, which are the males, while diploid individuals are generally female.

Referance:

http://en.wikipedia.org/wiki/Sex-determination_system

Mutation

staff.jccc.net/.../mutations/mutation.html

Mitochondrial Inheritance

Traditional inheritance views the nucleus as the central repository of genetic information and meiosis as the principal determinant of the segregation of traits in families. However, the existence of another genome, the mitochondrial genome, in all cells introduces another twist of biology leading to nontraditional inheritance.
Mitochondria are organelles that provide much of the energy cells use for the work they do. Most biologists now believe that these structures evolved from microorganisms that established symbiotic relationships with the ancestors of animal cells very early in the history of life on this planet. Selection for metabolic advantages gained through symbiosis explains how it has come to be that mitochondria contain their own DNA that codes for 13 of their proteins along with ribosomal and transfer RNA that specifically help express mitochondrial series.
As with any form of DNA, mitochondrial DNA (mtDNA) sequences are susceptible to mutation In fact, there is evidence that mitochondrial sequences may mutate at rates 3 to 5 times greater than nuclear sequences. The consequences of mitochondrial mutations, however, may be very different from those that occur in nuclear DNA. First, each cell contains about 100,000 mitochondria, each of which has 2 to 10 copies of its genome. The effect a mutation in mtDNA will have on a cell's function will therefore depend on the number of mutant organelles in a cell compared to the number of normal, or "wild type", present. In this respect, each cell is analogous to an organism in which somatic mutation can produce mosaicism (see above). Here the mixture of genotypes is termed heteroplasmy.
When cells divide, their mitochondria independently replicate and then distribute randomly into daughter cells. This leads to variable phenotypes within and among tissues ranging from non-viable cells (hence death of tissue), to energy generation dysfunction, to subthreshold changes (i.e. "silent" mutations) that do not affect overall cell function. What this means is that mitochondrial mutations may be variable in their clinical presentation, depending on their timing and prevalence.
The human mitochondrial genome, which contains 16,569 nucleotide pairs, has been completely mapped and sequenced. Interestingly, it uses a slightly different genetic code (sequence of nucleotide bases that specifies an amino acid) than that used by nuclear genes. Several mutations, both single base changes (or point mutations) and structural changes (deletions) have been described which produce clinical disorders.
A number of specific disorders have been described where mitochondrial mutations are either inherited or occur early enough in development to dominate most cells. These disorders characteristically affect muscle and nervous tissue, particularly the optic tracks. Among these conditions are Leber's Hereditary Optic Neuropathv (LHON), which usually presents with onset of symptoms after puberty; Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO), which both result in paralysis of external, but not internal, eye muscles; myoclonic epilepsy with ragged red fibers (MERRF), which presents at various ages; and mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS), which evolves during infancy.
Mitochondria are passed from generation to generation only through maternal egg cells where they are abundant. Those present in sperm are concentrated in the tail and do not contribute to the compliment of the fertilized zygote. Molecular genetic tracking of polymorphic or variable regions through families and even across the millenia of human evolution confirm maternal inheritance of mitochondrial DNA.
Maternal inheritance looks very much like mendelian autosomal dominant inheritance with two important exceptions. First, all maternal offspring are usually affected. Even in highly penetrant dominant disorders only 50% of offspring are expected to be affected. Secondly, mitochondrially-inherited traits are never passed through a male. Males are as likely to be affected as females, but their offspring are not at risk.
Although mitochondrial inheritance looks easy to identify in a pedigree like the one in Figure 3, it must be remembered that phenotypic variability is a hallmark for these disorders, especially in cases where there is heteroplasmy. Therefore, a family history where some individuals present with strokes, others with muscle weakness, and still others with psychiatric or ophthalmologic complaints might not be immediately recognizable as one expressing a single mitochondrial mutation. This is an important point because while the human mitochondrial genome has been sequenced, a complete spectrum of its viable mutations is far from assembled.
With frequencies approaching 1:50,000 LHON and other mitochondrial disorders would appear to be rare. It is likely, however, that since mitochondrial mutations are frequent, there are many new phenotypes yet to be discovered. In aggregate, clinically significant mutations may be eventually shown to be common. Indeed, it has been proposed that accumulating mitochondrial mutations contribute significantly to aging.

A final point about mitochondrial inheritance that needs to be stressed is that most of the proteins contributing to mitochondrial structure and function are encoded by nuclear genes and their mutations therefore segregate as mendelian traits. Thus, a clear distinction needs to be kept between mitochondrial disorders, most of which are inherited as recessive traits, and mitochondrial inheritance, which is concerned only with those mutations occurring in mitochondrial DNA. Disorders of mitochondrial function inherited by either classical mendelian or mitochondrial inheritance may have overlapping features.

Referance:

http://mostgene.org/gd/gdvol10b.htm

Multifactorial Inheritance

The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits that are due to the combined effects of multiple genes are polygenic (many genes). When environmental factors also play a role in the development of a trait, the term multifactorial is used to refer to the additive effects of many genetic and environmental factors. Expression of these traits may follow a normal, or "bell-shaped," curve. Examples of multifactorial traits include cleft lip and palate, congenital hip dislocation, schizophrenia, diabetes and neural tube defects such as spina bifida.
Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable as with single gene disorders. The chance of recurrence is also less than the risk for single gene disorders. The degree of risk of a multifactorial disorder occurring in relatives is related to the number of genes they share in common with the affected individual. The closer the degree of relationship, the more genes in common. The degree of risk also increases with the degree of severity of the disorder.
Although multifactorial conditions run in families, the risk is generally less than the 25% or 50% seen in Mendelian conditions. Identical twins who are exactly alike genetically, do not always have the same condition when inheritance is multifactorial. This indicates that there are nongenetic factors that also play a role in the expression of multifactorial traits. For instance, the risk of coronary heart disease increases with smoking or obesity. The risk of emphysema in individuals with alpha-1-antitrypsin deficiency increases greatly with smoking. Maternal ingestion of valproic acid, a medication for seizures, increases the risk of spina bifida. Maternal alcohol abuse or uncontrolled diabetes increases the risk of having a child with a congenital heart defect.
Empiric risks are used to predict the recurrence of a multifactorial disorder. This is a risk that is based on epidemiologic and population studies and on mathematical models.
For many multifactorial or polygenic disorders, parents who have had one affected child have a 3-5% risk in future pregnancies of having another affected child. Affected individuals have a similar risk in future progeny. More distant relatives, however, have a lower recurrence risk.
In conditions inherited in a multifactorial fashion, the risk may depend on the sex of the affected individual. For example, pyloric stenosis is a multifactorial disorder that occurs five times more frequently in males than in females. If a female child has pyloric stenosis, her risk and her parent's risk of having another affected child would be higher than if a male child has pyloric stenosis. Occurrence in a female suggests a greater genetic liability; presumably more abnormal genes are segregating in the family.

Referance:
http://www.usd.edu/med/som/genetics/curriculum/1GMULTI5.htm

Single gene disorders

Inheritance of a single gene disorder:
http://www.merck.com/mmhe/sec01/ch002/ch002c.html
Single gene disorder and disabilities:
http://www.cdc.gov/ncbddd/single_gene/