Changes in the Eukaryotic Genome

By: Sergio Aguilar

What is cancer?

• Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems.

How can cancer form?• Cancer may form by some deffects that occur in the genes.• Cancer cells are frequently found to contain chromosomes that have

broken and rejoined incorrectly, translocating fragments from one chromosome to another.

• Many cancer-causing mutations result from environmental influences, such as chemical carcinogenes, X-rays, and certain viruses.

• Some viruses as the Epstein-Barr virus, a herpes virus that causes infectious mononucleosis, has been linked to several types of cancer, notably Burkitt’s lymphoma.Papiloma viruses are associated with cancer of the cervix.The HTLV-1 causes a type of adult leukemia.

Oncogenes and Proto-Oncogenes• Research on tumor viruses led to the discovery of cancer-causing genes

called oncogenes.• Normal cellular genes, called proto-oncogenes, code for proteins that

stimulate normal cell growth and division.• Essential function genes in normal cells become cancer causing genes!

How?Well, an oncogene arises from a genetic change that leads to an increase either in the amount of the proto-oncogene’s protein product or in the instrinsic activity of each protein molecule.

• 3 main categories of how proto-oncogenes turn into oncogenes:Movement of DNA within the genome, amplification of a proto-oncogene, and point mutations in a control element or in the proto-oncogene itself.

Tumor-Suppressor Genes

• Genes whose products normally promote cell division, cells contain genes whose normal products inhibit cell division and are called tumor-suppressor genes because the proteins they encode help prevent uncontrolled cell growth.

• Normally they repair damaged DNA, a function that prevents the cell from accumulating cancer-causing mutations. In other words, this gene helps the cells to not develop cancer.

Cell-Signaling Pathways

• The Ras protein, encoded by the ras gene, is a G protein that relays a signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases.

• Mutations in ras occur in about 30% of human cancers; mutations in p53 in more than 50%.

• Let’s see this pathways!!

Cancer Development• The longer we live, the more likely we are to develop cancer!• The more mutations you have in your life, the higher are the chances of

getting cancer.• The best understood type of human cancer is colorectal cancer. About

135,000 new cases are researched each year, and the disease causes 60,000 deaths per year.

• When the colorectal cancer is devloping in the colon, it all starts by the loss of tumor-suppreser gene. A small benign is started to form in the colon wall, then the activation of oncogene and loss of tumor-suppressor gets the benign to grow. Additional mutations may form and the loss of tumor-suppressor gene p53 forms a Malignant tumor (carcinoma).

• About a half dozen changes must occur at the DNA level for a cell to become fully cancerous.

• http://www.youtube.com/watch?v=WhiDEBgH7zc

Inherited Predisposition to Cancer• Multiple genetic changes are required to produce a cancer cell.• An individual inheriting an oncogene or a mutant allele of a tumor-suppressor

gene is one step closer of having cancer.• About 15% of colorectal cancer involve inherited mutations and many of these

affect the tumor-suppressor gene called adenomatous polyposis coli (APC). This gene has multiple functions as regulating the cell migration and adhesion, and even in patients with no family history of the disease, the APC gene is mutated in 60% of colorectal cancers.

• There is evidence of a strong inherited predisposition in 5-10% of patients with breast cancer, and this is the second most common cancer in the US, striking over 180,000 women (some men) and annually killing 40,000 each year. BRCA1 or BRCA2 have been found in at least half of inherited breast cancers.

• A women who inherits one mutant BRCA1 allele has a 60% probability of developing breast cancer.

Noncoding DNA Sequences

• The small amount of noncoding DNA consists mainly of regulatory sequences, such as promoters.

• Humans have 10,000 times as much noncoding DNA as prokaryotes. Some of the noncoding DNA in multicellular eukaryotes is present as introns within genes.

• 15% of the DNA genome includes some unique noncoding DNA, such as gene fragments and mutated genes that are non-functional.

Transposable Elements• Eukaryotic transposable elements are of two types:

Transposons – which move within a genome by means of a DNA intermediate.Retrotransposons – which move by means of an RNA intermediate.

• Transposons can move by a “cut and paste” mechanism, which removes the element from the original site, or bya “copy and paste” mechanism, which leaves a copy behind.

• Retrotransposons always leave a copy at the original site during transposition, since they are initially transcribed into an RNA intermediate.

• Transposable elements and related sequences make up 20-25% of most mammalian genomes and even higher percentages in amphibians and many plants.

Genome Evolution• Transposable elements are a large fraction of some eukaryotic genomes and

these elements can contribute to the evolution of the genome in several ways:They can promote recombination, disrupt cellular genes or control elements, and carry entire genes or individual exons to new locations.

• The movement of transposable elements around the genome can have several direct consequences, for instance, if a transposable element “jumps” into the middle of a coding sequence of a protein-coding gene, it prevents the normal functioning of the interrupted gene.

• Transposable elements can lead to new coding sequences, this leads that an Alu element may hop into introns in a way that creates a weak alternative splice site in the RNA transcipt. During transcript, the regular splice sites are used more often, so that the original protein is made. On occasion, splicing occurs at the new weak site, with the reasult that some of tha Alu element ends up in the mRNA, coding for a new portion of the protein.

• http://www.youtube.com/watch?v=gngsL9FRpqc