Saturday, July 26, 2008

BRCA mutations in breast cancer

Genetic testing for BRCA1 and BRCA2 mutations can provide important information for women who are concerned about their breast and ovarian cancer risks and need to make relevant prevention and medical management decisions.

To date, lifetime risks of breast cancer in individual BRCA1/2 mutation carriers have been challenging to apply in clinical decision making. Published risk estimates vary significantly and are very dependent on the characteristics of the population under study. You can read more about in this article (free PDF download).

Another study interpreted validated functional data from the transactivation activity of BRCA1 in combination with analysis of protein modelling based on the structure of BRCA1 BRCT domains. With additional clinical and structural evidence, they were able to classify all missense variants in the BRCA1 COOH-terminal region. These results brought functional assays for BRCA1 closer to clinical applicability.

Cancer risks in a population-based study of BRCA1/2 mutation carriers have been recently estimated, but the numbers are still in their infancy and may be influenced by different risk factors. It is likely that there is broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations and ethnicity may also confer differences in risks associated with BRCA mutations.

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Sunday, July 20, 2008

How is cancer formed?

All cancers start with mutations in one single cell. The mutations are located in the cell's DNA and may be inherited, although less than 10% of all cancer mutations are inherited. Usually, the mutation arises as a result of environmental factors.

The DNA mutation may be a single nucleotide change, or a deletion or duplication of the DNA sequence. A change in the genetic sequence can then lead to the production of a mutant protein.

The structure of part of a DNA double helixImage via WikipediaIn rare cases such as chronic myeloid leukemia (CML) or gastrointestinal stromal tumours (GIST) one mutation is enough, but in most cancers, it is usually an accumulation of mutations that irreversibly transforms a normal cell into a cancerous one.  As we age, we accumulate more and more mutations as we are exposed to environmental carcinogens and this explains why cancer incidence increases with age.

These mutations can disrupt the cell’s life cycle of growth, proliferation, and death. This leads to the accumulation of more “rogue” cancer cells and the development of a tumour mass.

Normal cells have a natural lifespan and eventually die, a process known as apoptosis, or programmed cell death. They are replaced by new cells and so the process is repeated. Cancer cells do not respond to the signals that regulate cell growth and division. Thus these cells grow unchecked, producing more and more cancer cells.

A cell may die because it is damaged or old. Once a cell is signaled to die, the cell makes proteases and enzymes that degrade its components. The DNA in the nucleus is fragmented, the cell membrane shrinks, and, eventually, a neighboring cell engulfs the cellular remains.

To grow beyond a certain size, tumours must transport nutrients in and excrete wastes. The cancer cells that make up a tumour attract blood vessels to grow into the tumour mass, a process known as angiogenesis. The blood vessels then nourish the tumour just like any organ in the body; because the tumour is made of your own cells, the body does not recognise it as foreign, in the way it would a virus or bacteria.

The age of a cell and its ability to divide is related to structures or telomeres. The telomeres are specialised sequences at the ends of each chromosome and they prevent end-to-end fusion of chromosomes. These telomeres protect the ends of chromosomal DNA from accidents.

As normal cells go through cycles of growth and division, their telomeric DNA gets shorter and shorter and shorter and ultimately so short it can no longer protect the ends of chromosomal DNA. Eventually, the telomeres start fusing, chromosomes start fusing in those cells, and those cells die.

Cancer cells must avoid this problem because they want to grow indefinitely. Instead of dying, they turn on an enzyme called telomerase that is normally expressed only early in embryologic development and in a small number of so-called stem cells in the body.

The telomerase enzyme is able to extend the telomeres, making them longer and longer thereby enabling the cancer cell to go through many cycles of growth and division without worrying about the imminent collapse of its telomeres. The telomerase ensures the telomeres stay very long and essentially protects them from harm.

Most of the deaths from cancer (90%) are due to cancer cells spreading and establishing colonies in other parts of the body, a process known as metastasis. To do that, inactivation of a whole series of controls that normally confines a cell to the site and the tissue where it normally grows occurs, enabling the cancer cells to move to other sites in the body.

Another interesting thing about cancer cells is that they are often different in shape and size to normal cells, and they no longer respond to signals that control normal cellular functions. Our body's immune response is constantly searching for these emerging pre-cancers or pre-tumour cells.  Successful cancers have to avoid detection long enough to grow into a tumour.

The body has two adaptive immune responses, enabling it to adapt to changes in cells in our body, whether they be by infection or other changes, such as cancer. One of these responses is making antibodies produced by B cells, which bind and direct the elimination of those cells. The other response is the T cell immune response where T cells actually kill cells that are changed in the body. The body is in constant surveillance of the cells in our body, so that emerging pre-cancers or pre-tumour cells could be eliminated by the immune response.

So how does cancer arise in the first place?

Well, a cell carries the entire set of genetic instructions, the genome, that makes an entire organism.  The instructions are encoded in DNA as genes and packaged as chromosomes in the nucleus.  DNA is not indestructable and is subject to damage and mutations.  Crucial changes in the genome affect the chance and rate of the development of a cancer cell.

A defining characteristic of cancer cells is that those cells have changes in the nature of the genes that are compared to the normal cells. These changes can be either mutations, or they can be deletion of whole genes, or they can be the addition of extra copies of genes. This is called genomic instability.

The changes in our genes that accumulate in cancer cells can be acquired by a number of mechanisms. One is that during the process of copying the genetic information, mistakes can be made. After the genetic information is copied, it has to be segregated to the two daughter cells. During that segregation process, it is often that the numbers of genes get distributed unevenly to those daughter cells. Cancer cells also have an inability to repair alterations in the DNA.

Overall, you need to acquire multiple changes in the genes or multiple genes, to get cancer, perhaps 5-7 genes on average. Those changes accumulate over a period of time. Some of those changes accelerate the rate of accumulation. A person might have inherited one gene change, for example, and others develop as we age. Developing these mutational changes will weaken the DNA and increase the risk of cancer developing.

Sources (downloadable PDF):

Hallmark of Cancer

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Monday, July 14, 2008

Colorectal cancer screenings still low

Colorectal cancer screening tests have been proven to reduce colorectal cancer mortality, but a recent National Health study showed that only about half of U.S. men and women 50 and older receive the recommended tests.Endoscopic image of colon cancer identified in...Image via Wikipedia: endocopic screening of colon cancer
The Centers for Disease Control and Prevention conducted a National Health Interview Survey and found only 50 percent of men and women 50 and older had received screening in 2005. Although this was an improvement over the 43 percent of screened individuals reported in 2000, it is still suboptimal.

Colorectal cancer is one of the leading cancer killers in the United States, behind only lung cancer. Screening has been shown to significantly reduce mortality from colorectal cancer, but a lot of people are still not getting screened.

A major problem could be insurance coverage in the US. Among people without health insurance, the rate of colorectal cancer screening was 24.1 percent compared to over 50 percent of insured Americans, depending on the type of insurance. Among patients without a usual source of health care, the screening rate was 24.7 percent compared to 51.9 percent of patients with a usual source of health care.

The increase in colorectal cancer screening rates observed from 2000 to 2005 may have been due in part to increased media coverage of the importance of colonoscopy as a measure to prevent cancer and detect it early. Other factors for the increase include the fact that Medicare expanded its coverage for colonoscopy screenings to a wider range of patients in 2001.
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Tuesday, July 8, 2008

FDA approves HER2 test for breast cancer

A genetic test to determine whether a breast cancer patient is likely to respond to treatment with the drug Herceptin (trastuzumab) has been approved by the U.S. Food and Drug Administration.

The SPOT-Light HER2 CISH kit helps calculate how many copies of the HER2 gene, which regulates the growth of cancer cells, are in tumour tissue. A healthy breast cell should have two copies of the HER2 gene, but patients with breast cancer may have many more. Since the gene signals cells when to grow, divide and make repairs, too many copies may cause cells to grow and divide too rapidly.

Herceptin targets HER2 protein, helping stop the growth of such cancer cells in breast cancer patients overproducing that particular protein. HER2 is overexpressed in about 30% of breast cancer cases.

This test can potential provide health care professionals with additional insight on treatment decisions for patients with breast cancer when used with other clinical information and laboratory tests.

The SPOT-Light test counts HER2 genes through a chemically stained sample of removed tumor observed under a standard microscope. Previous tests required more expensive and complex fluorescent microscopes. The SPOT-Light also allows labs to store the tissue for later reference, a feature not possible with previously available tests.

Wednesday, July 2, 2008

What's stopping EGFR inhibitors from being more effective?

Response rates with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been low. However, a recent study may have shed some light by revealing a kinase-independent function of EGFR in maintaining cell survival.

Mediating RNA interference in cultured mammali...Image via Wikipedia
Using prostate, breast and colon cancer cells, it was demonstrated that small interfering RNA (siRNA)-mediated knockdown of EGFR, but not inhibition of EGFR kinase activity, leads to autophagic cell death. Autophagy can occur when external energy sources are low or unobtainable and, although glucose levels remained constant in cells treated with kinase inhibitors, they were decreased by around 50% in cells transfected with EGFR siRNA.

The study found that EGFR–SGLT1 may confer a survival advantage to cancer cells by maintaining a basal level of intracellular glucose and preventing autophagy. This may help to explain previous data indicating that inhibition of EGFR kinase activity is not sufficient to induce cell death, or to negate all of the functions of EGFR.

Targeting both kinase-dependent and kinase-independent functions of EGFR may be necessary for more successful therapy in the future.


Cancer Cell
(free download)
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