Cancer is a disease caused by uncontrolled growth of abnormal cells within our body. As a whole, cancer has a major impact on the health of our society. According to the National Cancer Society, it is estimated that 1.4 million new cases of cancer will be diagnosed and more than 560,000 people will die of cancer in American in 2008. (Cancer Facts and Figures, 2008. American Cancer Society. 2008. www.cancer.org)
All cancers are genetic in nature because the genetic makeup of a cancer cell is changed, causing them to grow uncontrollably and spread around a person’s body. The fact that genetic changes within cells cause cancer, not all cancers are inherited. Many times the genetic changes, or mutations, that occur in cancer cells happen spontaneously in a particular cell type and are not passed from generation to generation.
However, some cancers can be traced to a specific genetic mutation that is passed through a family increasing the risk for cause cancers to develop. We call these inherited cancer syndromes. The mutations causing these syndromes do not directly cause a cancer to develop but rather give the patient a predisposition or higher risk for developing cancer. This is because the mutations are found in genes that would normally work to correct mutations and suppress cancer development.
Only about 5% of all colon cancers can be linked to a familial inherited mutation. The rest are caused by spontaneous mutations occurring in colon cells or other inherited genes that have not yet been discovered.
There are two different inherited colon cancer syndromes. One is called Familial Adenomatous Polyposis (FAP) and is characterized by multitudes of polyps found in the colon of the patient. These polyps are the groups of cells which eventually become cancerous if not removed.
The other syndrome is called Hereditary Non-polyposis Colon Cancer (HNPCC) and also can be called Lynch Syndrome. Patients with this syndrome have some polyps in their colon but far fewer than people with FAP. Families with these syndromes also can have a higher risk of developing some other cancers but the greatest risk is with colon cancer. All colon cancers begin as a benign polyp but mutations in the polyp cells can cause them to become cancerous.
People with a family history of colon cancer are often referred to a genetic counselor who will look in depth at their family history and possibly suggest genetic testing to see if they carry a mutation associated with one of these two syndromes.
In this particular experiment we will be looking at a family that has a known history of HNPCC. HNPCC is caused by a mutation on one of several genes called “mismatch repair genes.” These genes code for proteins directly involved in the mismatch repair pathway. When cells undergo division and the DNA is replicated, sometimes an error can occur and the wrong DNA base is inserted which is called a “mismatch.” Usually the mismatch is the insertion of a uracil base instead of a thymine base. The proteins in the mismatch repair pathway would normally correct these mismatches in the DNA. However, if a person’s mismatch repair system is not working properly in that cell these mismatch mutations will not be corrected and that can lead to uncontrolled cell growth and cancer. As of now, there are three known genes that correlate to Lynch Syndrome (HNPCC): MSH2 and MSH6 which are on chromosome 2 and MLH1 which is on chromosome 3. These genes are also called “tumor-suppressor” genes meaning that they normally function to suppress mutations which can cause cancer. Suppose the tumor suppressor gene acts like is a stop light and stops a cell if it finds a error in the DNA. If the tumor-suppressor mismatch repair gene is mutated, it acts like a constant green light and will allow cells with damaged DNA to survive and reproduce (see illustration below.)
Breast and Ovarian Cancer
Another type of a hereditary cancer syndrome is the Hereditary Breast and Ovarian Cancer (HBOC) syndrome. This syndrome is caused by a mutation in one of several genes that when mutated can indirectly lead to cancer formation. There are two known genes relating to this syndrome: BRCA1 and BRCA2. Other genes that increase susceptibility to these cancers are still yet to be discovered. These genes are classified as “caretaker genes.” Caretaker genes are involved in several cellular functions including DNA repair. Mutations in these caretaker genes lead to DNA instability. This instability can lead to higher than normal mutation rates in the cell leading to uncontrolled cell growth and cancer.
It is important to note that having Lynch Syndrome (HNPCC) or HBOC Syndrome does not mean that you have cancer. These are syndromes that dramatically increases your odds of developing cancer at some point in your life. For example, if a person with Lynch Syndrome (HNPCC) did not screen regularly he would have an 80% chance of developing colon cancer in his life. That is a very large risk, and is why those people with known HNPCC have regular colonoscopies (colon screenings) to check for polyps and remove any that are found before they can become cancerous.
All of these cancer syndromes are inherited in an autosomal dominant manner. However, on a molecular level, it is actually a recessive trait because mutations have to occur on both copies of the gene for cancer to develop. The reason for this discrepancy is that through a person’s lifetime he will accumulate a certain amount of mutations in his DNA. Because of this, the chance that a person will accumulate a mutation in one of his copies of the above mentioned genes is high while the chance that he will accumulate a mutation in both copies is much lower. This accounts for why cancer often affects older people because more time has passed for multiple mutations to occur.
People who have one of these cancer syndromes are born with one mutation. Therefore, this person only has to accumulate one more mutation (in the other copy of the particular gene) and he will have both genes knocked out and cancer can develop. This also accounts for why people with these syndromes often develop cancer at earlier ages. See the diagram below.