Why?

It's a question we ask daily of many different situations, good and bad. A cancer diagnosis happens to be one of those situations that falls on the 'bad' end of that scale. While there is much we do know about cancer, there is a lot we do not. My personal experience with cancer to this point has actually not really been focused on the 'why' but more on the 'how do i get through'. But the more I learn about cancer, the more the question of 'why me?' comes to the fore front.

Colon cancer is pretty rare in people my age. Often when cases are found in people so young there is some genetic explanation and/or a significant family history. So as part of my initial consultation with the medical oncologists I was referred to the Cancer Genetics Clinic at the Children's Hospital with the thought that perhaps there might be an 'easy' explanation for all of this.

As part of the initial meeting, the Cancer Genetics Clinic collected detailed information about my family medical history and obtained the biopsy samples of my tumor taken during my colonoscopy. With this information they built a chart which enabled them to a) assess if I have a family history of colon cancer, b) determine if my cancer shows genetic abnormalities suggesting the possibility of a hereditary source. Before I discuss their findings I should give a little background.

In order to say that someone has a family history of colon cancer, one must meet what is called Amsterdam I criteria (there are other criteria too depending on who you ask but Amsterdam I is what they were using at the Cancer Genetics Clinic). The Amsterdam I criteria has 3 elements: (1) there are at least three relatives with histologically verified colorectal cancer (one a first degree relative of the other two), and familial adenomatous polyposis should be excluded (more on FAP below); (2) at least two successive generations should be affected; and (3) one of the relatives colorectal cancers should be diagnosed before age 50. It turns out that I do loosely meet the Amsterdam I criteria.

Colon cancer in people of any age can generally be classified into three causes/sources. (1) 65-85% of all colon cancer cases are sporadic, meaning there is no known family history or genetic cause. These colon cancer cases start with natural mutations of some genes that gets out of control. (2) 15-20% of all colon cancer cases are what they call familial. This means there appears to be a history in the family but no known colon cancer 'suspect genes' are the cause. In some instances there may also be an environmental component (families living in the same part of the world, eating the same food, drinking the same water etc.). These familial colorectal cancers also go by the name of 'familial colorectal syndrome X'. (3) 4-6% of all colon cancer cases are hereditary being caused by a genetic mutation in one of a handful of genes. These genetic mutations result in either HNPCC (hereditary nonpolyposis colorectal cancer) or FAP (familial adnomatous polyposis). Because I do have a family history of colon cancer (I meet the Amsterdam I criteria) and because I do not have multiple polyps in my colon (FAP is characterized by the development of hundreds to thousands of polyps in the colon) the focus of this genetics study was on HNPCC and looking at the genetic mutations that cause it.

HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway. When cells divide and their genetic information is copied, mistakes are often made. There are a number of special genes whose function during cell division is to repair these mistakes (my genetic counsellor called them "repair man" genes - this is the 'DNA mismatch repair pathway' mentioned above). If the mistakes are not repaired by these 'repair men' in a portion of the genetic code that controls either starting cell division or stopping cell division, then cells can divide faster than usual and without constraint resulting in a malignancy.

The testing process for HNPCC involves 2 screening tests and if those are both positive then a detailed genetic study is done to determine which specific gene is causing the problems. The first test is called an IHC (immunohistochemistry) test. This test involves staining the tumor tissue to make sure all of the 'repair man' genes are present. My IHC test came back positive meaning that all my repairmen genes are present. The second test is called an MSI (microsatellite instability) test. This test looks at all the repairmen to make sure they are working properly. My MSI test came back normal meaning that all my repairmen are working properly and aren't standing around leaning on a shovel having a smoke. The bottom line, in plain English, is that all my genetic "stuff" seems to be present and in good working order. This means that my particular case of colon cancer does not fall into the 4-6% of colon cancers that are strictly hereditary ( like HNPCC). This is exceptionally good news since HNPCC carriers can pass those genetic defects to their children (carriers of HNPCC have up to an 80% lifetime risk of cancer).

My case has been lumped into the 15-20% of colorectal cancers that are labeled "familial colorectal syndrome X". Relatives in such families have a lower incidence of colorectal cancer than those families with HNPCC syndrome and incidence may not be increased for other cancers. Sounds like good news, but it still doesn't answer the "why?' does it. Hmmm.

For more reading you can check out:

Lower Cancer Incidence in Amsterdam I Criteria Families Without Mismatch Repair Deficiency. JAMA. 2005;293 pp1979-1985.

Ok, I just re-read that whole thing. If you made it to the end then good for you. You deserve a gold star.