Chicago Center for Jewish Genetics Disorders - Cancer Genetics

Hereditary Colorectal Cancer Syndromes

Overview of Colon Cancer syndromes
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Familial Adenomatous Polyposis (FAP)
Factors to Consider When Pursuing Genetic Testing

Overview of Colon Cancer syndromes

The majority of all colorectal cancers have no known genetic cause. However, several genetic risk factors are known to correlate with colorectal cancer. Inherited gene changes (also called mutations) cause about 10% of all colorectal cancers, and individuals with these mutations are more likely to develop colon cancer but are not always destined to do so. Overall, two colon cancer syndromes are responsible for about 3-5% of all cases of colorectal cancer, while other familial forms account for 10-30% of colon cancer. The two most common types are Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and Familial Adenomatous Polyposis (FAP).

Hereditary Non-Polyposis Colorectal Cancer (HNPCC): This is the most common, and accounts for 2-5% of all colorectal cancer cases.
Familial Adenomatous Polyposis (FAP): This syndrome accounts for approximately 1% of all colorectal cancers.
Bloom's Syndrome: The BLM gene is known to cause Bloom's syndrome when both copies of the gene are changed. Some reports have suggested an increase in the risk of colorectal cancer from a mutation in only one copy of the BLM gene, but other reports deny this association, which if present, is weak. Bloom's Syndrome occurs at a higher incidence in the Ashkenazi Jewish population and is covered elsewhere in the Bloom's Syndrome section.
Muir-Torre Syndrome, Peutz-Jeghers syndrome, Juvenile Polyposis syndrome, and PTEN Hamartoma Tumor syndrome: Each account for much less than 1% of all hereditary colorectal cancer cases. They do not have a connection to Ashkenazi Jewish ancestry. Muir Torre syndrome is briefly covered further in the Muir-Torre and Turcot Syndrome section. The National Library of Medicine and The National Cancer Institute Genetics of Colorectal Cancer websites have more information on Peutz-Jegher syndrome, Juvenile Polyposis syndrome and PTEN Hamartoma syndrome.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Overview

HNPCC (formerly called "Lynch Syndromes I and II" or "Cancer Family Syndrome") is a colorectal cancer syndrome that generally occurs at an earlier age (40-45) than is typically seen in the general population. Those with a genetic predisposition for HNPCC have an 80% chance of developing colorectal cancer. Patients with HNPCC tend to develop adenomas (non-cancerous tumors of the cells lining some organs) at the same rate as individuals in the general population, but these adenomas are more likely to progress to cancer at a quicker rate through the stages of carcinogenesis. Unlike Familial Adenomatous Polyposis (FAP), the other most common hereditary colorectal cancer syndrome, there is NOT a profusion of polyps before the progression to cancer. HNPCC also predisposes an individual to tumors outside of the colon. For a more in depth discussion, please see Extracolonic Manifestations of HNPCC.

Inheritance

Mutations causing HNPCC display autosomal dominant inheritance. Therefore, every child whose parent has HNPCC has a 50% chance of inheriting the gene mutation known to occur in that family. Both copies of the gene causing HNPCC need to be changed before an HNPCC-associated cancer can develop by pathway described in the section Molecular Basis for Colorectal Cancer.

In an individual born with a gene (or germline) mutation, the lifetime risk to develop one of the cancers associated with HNPCC is much higher than in an individual born with two functional copies of the same gene. A single germline mutation does not cause cancer; it is not until both copies of the same gene are changed that progression to cancer can occur. A way to think of this is to compare the function of the genes to the brakes on a car. If the rear set of brakes does not work, the front brakes can still stop the car. However, if both sets of brakes do not work, the car cannot be controlled. Unfortunately, mutations of the second, "normal" gene occur relatively commonly during one's lifetime.

Inheritance and Culture

The majority of mutations characterized in the HNPCC genes are unique to one’s own family, although some population-specific mutations have been seen within the Finnish and Swedish populations. Historically, HNPCC has not been seen at increased rates in Ashkenazi Jews. Recently, however, founder mutations have been detected in the Ashkenazi Jewish population. For a more in-depth discussion, please see Ashkenazi Jews and Colorectal Cancer.

Gene Mutation

Mutations in two specific genes, MLH1 and MSH2, also known as mismatch repair genes, account for the majority of cases of HNPCC. They have been found in 40% of individuals meeting the criteria for genetic testing. Other mismatch repair genes account for a small amount of cases of HNPCC. Mismatch repair is the process by which cells fix mistakes made during DNA replication. Uncorrected mistakes are rare when DNA is replicated and mismatch repair functions normally. However, if any of the several proteins involved in mismatch repair are not functioning correctly, these errors can occur up to 100 times more often. These errors may accumulate and interrupt effective gene functioning.

Genetic Testing for HNPCC

According to the American Society of Clinical Oncology, the medical benefit of genetic testing for HNPCC mutations has not been proven because the clinical management is unclear and it is not known whether an individual with a HNPCC mutation will develop the disease. Genetic testing may be helpful by providing genetic confirmation of a suspected clinical diagnosis of HNPCC, or it can be used for pre-symptomatic testing of family members if a mutation is identified. Determining whether one should get tested for HNPCC is a complex and difficult decision, best accomplished in conjunction with genetic education and counseling at centers with hereditary cancer risk assessment programs. Testing should be done at a center with expertise in colorectal cancer genetics.
For ethical and emotional issues related to HNPCC testing, see Factors to Consider When Pursuing Genetic Testing below.

Familial Adenomatous Polyposis (FAP)

Overview

FAP is caused by mutations in a tumor-suppressor gene (APC) and, if gone untreated, the chance of developing colorectal cancer is very high. FAP is an inherited condition primarily affecting the large intestine, even though other manifestations may occur outside the colon in a variety of tissues. Large numbers of polyps (projectile masses from the intestinal walls) develop on the inner lining of the bowel, most often in individuals during puberty, with most people developing polyps by age 25. Untreated individuals with FAP will develop thousands of these precancerous polyps in the colon, and colorectal cancer typically occurs before age 40. Colorectal cancer development is inevitable without a colectomy (removal of the colon).

A clinical diagnosis of classic FAP is given either when there are greater than 100 colorectal polyps in someone who has no family history of FAP, or if there are fewer than 100 colorectal polyps in someone who does have a family history of FAP. Other manifestations of FAP and other types of cancers are also more likely to occur in individuals with FAP. For a more in depth discussion of these features, please see Extracolonic Manifestations of FAP.

Inheritance

The predisposition to cancer is inherited in an autosomal dominant manner. Therefore, every child or sibling of an individual with a cancer mutation has a 50% chance of also inheriting the mutation. The majority of patients with FAP have an affected parent.

Inheritance and Culture

FAP does not occur at an increased rate in Ashkenazi Jews, but a specific APC gene mutation leading to an increased risk of colorectal cancer is found in the Ashkenazi Jewish population. See Ashkenazi Jews and Colorectal cancer for more information.

Gene Mutation

FAP is caused by mutations in the APC gene. APC is a tumor suppressor gene that controls cell growth, often considered a gatekeeper to colorectal cancer. Both copies of the APC gene need to be changed for cancer to actually develop. Individuals born with a FAP mutation in only one gene (inherited mutation), are often very likely to lose the second “normal” gene during one’s lifetime, leading to a high risk of developing cancer. Most carriers inevitably get polyps, and an individual with a mutation is often considered guaranteed to develop colorectal cancer. This means that inheriting one copy of the changed gene is often enough to lead to the clinical syndrome of polyps and cancer during one's lifetime.

Genetic Testing and FAP

The American Society of Clinical Oncology (ASCO) advises that anyone with a strong family history of colorectal cancer consider predisposition counseling and possible testing for FAP. Seventy-five to 80% of affected patients have an affected parent and almost all individuals with the FAP gene mutation eventually develop the disease. A physician trained in predisposition genetic testing should be involved in the testing process in order to accurately interpret the results. This is best accomplished through a center that specializes in cancer genetic counseling. The results of the FAP genetic testing are highly accurate, with an estimated 95% mutation detection rate. In those families with an FAP mutation, children as young as eight years of age should be tested, and should get colonoscopies by the age of 10. For ethical and emotional issues related to HNPCC testing, see Factors to Consider When Pursuing Genetic Testing below.

Factors to Consider When Pursuing Genetic Testing

With both FAP and HNPCC, there are several factors to consider when pursuing genetic testing.

A mutation might not be found in any affected individuals of a family with a clinical diagnosis of FAP or HNPCC.

Testing can be expensive, and unaffordable without health insurance.

There is the potential for discrimination, in terms of health insurance, employment, and life insurance. Few cases of discrimination have been documented, and while laws have been enacted to combat the possibility, it is still a possibility that people should be made aware.

Genetic information cannot be unlearned. It is important that each member of the family recognizes and knows the implications of what their test results are.

For these reasons, it is important that genetic testing be coordinated through a center that specializes in cancer genetic counseling. To find clinicians involved in cancer risk counseling, visit the National Society of Genetics Counselors, the American Society of Clinical Oncology, or the American College of Medical Genetics.

Reviewed by Gershon Locker, MD, Head, Division of Hematology and Oncology, Evanston Northwestern Healthcare