Colon cancer is one of the most common types of cancer. Most colon cancers are sporadic: that is, they are not inherited and cannot be passed to your children. Although the cause is usually unknown, sporadic cancers may occur due to environmental exposures. In other cases, mistakes (mutations) can occur in genes by chance when a cell divides. Since these mutations occur only in the cancer cells, they cannot be passed on to one’s children.

Sometimes, several members of a family will develop colon cancer. In these cases, cancer is occurring more often than would be expected by chance, yet does not appear to be clearly hereditary (passed from parent to child). Very little is known about the causes of cancer in these families. It is possible that interactions are occurring between genes and the environment or among several genes. This type of moderately increased cancer risk can be called a "familial colon cancer."

About 5-10% of colon cancers are believed to be hereditary. When a person is at risk for hereditary cancer, this means that he or she has inherited a gene with a change in it, called a mutation, that makes the person more prone to developing cancer. Individuals who inherit a mutation in a cancer susceptibility gene have a much greater chance of developing cancer. However, not everyone with a cancer susceptibility gene mutation will develop cancer.

This article will focus on the most common inherited colorectal cancer syndromes: hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and MYH-associated polyposis (MAP). Other syndromes include juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), and the PTEN-hamartoma tumor syndrome. Genetic testing is available for all of these syndromes. Genetic testing is usually done on a blood sample. The sample is sent to a laboratory for analysis of one or more genes associated with a syndrome and the results are reported back to your healthcare provider for interpretation.

Hereditary nonpolyposis colorectal cancer (HNPCC)

HNPCC, also known as Lynch syndrome, is the most common form of hereditary colon cancer, accounting for about 3 percent of all colorectal cancer diagnoses each year. Although not everyone with HNPCC will develop colorectal cancer, the risk is greatly increased compared with that of the general population. For someone with HNPCC, the risk of developing colorectal cancer is approximately 80 percent over his or her lifetime. Women with HNPCC also have a 60 percent lifetime risk of developing uterine cancer and up to a 12 percent risk of developing ovarian cancer. Stomach cancer is the third most common type of cancer associated with HNPCC; the lifetime risk is as high as 13 percent. People with HNPCC also have a higher risk of developing other cancers in organs such as the small intestine, pancreas, renal pelvis, and biliary tract.

There are two variant (alternative) forms of HNPCC--Muir-Torre syndrome and Turcot syndrome. People with Muir-Torre have the same cancer risks as people with HNPCC, and they also develop sebaceous skin neoplasms (growths). People with Turcot syndrome also have the same cancer risks and a higher chance for developing certain brain tumors.

A diagnosis of HNPCC is considered in families that have certain characteristics, including the following:

• At least three members of the family have an HNPCC-related cancer
• At least two successive generations of the family have cancer
• Two family members with cancer are first-degree relatives (i.e. parents, brothers, sisters, or children) of another affected family member
• At least one member was diagnosed with cancer before age 50
• Familial adenomatous polyposis (FAP, see below) is excluded from the family member's diagnosis

HNPCC Genes

The genes that have been associated with HNPCC are called MLH1, MSH2, MSH6, and PMS2. Everyone has two copies of each of these genes; one they inherit from their mother and one they inherit from their father. People with HNPCC have a mutation in one copy of one of these genes, which can be passed on to future generations. If a parent has a mutation in one of these genes, each of his or her children has a 50% (1 in 2) chance of inheriting the gene mutation. Each child also has a 50% (1 in 2) chance of inheriting the copy of the gene without the mutation, in which case his or her cancer risk would be no higher than that of the general population.

Familial adenomatous polyposis (FAP)

FAP is a rare condition in which a person has hundreds to thousands of polyps in the colon. The polyps are growths, also known as adenomas, that are not cancer. However, they do have the potential to develop into cancer. Typically, the polyps begin to develop in the teenage years. If the colon of a person with FAP is not removed by surgery, he or she will eventually develop colon cancer. FAP accounts for approximately 1 percent of all people diagnosed with colorectal cancer each year.

People with FAP can also develop polyps in the stomach and small intestine. With this syndrome, there is an increased risk of cancers of the stomach, small intestine, pancreas, thyroid, liver, bile ducts, and adrenal glands. Other non-cancerous features of FAP include soft tissue tumors, osteomas (bony growths), skin cysts, dental abnormalities, and an eye condition known as congenital hypertrophy of the retinal pigment epithelium [benign, large, flat, pigmented (colored) areas beneath the retina].

The link among colon polyps, osteomas, and soft tissue tumors is also referred to Gardner syndrome, which is form of FAP. Other forms of FAP include:

• Turcot syndrome (the association of colon polyps and certain brain tumors) and
• Attenuated FAP (AFAP, the presence of 20 to a hundred adenomas in the colon)

People with attenuated FAP usually develop polyps in their 20s and develop cancer at a later age than those with FAP.

FAP Gene

The gene that has been associated with FAP is called APC. Everyone has two copies of this gene; one they inherit from their mother and one they inherit from their father. People with FAP have a mutation in one copy of the APC gene, which can be passed on to future generations. If a parent has a mutation in one of copy of the APC gene, each of his or her children has a 50% (1 in 2) chance of inheriting the gene mutation. Each child also has a 50% (1 in 2) chance of inheriting the copy of the gene without the mutation, in which case his or her cancer risk would be no higher than that of the general population.

MYH-associated polyposis (MAP)

MAP is an inherited condition that primarily affects the colon and rectum. People with MAP can develop anywhere from a dozen to hundreds of polyps (adenomas) within the colon. It is estimated that everyone who has MAP will develop colon cancer by the age of 65, unless they have surgery. Most colon cancers associated with MAP will occur in people between the ages of 50 and 70. People with MAP also have a 4 to 25 percent chance of developing polyps in part of the small intestine known as the duodenum.

People with MAP and AFAP have very similar polyp development. The only way to distinguish the two syndromes is by performing genetic testing.

MAP Gene

The gene that is associated with MAP is called MYH. Everyone has two copies of this gene; one they inherit from their mother and one they inherit from their father. People with MAP have a mutation in both copies of the MYH gene. The parents of people with MAP are called "carriers," because they have a mutation in one copy of their MYH gene.

The children of MYH carriers have a 25 percent (1 in 4) chance of inheriting two copies of the gene with a mutation (which is a diagnosis of MAP), a 50 percent (2 in 4) chance of being a carrier, and a 25 percent (1 in 4) chance of inheriting two copies of the gene without a mutation. If a person with MAP has children, all of the children will be carriers. Carriers are not believed to be at an increased risk to develop polyps or cancer.

Other forms of hereditary colon cancer

Juvenile polyposis syndrome (JPS)

The genes associated with JPS are called BMPR1A and MADH4. People who have JPS develop anywhere from a few to hundreds of hamartomatous (juvenile) polyps in the gastrointestinal tract. People with JPS are at greater risk for colorectal, stomach, small intestine, and pancreatic cancer.

Peutz-Jehgers syndrome (PJS)

The gene associated with PJS is called STK11. People who have PJS develop hamartomatous (Peutz-Jeghers) polyps in the gastrointestinal tract. They also have pigmentation, or freckling, on the lips, mouth, hands, and/or genitals. People with PJS have a greater risk of colorectal, breast, pancreatic, and stomach cancer.

PTEN-hamartoma tumor syndrome

This is a group of disorders caused by mutations in the PTEN gene. Included in this group are the following:

• Cowden syndrome, which is characterized by hamartomatous growths, macrocephaly (a large head), skin lesions, and an increased risk of breast, uterine, and thyroid cancer. It is unknown how many people with Cowden syndrome develop colon cancer or colon polyps.
• Bannayan-Riley-Ruvalcaba syndrome (BRRS), which is characterized by macrocephaly, developmental delay, lipomas (fatty tumors), and freckling on the penis in males with the condition. Half of patients with BRRS will develop hamartomatous polyps in their gastrointestinal tract.
• Proteus syndrome, which is characterized by overgrowth of parts of the body, hamartomatous growths, and moles. Proteus syndrome is not associated with an increased risk of colon cancer or colon polyps.

If you suspect you are at risk for an inherited form of colorectal cancer, talk to your doctor about a referral to a genetic counselor.

Genetic counselors are healthcare providers who:

• evaluate the pattern of cancers in a person’s family,
• explain the natural history and inheritance of hereditary cancer syndromes,
• discuss the testing process and options,
• review medical management options, and
• evaluate the risks to other family members.

If you would like to meet with a cancer geneticist or genetic counselor at the Center for Personalized Genetic Healthcare at Cleveland Clinic, please call 216.445.5686 to schedule an appointment.

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