Hereditary Colorectal Cancer

Hereditary Colorectal Cancer

Hereditary colorectal cancer is a category of large bowel cancer (colon or rectum) caused by a genetic susceptibility to certain types of cancer.  Individuals with hereditary colorectal cancer have an alteration (known as a mutation ) in their genes which causes them to have an increased risk of developing cancer.  These mutations can be passed from generation to generation and are present from birth. If an individual or their family member is identified as having an altered gene (mutation) then this knowledge can be used to encourage proper screening and prevention strategies.

There are currently several syndromes known to be associated with hereditary colorectal cancer. These include: Hereditary Non-Polyposis Colorectal cancer (HNPCC), Familial Adenomatous Polyposis (FAP), Attenuated Familial Adenomatous Polyposis (AFAP), MYH Associated Polyposis (MAP) and Juvenile Polyposis Syndrome (JPS). These syndromes have differing characteristics and are caused by mutations in specific genes.

Chromosomes and genes

There are 46 chromosomes arranged in 23 pairs in each cell of the body and there are approximately 30,000 genes on these chromosomes. Genes are units of hereditary material and contain the body's blueprint or instructions. Each gene produces a protein which has a specific role in the body. Genes come in pairs and each gene has a long code which can be thought of as a long sentence with thousands of letters. Changes in this code can interfere with the normal functioning of the gene and are called mutations. Mutations in specific genes can be associated with certain types of cancer. Mutations can be transmitted from generation to generation in the sperm or egg of the parent.

Genetic Testing

Genetic testing can guide appropriate cancer screening and health management. Depending on the suspected hereditary cancer syndrome different screening tests may be indicated and specific genetic testing may be appropriate. Some of this testing is performed via blood tests and others directly on tissue/tumor samples.

Families with Lynch Syndrome /
Hereditary Non Polyposis Colorectal Cancer (HNPCC)

Families with Lynch Syndrome typically have:

• Three or more closely related family members diagnosed with colorectal or endometrial cancer
• Affected family members in two or more generations
• At least one person with colorectal cancer or endometrial cancer diagnosed before the age of 50

Colorectal cancer is the most common cancer associated with Lynch syndrome; however the syndrome is also associated with an increased risk for cancers of the uterus (endometrium), ovaries, stomach, small intestine, biliary system, brain, pancreas, and urinary tract. Mutation carriers who have already been diagnosed with colorectal cancer also have an increased risk of developing a second colorectal cancer.

Individuals who inherit a typical gene mutation have an 80 percent lifetime risk of developing colorectal cancer and an 11-19% risk of stomach cancer. The average age of colorectal cancer is 44 years of age. Women with Lynch syndrome also have a 20 - 60% lifetime risk of developing uterine (endometrial) cancer and a 9-12% lifetime risk of developing ovarian cancer.

If an individual has a mutation in one of the Lynch syndrome-associated genes then their siblings and children will have a 50% chance to also have the mutation. Mutations can be inherited from either the individual's mother or father and an individual who carries a mutation can still pass it on even if they did not develop cancer themselves. This is known as an autosomal dominant pattern of inheritance.

The following screening is recommended for individuals with Lynch syndrome:

Colorectal cancer screening:

• Colonoscopy every 1-2 years beginning age 20-25 or 10 years before youngest age of diagnosis in the family.

Urinary tract cancer (if there is a family history):

• Urine cytology and renal ultrasounds every 1-2 years beginning age 30-35

Stomach Cancer screening (if there is a family history):

• Gastroscopy every 1-2 years beginning at the age of 30 to 35.

Endometrial and Ovarian cancer screening:

• Transvaginal ultrasound every 6-12 months beginning by the age of 30.
• Annual endometrial biopsies beginning at the age of 30.
• A blood test (CA125) every 6-12 months, beginning at age 30.
• A pelvic examination every 6 months beginning by the age of 30.

Familial Adenomatous Polyposis

Characteristics of Familial Adenomatous Polyposis (FAP)

FAP is clinically diagnosed on the basis of colonoscopy and is characterized by the development of hundreds or thousands of polyps in the colon during childhood or adolescence. Almost all individuals with FAP will develop colon polyps by age 16 and colorectal cancer by age 40. Individuals with FAP also have a 90% chance of developing polyps in the duodenum (small intestine) but only 4-12% of these polyps will develop into cancer. Ten percent of affected individuals will also develop gastrointestinal or gastric fundic polyps. Additionally, individuals with FAP have slightly increased risks of thyroid, pancreatic, brain (medulloblastoma) and hepatobiliary cancer. Affected individuals may also have sebaceous cysts, lipomas, fibromas, osteomas (bony growths most often on the skull), adrenal masses, dental anomalies (missing or extra teeth) and/or benign desmoid tumors

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is another characteristic of FAP. CHRPE does not affect eye sight. However, it can be used to determine whether an individual has FAP by performing a funduscopic examination.

Genetics of FAP

FAP is caused by mutations in the APC gene, located on chromosome 5. An individual who has inherited an APC gene mutation has a 50 percent chance of passing the mutation on to his/her child. If the child inherits the mutation, he/she will be at increased risk of developing cancer. However, if the child does not inherit the mutation, his/her cancer risk will be equal to that of the general population. This is known as autosomal dominant inheritance.

Approximately 25% of individuals with FAP have a spontaneous or de novo mutation in the APC gene. This means that the mutation has occurred for the first time in that individual and he/she would not have a family history of colorectal cancer. Although an individual with a de novo mutation does not have an existing family history, the mutation can still be passed onto to the individual's offspring in an autosomal dominant pattern.

Genetic Testing

It is possible to look for mutations and rearrangements in the APC gene. A positive result means that a mutation or rearrangement was detected and that it is most likely to be responsible for the colon cancers in the individuals' family.

A negative result means that a mutation or rearrangement was not detected. The chance that the cancers in the individual's family are due to a mutation in the APC gene is much lower but cannot be ruled out, as current methods cannot detect 100% of mutations. Additionally, colorectal cancer within the family could be due to mutations in another gene.

It is also possible that the genetic test results may be ambiguous due to the identification of a "genetic variant". Currently there are some changes in the APC gene, which may be identified called "genetic variants" of which there is little understanding. These changes may be associated with cancer or they may be normal variations in the code of the gene. Research is ongoing to determine whether these changes are harmful or not.

Screening for FAP

Individuals with a family history of FAP

The following screening is recommended for individuals with a family history of FAP.

• Annual flexible sigmoidoscopy or colonoscopy beginning at age 10 to 15 years.
• If no polyps are detected, the frequency of sigmoidoscopy may be reduced to:
• every 2 years after age 24
• every 3 years after age 34
• every 3 to 5 years after age 44.
• If polyps are detected annual colonoscopy and polypectomy are necessary, with consideration of colectomy and ileorectal anastomaosis

Individuals with a personal history of FAP

Individuals who have clinically diagnosed FAP usually consider prophylactic colectomy (removal of the colon) in their adolescence / early 20s or if medically required. If the rectum is left intact, annual endoscopy of the rectum is recommended.

Some studies have suggested the long-term use of oral chemopreventive agents, such as cyclooxygenase-2 (COX-2) inhibitors, sulindac, aspirin, folate, and calcium, may be effective in reducing the incidence of adenomatous polyps and their subsequent progression to colorectal cancer.

Attenuated Familial Adenomatous Polyposis (AFAP)

Familial Adenomatous Polyposis (FAP) and Attenuated Familial Adenomatous Polyposis (AFAP) are rare forms of hereditary colon cancer. FAP can be clinically diagnosed on the basis of colonoscopy, as this condition is characterized by the development of hundreds or thousands of polyps in the colon during childhood or adolescence. AFAP is a milder more variable version of FAP. There is also less known about this condition.

Individuals with AFAP usually have between 10 and 100 colon adenomas (polyps), with the average being 30 polyps. Polyps are also more likely to be located in the proximal colon (right side) and the average age of colorectal cancer development is 50-55.

The most common cancer associated with AFAP is colorectal cancer but there may also be small, increased risks for upper gastrointestinal (duodenal, gastric fundic, and hepatobiliary) polyps and/or cancers. Other findings seen in classic FAP families, such as desmoid tumors, bone osteomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE), are only rarely seen in AFAP. The particular symptoms displayed by an individual show considerable variability within a family.

Genetics of AFAP

AFAP is caused by a mutation in the APC gene, located on chromosome 5. An individual who has inherited an APC gene mutation has a 50 percent chance of passing the mutation on to his/her child. If the child inherits the mutation, she/he will be at increased risk of developing cancer. If the child does not inherit the mutation, her/his cancer risk (in most cases) will be equal to that of the general population. This is known as autosomal dominant inheritance.

Some individuals have a spontaneous or de novo mutation in the APC gene. This means that the mutation has occurred for the first time in that individual and he/she would therefore not have a family history of colorectal cancer. Although this mutation is not inherited it can still be passed onto to the individual's offspring in an autosomal dominant pattern.

Genetic Testing

It is possible to look for mutations and rearrangements in the APC gene. A positive result means that a mutation or rearrangement was detected in the APC gene, and that this is most likely responsible for the colon cancers in the individuals' family.

A negative result means that a mutation or rearrangement (depending on the testing performed) was not detected. The chance that the cancers in the individual's family are due to APC are much lower but cannot be ruled out, as current methods cannot detect 100% of mutations in the APC gene. Additionally, colorectal cancer within the family could be due to mutations in another gene.

It is also possible that the genetic test results may be ambiguous due to the identification of a "genetic variant". Currently there are some changes in the APC gene, which may be identified called "genetic variants" of which there is little understanding. These changes may be associated with cancer or they may be normal variations in the code of the gene. Research is ongoing to determine whether these changes are harmful or not.

Screening

For individuals with AFAP subtotal colectomy may be necessary. Management is based on the number of polyps and the ability to perform colonoscopies. Current screening recommendations are:

• Colonoscopy every 1-2 years beginning at 18.
• Upper endoscopy and side viewing duodenoscopy 3-5 years beginning 20-25y
• Additional surveillance for other associated cancers if present in the family.

MYH Associated Polyposis (MAP)

Characteristics of MAP

MAP has been discovered very recently and the syndrome is currently not well understood. Its presentation is similar to Attenuated Adenomatous Polyposis (AFAP). MAP can be responsible for the development of colorectal cancer in some families in which individuals have a few to many colon polyps.

Genetics of MAP

MAP is caused by mutations in the MYH gene. Unlike most hereditary colorectal syndromes MAP is thought to be inherited in an autosomal recessive pattern. This means that an affected individual inherits a mutated copy of the MYH gene from both their mother and their father. Individuals with MAP may have no family history of colorectal cancer. Individuals with two MYH mutations are known to be at an increased risk to develop colon polyps and colorectal cancer. However, the significance of carrying only one MYH mutation is unknown.

Genetic Testing

Testing is available to look for mutations in both copies of the MYH gene.

A positive result indicates that two mutations were found and that the individual is known to be at an increased risk for colorectal cancer due to MAP. If results indicate that one mutation was found, it is uncertain whether the individual is at an increased risk for colorectal cancer or not.

A negative result means that no mutations were detected. The chance that the cancers in the individual's family are due to MAP is much lower but cannot be ruled out, as current methods cannot detect 100% of mutations in the MYH gene. Additionally, colorectal cancer within the family could be due to mutations in another gene.

It is also possible that the genetic test results may be ambiguous due to the identification of one or more "genetic variants". Currently there are some changes in the MYH gene, which may be identified called "genetic variants" of which there is little understanding. These changes may be associated with cancer or they may be normal variations in the code of the gene. Research is ongoing to determine whether these changes are harmful or not.

Screening

The following are recommendations for individuals with a family history or personal history of MAP.

Family History of MAP:

• Colonoscopy 3-5 years beginning age 25-30
• Consider upper endoscopy and side viewing duodenoscopy 3-5 years beginning age 30-35

Personal History of MAP:

• Colonoscopy and polypectomy every 1-2 years
• Consider upper endoscopy and side viewing duodenoscopy every 3-5 years beginning age 30-35