**Hereditary Colorectal Cancer Fact Sheet**

Colorectal cancer is the second most common cause of cancer death in the
United States. Approximately 1 in 17 Americans will develop colorectal
cancer in their lifetime. Approximately 10% of all colorectal cancers
are directly caused by inherited genetic abnormalities. These hereditary
colorectal cancers often feature colonic polyps or growths that
eventually become cancerous. Other risk factors for hereditary
colorectal cancers include early age of cancer onset, typically in the
30s to 50s, having more than 1 occurrence of colorectal cancer, having
other types of cancer (e.g. ovarian, endometrial, or urinary tract), or
having multiple family members with colorectal or other cancers.

There are several inherited syndromes associated with colorectal
cancers, including hereditary non-polyposis colorectal cancer (HNPCC),
familial adenomatous polyposis (FAP), and a variant called Gardner's
syndrome. Hereditary colorectal cancer often occurs in younger
individuals; sporadic colorectal cancer rarely occurs before age 40.

Genetic counseling is recommended for high-risk families considering
genetic testing. Counseling includes a review of the risks, benefits,
and limitations of genetic testing as well as a personalized assessment
of the probability of being a mutation carrier. In order to maximize the
likelihood of obtaining a useful and "informative" test result, it is
recommended that the first individual tested be the individual who has
been diagnosed with early onset colorectal cancer. When someone with a
cancer diagnosis and a family history of the disease has been tested and
found to have an altered gene, the family is said to have a \"known
mutation.\" Others in the family can be tested to see if they have that
mutation. Risks for insurance and employment discrimination must be
considered before undergoing genetic testing.

A *positive* test result indicates that an individual has inherited a
gene alteration and has an increased risk of developing colorectal
cancer. However, a positive result only provides risk information and
cannot tell a person whether or when cancer might develop. A *negative*
test result in a family ***with a known mutation*** will mean that the
tested individual is not at an increased risk for developing cancer. In
a family where a mutation ***has not been identified***, however, a
negative test result will be "uninformative". In this situation, there
is the potential for the tested individual to be falsely reassured and
to relax screening practices.

**Hereditary non-polyposis colorectal cancer (HNPCC)** is the most
common form of inherited colorectal cancer that occurs at an early age.
In HNPCC, only a small number of polyps or no polyps are present and
colorectal cancer primarily occurs on the right side. Cancer of the
uterus, ovary, stomach, urinary tract, small bowel, and bile ducts may
also be found in some families with HNPCC. Mutations in several genes
(hMSH2, hMLH1, hPMS1, and hPMS2 located on chromosomes two, three, two,
and seven, respectively), have been found to be responsible for most
cases of HNPCC. Individuals with these mutations have a 90% chance of
developing colorectal cancer by age 70 and women have a 50% chance of
developing endometrial cancer. Some individuals with HNPCC do not have
an affected parent with HNPCC. These individuals have a new mutation.

**Exam Guidelines** **for people AT RISK for HNPCC** (those who have not
undergone genetic testing but in whom a family member has HNPCC):

Colonoscopy every 1-3 years beginning by age 25, or 5-10 years before
the earliest colorectal cancer in the family.

Annual endometrial screening with biopsy for women beginning at age 25.

If an individual is positive for the HNPCC gene, careful colorectal
exams are recommended. If surgery is required, the procedure of choice
is a total abdominal colectomy. After surgery for individuals with
HNPCC, follow-up recommendations include a sigmoidoscopy every year
(depending on type of surgery), an annual physical exam, and for women,
an annual gynecologic exam, including endometrial screening with biopsy.

**Familial adenomatous polyposis (FAP)** is a form of inherited
colorectal cancer in which hundreds to thousands of polyps form in the
colon and rectum at a young age, usually in teenagers or young adults.
Colorectal cancer usually develops in these individuals by the fifth
decade of life if colectomy is not performed. Other features of the
syndrome include upper gastointestinal tract polyps, desmoid tumors,
osteomas, epidermoid cysts, congenital hypertrophy of the retinal
pigment epithelium, and other malignant neoplasms.

FAP is caused by an abnormal gene \-- APC (for Adenomatous Polyposis
Coli), on chromosome five. Almost every person with the abnormal gene
will develop FAP. Children of individuals with a mutation in the APC
gene have a 50% chance of inheriting the same mutation. About one-third
of individuals with FAP do not have a parent with FAP. These individuals
have new mutations.

Conventional treatment for those at risk for FAP includes an annual
sigmoidoscopy starting at age 10-12. Prophylactic colectomy is indicated
when polyposis develops, enabling a normal life for the individual.
Follow-up surveillance by endoscopy for upper gastrointestinal tract is
recommended.

**Exam Guidelines** **for people AT RISK for FAP** (those who have not
undergone genetic testing but in whom a family member has FAP):

[Age]{.underline} [Exam]{.underline}

11-24 Flexible sigmoidoscopy every year

25-34 Flexible sigmoidoscopy every other year

35-44 Flexible sigmoidoscopy every 3 years

over 44 Flexible sigmoidoscopy every 3-5 years

If a person is positive for the APC gene, the same guidelines should be
followed. In those individuals who have surgery, follow-up care may be
recommended including a sigmoidoscopy every 6 months to 1 year
(depending on type of surgery), an upper endoscopy at least every 4
years, and a complete physical every 1-2 years.

Individuals with mutations in HNPCC or FAP should also be offered
counseling about the risks, benefits, and limitations of other
management options including chemoprevention, and lifestyle
modifications. In individuals who have tested negative for hereditary
colorectal cancer syndromes or who have not been tested, careful
evaluation to determine screening guidelines is recommended.