Cancer arises from the uncontrolled growth of cells. Cancer is caused by harmful changes (mutations) in the genetic messages (genes) which control the growth and division of cells.  It is the accumulation of multiple mutations over many years that disrupts the growth control of the cell and allows a normal cell to grow without control, and eventually become a cancer.
 
Most cases of cancer occur in the absence of a significant family history, and are not inherited.  In these families the mutations causing the cancer occur only in the tumor itself and are all acquired after birth. Although the cause is seldom known, these acquired mutations may be the result of environmental or hormonal exposures, or mistakes which can occasionally occur when a cell divides.  Acquired gene mutations cannot be passed from one generation to the next, so this type of cancer is considered “sporadic” (a chance event) and not hereditary. Just by chance, some families have several members affected with sporadic cancers.

The interaction of multiple minor genes and environmental influences may also increase the risk of developing cancer.  Although little is known in this area, it is possible, for example, that individuals with a moderate family history of cancer may be more susceptible to cancer-causing agents in the environment.  This type of moderately increased cancer risk can be called a “familial” risk.

About 5-10% of cancers are thought to be hereditary.  In these cases, an individual inherits a copy of a growth control gene with a mutation from one parent, and a working copy of the same gene from the other parent. The gene with the mutation is also called a “cancer susceptibility gene”. Since this cancer susceptibility gene is inherited, it is found in every cell of the body, but the working copy of the gene keeps each cell working properly. However, if the working copy of the gene in a cell becomes damaged by a mutation, that cell can lose its growth control and become cancerous. Thus, individuals who inherit a cancer susceptibility gene have a much greater chance for developing certain cancers in their lifetime. However, not everyone with an inherited cancer susceptibility gene will develop cancer.

We discussed that damaged cancer susceptibility genes can be inherited, and passed on, by men just as easily as women. If a parent carries a cancer susceptibility gene, each of their children has a 50% chance of inheriting the gene, and thus the susceptibility to cancer. Each child also has a 50% chance of inheriting the working copy of the gene, in which case their cancer risk would be no higher than that of the general population.

Hereditary cancers generally are not significantly different from non-hereditary cancers. It is the way the cancers occur in the family that indicates whether they may be hereditary. Signs suggesting hereditary cancer include:

• two or more relatives with the same type of cancer, on the same side of the family
• several generations affected
• early ages of cancer diagnosis
• individuals with more than one primary cancer
• the occurrence in one family of cancers which are known to be genetically related (such as breast and ovarian cancer, or colon and uterine cancer)
• the presence of physical signs which are known to be associated with hereditary cancer (such as moles and melanoma, or polyps and colon cancer)

Hereditary nonpolyposis colon cancer (HNPCC) is a form of inherited colon cancer which usually presents with a few to less than 50 polyps.  It has been defined for research purposes (known as the Amsterdam Criteria) as a family with at least three cases of colon cancer, at least one of which is diagnosed by 50 years of age, and in which individuals are affected in at least two generations.  However, it is known that a number of other cancers are also at increased risk in HNPCC gene carriers, including endometrial and ovarian cancer in women, and stomach, pancreatic, small intestine, biliary tract, ureter, and renal pelvis cancers in both men and women. Recently, Revised Amsterdam Criteria have been adopted which allow for the inclusion of these other HNPCC-related cancers, in addition to colon cancer.  The lifetime colon cancer risk in HNPCC is estimated to be between 80 and 90%, while the risk for endometrial cancer in women is about 40%. The other cancers occur at significantly lower rates.

Mutations in at least five different genes have been shown to cause HNPCC.  Two of these (MLH1 and MSH2) account for the majority of cases, and can be analyzed on a commercial basis.  MLH1 and MSH2 mutations are found in about 70-80% of families meeting Amsterdam Criteria, but in only about 10-30% of families with evidence of hereditary cancer but not meeting Amsterdam Criteria.  MSH6 has recently been found to account for approximately 10% of cases of HNPCC.  MSH6 mutations may cause colon cancer at a later age of onset than MLH1 and MSH2.  Therefore, families who do not meet the Amsterdam criteria may have mutations is MSH6.

In addition, tumor tissue from most (80-90%) individuals with HNPCC show an abnormality in the copying of the genetic material (DNA).  This abnormality is called micosatellite instability (MIS) by some groups and replication error (RER+) by others.  Testing for MIS/RER can be used as a cost effective screen to assess whether HNPCC gene studies are indicated, since patients with an MIS negative tumor tissue are unlikely to test positive for an HNPCC gene mutation.  However, about 10-15% of non-HNPCC tumors will also test positive. Testing for the two major HNPCC genes costs approximately $1500 to $2700, depending on the laboratory used.  Analysis of tumor tissue for MIS/RER costs approximately $300-$500.  Children (under 18 yo) will not be tested for HNPCC mutations since it will not affect their medical management.

Genetics
HNPCC is inherited as an autosomal dominant condition.  This means that each child of an individual having one of these gene mutations has a 50% chance themselves of inheriting the mutation.  Genetic testing is available which can identify mutations in many, but not all, families with hereditary colon cancer.  We emphasized that because of limitations in the technology, failure to detect a mutation in a family does not rule out hereditary cancer.  If a mutation is identified in an affected individual in a family, at-risk family members can be tested with nearly 100% accuracy.  Those relatives inheriting the mutation face increased cancer risks, and should be followed appropriately.  Relatives who have not inherited the gene mutation are at no increased risk for cancer over the general population.

Management Guidelines
Guidelines for HNPCC patients call for colonoscopy every 1-2 years (every year following detection of an adenoma) starting at 25 y.o. (or 5 years before the earliest colon cancer diagnosis in family, if it was under 30 y.o.).  All adenomas are removed, and removal of the colon by subtotal colectomy is generally performed if cancer is found, with continued screening for rectal cancer.  Some centers consider offering prophylactic subtotal colectomy.  Women should also receive an annual pelvic exam, transvaginal ultrasound and CA 125 blood testing, starting at 25-30 y.o., for ovarian cancer; and annual ultrasound /endometrial aspiration biopsy after 30 y.o. for endometrial cancer. Some programs consider prophylactic removal of the uterus and/or ovaries if a strong family history of these cancers is present.  Men and women should also be examined for other HNPCC-related cancers if present in the family (stomach: gastroscopy q 1-2 years, starting at 30 y.o.;  urinary tract: ultrasound q 1-2 years, starting at 30 y.o. and urine analysis).  At-risk family members generally undergo colonoscopy every 2-3 years, starting at 25 y.o., with screening for other HNPCC-related cancers if they are present in the family.  At-risk women should be screened for gynecologic cancers with the same protocol as HNPCC patients.