What is Hereditary Nonpolyposis Colorectal Cancer?

HNPCC is also known as Lynch syndrome or cancer family syndrome. HNPCC is a condition in which the tendency to develop colorectal cancer is inherited. “Nonpolyposis” means that colorectal cancer can occur when only a small number of polyps are present (or polyps are not present at all). In families with HNPCC, cancer usually occurs on the right side of the colon. It often occurs at a younger age than colon cancer that is not inherited. Other cancers can occur in these families including cancer of the uterus, ovaries, stomach, urinary tract, small bowel, and bile ducts.

Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome was first described over 100 years ago. It is the most common of the recognized inherited colorectal cancer syndromes. HNPCC is usually characterized by a predisposition to cancer in the third and fourth decades of life, although it is not infrequent to have earlier or later onset. It accounts for approximately 5% of all colon cancer cases. Tumors in patients with HNPCC begin as adenomas and frequently transform to carcinoma. Endometrial, ovarian, urinary tract, biliary tract, small intestine, and gastric cancer are also characteristic of this syndrome and are seen more often in these families with HNPCC than in the general population. 

How is HNPCC Inherited?

HNPCC is an autosomal dominant condition. This means that people with HNPCC have a 50% chance of passing the HNPCC gene mutation (change) to each of their children. The gene mutation can be passed on even if the parent has had surgery to remove his or her own colon. Individuals who do not inherit the gene mutation cannot pass it to their own children. The vast majority of individuals with HNPCC develop cancer (Figure 1).

Some individuals with HNPCC do not have an affected parent. These individuals, who are the first in the family to have the condition, are referred to as having a new mutation (newly altered gene). They can, however, pass this HNPCC gene mutation to their children.

Fig. 1 HNPCC Family Pedigree

  1. George has HNPCC.  His wife, Susan, is unaffected.  They have three children, George, Jr., Stephen, and Carol.  All were at 50 percent risk of developing HNPCC. George, Jr., and Carol are affected.

  2. George, Jr. and his wife, Connie, have two children.  Both children have a 50 percent chance of inheriting HNPCC. Their daughter, Alice is affected.

  3. Stephen and his wife, Gloria, have two children.  Because Stephen is unaffected, there was no risk to his children of developing HNPCC.

  4. Carol and Bill have three children.  Each child had a 50 percent change of inheriting HNPCC and two are affected; son Billy is not.

How is HNPCC Diagnosed?
Persons at risk for HNPCC usually have a family history of two successive generations of colorectal cancer or at least one generation with colorectal cancer and one generation with polyps. Men and women at risk for HNPCC need examinations of the entire colon. Women at risk should also have yearly endometrial and ovarian screening. Tests such as colonoscopy and barium enema with flexible sigmoidoscopy are available to tell whether polyps or cancer are present in the colon. For patients at risk for HNPCC, colonoscopy is the preferred method of screening.

Why is Early Diagnosis Important?
Early diagnosis is important for early detection and prevention of cancer. Regular screening should start at the ages described in the exam guidelines below. When colorectal cancer is detected early, the chance of cure is much better.

Genetic Counseling and Testing
Genetic counseling is available, and recommended, for individuals with HNPCC and their family members. Genetic counselors will explain the inheritance pattern of HNPCC, discuss which family members are at risk for developing the condition, and provide necessary information regarding genetic testing. Counseling services are available through genetic and oncology departments in many hospitals. To make an appointment with a member of the Johns Hopkins professional medical team or to speak with someone at the Colorectal Cancer Risk Assessment Service, please call (410) 614-LIFE (5433). Also, it is recommended that HNPCC families contact registries for access to resources and for help with identification of family members at risk. 

Mutations (alterations) of one of five genes are now known to be responsible for most cases of HNPCC. These genes are called hMSH2, hPMS1, MSH6 (all on chromosome 2), hMLH1 (chromosome 3), and hPMS2 (chromosome 7). Other genes, presently undiscovered, may also cause HNPCC. Gene tests for HNPCC are available for selected individuals from families who have HNPCC. A family member affected with colon cancer should be tested first, whenever possible.

Fig 2. Chromosomes 2, 3, and 7


Microsatellite Instability Testing
Microsatellite instability (MSI) testing is used as a screening test to see how likely it is that a person’s cancer was caused by one of the genes associated with HNPCC. It is usually done on colon tumor tissue that is removed and stored as part of the normal process when a person has surgery for colon cancer.

If the tumor tissue tests MSI positive, it is considered more likely that the cancer is due to one of the HNPCC gene mutations. People who have a positive MSI test have the option to pursue the genetic blood test. If the tumor tissue tests MSI negative, however, it is highly unlikely that current genetic testing will be helpful for the affected person’s family. An MSI negative test result does not rule out the diagnosis of HNPCC.

Results and Screening Guidelines For Individuals Who Have Had HNPCC Gene Testing

        The following four outcomes are possible results from your genetic testing:

  1. Positive gene test—an HNPCC gene mutation was found in a person’s blood sample. Persons with a positive gene test should have a colonoscopy every year and follow the exam guidelines for people at risk listed below. In addition, other ways to prevent cancer, surgeries such as colectomy, hysterectomy, and oophorectomy, may be considered.

  2. Negative gene test—No HNPCC gene mutation was found in a person’s blood sample and an affected family member has had a positive gene test. Persons with a negative gene test (an HNPCC gene mutation was not found), require careful evaluation by their doctor and a genetic counselor to determine the best screening guidelines to follow.

  3. No mutation found—No HNPCC gene mutation was found in a person’s blood sample and no affected family member has had a positive gene test. Continue to follow screening guidelines for persons with a family history of colorectal cancer.

  4. Variant of Unknown Significance - A mutation was detected in a person's blood, however the significance of the mutation is unclear.  It is not possible at this time to determine the effects of a variant of unknown significance until a sufficiently large populatin with a similar variant is studied.  Your genetic counselor will make screening recommendations based on your family history and the likelihood of your specific result being deleterious. 

At this time, the available gene tests cannot detect all HNPCC-causing genes. Future advances in technology may provide more accurate diagnosis. A genetic counselor or physician will assist in finding a laboratory that provides the best testing


Screening Guidelines For Individuals at Risk Who Have Not Had HNPCC Gene Testing

  1. Colonoscopy every 1–2* years starting by age 25 years or 5–10 years before the age of earliest colorectal cancer diagnosed in the family, whichever is younger. At age 40 begin annual colonoscopy.

  2. Annual stool hemoccult tests, urinalysis, and blood tests for liver function starting when colonoscopy begins.

  3. For women: yearly pelvic exam with Pap test and transvaginal ultrasound of the uterus and ovaries or Pipel biopsy starting at age 25 and continuing annually.

  4. Consider annual upper endoscopy in families with gastric cancer.

   *Colonoscopy is recommended every year for a person with a positive gene test. 
         If colon polyps or cancer is found, follow the treatment guidelines.

Contact our Registry for more Information