Hereditary Non-Polyposis Colorectal Cancer Syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC) is a type of colorectal cancer caused by genetic changes that run in families, increasing the risk of developing cancer before age 50 and affecting multiple generations.

Table of contents

• What Is Hereditary Nonpolyposis Colorectal Cancer?
• The Relationship Between HNPCC and Lynch Syndrome
• How Common Is HNPCC?
• Symptoms of HNPCC
• What Causes HNPCC?
• Cancer Risks Associated with HNPCC
• The Hereditary Nature of HNPCC
• How Healthcare Providers Diagnose HNPCC
• Treatment Options for HNPCC
• Prevention and Screening

What Is Hereditary Nonpolyposis Colorectal Cancer?

Hereditary nonpolyposis colorectal cancer (HNPCC) is a type of colorectal cancer caused by genetic changes, also called mutations (permanent changes in the genetic material), that run in families.^[1] These genetic changes are passed from parents to children. When you inherit certain gene mutations from your biological parents, you have a family cancer syndrome, which is a genetic disorder associated with an increased risk of developing certain cancers.^[1]

HNPCC is the most common cause of inherited colorectal cancer. Between 2% and 4% of all colorectal cancers are HNPCC, though inherited syndromes are thought to account for up to 10% of all colorectal cancers.^[1][2] Anyone can develop HNPCC, and most people receive a diagnosis before age 50.^[1]

The Relationship Between HNPCC and Lynch Syndrome

HNPCC is sometimes called Lynch syndrome, but they are related yet not exactly the same. Lynch syndrome is a broader hereditary cancer syndrome (a group of cancers that run in families due to inherited genetic changes) that increases the risk of many types of cancer.^[3] HNPCC specifically refers to people and families who have Lynch syndrome-associated cancer that is diagnosed before age 50.^[1] This can include colorectal cancer and cancers of the endometrium (the inside lining of the uterus), small bowel, ureter, and renal pelvis.^[1]

Lynch syndrome used to be called hereditary nonpolyposis colorectal cancer (HNPCC). The term HNPCC is used to describe families with a strong history of colon cancer. Lynch syndrome is the term used when healthcare professionals find a gene that runs in the family and causes cancer.^[3]

How Common Is HNPCC?

In the United States, it is estimated that 1 in 279 individuals have a genetic variant associated with Lynch syndrome.^[4] HNPCC accounts for approximately 1% to 3% of all colorectal cancers.^[9] Lynch syndrome causes about 3,800 colorectal cancers and 1,600 uterine (endometrial) cancers per year in the United States.^[6]

Symptoms of HNPCC

HNPCC may not cause any symptoms at first. As cancer grows, you may experience the following:^[1]

• Abdominal pain or bloating
• Appetite loss
• Bloody stools
• Fatigue
• Unexplained weight loss

Other common signs and symptoms include blood in the stool, diarrhea or constipation, and unintended weight loss.^[5] Two-thirds of colon cancers in people with HNPCC occur in the proximal colon (the right side of the colon).^[5]

The mean age of colorectal cancer diagnosis is 44 for members of families that meet specific diagnostic criteria for HNPCC.^[5]

What Causes HNPCC?

Lynch syndrome, the family cancer syndrome that causes HNPCC, develops when you have mutations in specific genes called mismatch repair (MMR) genes (genes responsible for fixing errors that occur when DNA is copied).^[1] The primary genes involved are MLH1, MSH2, MSH6, and PMS2. In certain cases, a deletion of the promoter region of the EPCAM gene leads to MSH2 inactivation, and thus Lynch syndrome.^[7]

These genes help correct the mistakes that happen during DNA replication (the process by which cells copy their genetic material before dividing). With these genes mutated, cells are unable to fix DNA replication errors, resulting in an increased tendency of normal cells to become cancer cells.^[1]

People with mutations in the MLH1 or MSH2 genes tend to have a higher risk of developing cancer during their lifetime than people with mutations in the MSH6 or PMS2 genes.^[4]

Cancer Risks Associated with HNPCC

Individuals with HNPCC have a lifetime risk of colorectal cancer between 50% and 80%, often diagnosed before age 50.^[2] Patients with HNPCC must be identified because they have about an 80% lifetime risk of colorectal cancer and a 60% lifetime risk of endometrial cancer.^[2]

In addition to colorectal and endometrial cancers, Lynch syndrome increases the risk of several other cancers, including:^[4][6]

• Stomach (gastric) cancer
• Ovarian cancer
• Small intestine cancer
• Liver cancer
• Gallbladder and bile duct cancers
• Upper urinary tract cancers (kidney, ureter, bladder)
• Pancreatic cancer
• Prostate cancer
• Brain cancer
• Certain types of skin cancers

The average age of diagnosis of gastric cancer in people with HNPCC is 56 years. For ovarian cancer associated with HNPCC, the average age of diagnosis is 42.5 years old, with approximately 30% diagnosed before age 40.^[5]

Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common first cancer detected in Lynch syndrome.^[5]

The Hereditary Nature of HNPCC

HNPCC isn’t contagious. However, the HNPCC gene mutation runs in families. Families that have this mutation may have several members with colorectal cancer or other cancers linked to Lynch syndrome. The mutated genes and the associated risk of developing HNPCC can pass from one generation to the next.^[1]

Lynch syndrome is typically inherited in an autosomal dominant pattern (a pattern of inheritance where only one copy of an altered gene from one parent is sufficient to increase the risk), which means one copy of the altered gene in each cell is sufficient to increase the risk of cancer.^[4] The children of those who carry these genes have a 50 percent chance of inheriting them.^[15]

Although people with Lynch syndrome have a higher risk of cancer, not all people with Lynch syndrome will develop cancer.^[4]

How Healthcare Providers Diagnose HNPCC

Healthcare providers typically diagnose colorectal cancer with a physical examination and colonoscopy (a procedure where a tube is inserted into the anus to view the inside of the large bowel).^[1] It is important to tell your provider if you have a family history of HNPCC.

Your provider may recommend genetic testing to confirm that you have the genetic mutations associated with Lynch syndrome.^[1] Several organizations recommend universal screening for Lynch syndrome in all patients with endometrial cancer or colorectal cancer.^[7]

Your provider will also ask you if anyone in your immediate family has or had colorectal cancer, especially if their diagnosis occurred before age 50. They will also rule out familial adenomatous polyposis (FAP), another inherited form of colorectal cancer caused by genetic mutations different from HNPCC.^[1]

Doctors use a set of criteria to determine if HNPCC is present in your family. These criteria are known as the Amsterdam criteria and include:^[15]

• Three family members with HNPCC-related cancer
• Two successive generations with HNPCC-related cancer
• Two affected family members are first-degree relatives of another affected family member
• One family member develops HNPCC cancer before age 50
• FAP is not present in any family member’s diagnosis

Treatment Options for HNPCC

Healthcare providers typically treat HNPCC with surgery called colectomy (surgical removal of all or part of the colon). You may have:^[1]

• Partial colectomy or segmental colectomy (removal of part of your colon)
• Proctectomy (removal of your colon and rectum)
• Total colectomy (removal of your entire colon)

Subtotal colectomy with ileorectal anastomosis (connecting the small intestine to the remaining rectum) is recommended when colon cancer develops in patients with HNPCC. This operation is preferred over segmental resection or removal of half the colon for HNPCC-associated cancers.^[12]

If colorectal cancer has spread (metastasized, meaning the cancer has spread from where it started to other parts of the body), your healthcare provider may recommend other treatments in addition to surgery:^[1]

• Chemotherapy (treatment that uses drugs to stop the growth of cancer cells)
• Immunotherapy (treatment that uses the body’s immune system to fight cancer)

Healthcare providers usually prefer immunotherapy because it’s often more effective with fewer side effects.^[1]

Prevention and Screening

Early identification of affected individuals and appropriate screening significantly reduce the risk of malignancy.^[2] Regular screenings and surveillance become crucial elements in managing the uncertainty of Lynch syndrome.^[23]

For those with HNPCC families, routine cancer screenings should start between the ages of 20 and 25. Colonoscopies are recommended for family members who are 10 years younger than the youngest family member diagnosed with cancer. This allows doctors to detect and treat any abnormalities as early as possible.^[15]

If a family member has Lynch syndrome, you should tell your healthcare professional and ask for help in setting up an appointment with a professional trained in genetics, such as a genetic counselor (a healthcare professional who helps people understand genetic conditions and testing). This person can help you understand Lynch syndrome, what causes it, and whether genetic testing is appropriate for you.^[3]

Lynch syndrome, HNPCC, hereditary nonpolyposis colorectal cancer