Hereditary Nonpolyposis Colon Cancer - Causes, Symptoms, Diagnosis, and Treatment

What Is Hereditary Nonpolyposis Colon Cancer?

Hereditary nonpolyposis colon cancer (HNPCC) is a genetic disorder inherited in an autosomal dominant pattern. Hereditary nonpolyposis colon cancer increases the risk of developing several other types of cancer, especially colon and rectum cancer. The colon is a part of the large intestine, and cancer associated with the colon and rectum is collectively called colorectal cancer. In addition, individuals affected by HNPCC are at a higher risk of developing cancer of the stomach, liver, small intestine, renal pelvis, gallbladder duct, urinary tract, brain, skin, ovaries, and endometrial lining. Out of all these, the most prevalent extracolonic association in HNPCC is endometrial cancer. The condition is characterized by a substantial family history of HNPCC-associated malignancies (cancers) in first-degree relatives that spans at least two generations and at least one case diagnosed before fifty years of age.

What Are the Other Names of Hereditary Nonpolyposis Colon Cancer?

Other names of the condition are:

• Lynch syndrome.

• Hereditary nonpolyposis colorectal cancer.

• HNPCC.

What Causes Hereditary Nonpolyposis Colon Cancer?

• Hereditary nonpolyposis colon cancer is a genetic disorder associated with a mutation (or variation) in several genes.

• Genes affected are; MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), PMS2, and EPCAM (epithelial cell adhesion molecule).

• The MLH1, MSH2, MSH6, and PMS2 genes are responsible for giving instructions for the production of a protein crucial for DNA repair. Therefore, mutations in any of these genes will lead to DNA repair and replication errors. The cumulative errors could lead to unchecked cell growth and possibly cancer when the abnormal cells continue to multiply.

• Variations in the MSH6 or PMS2 genes have a decreased probability of developing cancer, whereas variants in the MLH1 or MSH2 genes tend to increase the risk of developing cancer in an individual. Mutations in the MSH6 and PMS2 genes have approximately a 25 to 60 percent chance of cancer development. At the same time, mutations in the MLH1 and MSH2 genes risk 70 to 80 percent.

• Even though these gene variations increase the risk of developing cancer, not everyone who has them does.

How Is Hereditary Nonpolyposis Colon Cancer Inherited?

HNPCC is inherited in an autosomal dominant pattern. When there is an inherited gene mutation, it is usually present in the cells of all organs of the body. This facilitates cancer development in other parts of the body as well. One inherited copy of the mutated gene in each cell is sufficient to raise cancer risk in HNPCC patients.

How Common Is the Hereditary Nonpolyposis Colon Cancer?

• According to estimates, one in 279 people in the US has a genetic variation linked to HNPCC.

• Among people of the White race, hereditary non-polyposis colorectal cancer prevalence ranges from one to six percent.

• HNPCC is diagnosed in both men and women equally.

What Are the Symptoms of Hereditary Nonpolyposis Colon Cancer?

The symptoms and clinical features of HNPCC are:

• Constipation or diarrhea (gastrointestinal upset).

• Abdominal pain and cramps.

• Bloating.

• Visible blood loss along with stool.

• Melena (dark sticky feces with semi-digested blood due to internal bleeding or blood ingestion).

• Iron deficiency.

• Reduced appetite.

• Weight loss.

• Weakness and fatigue.

How Is Hereditary Nonpolyposis Colon Cancer Diagnosed?

A positive family history of colorectal cancer and other cancers was traditionally the primary indicator of HNPCC. Moreover, the presence of several clinical features (mentioned above) also suggests a diagnosis of HNPCC. However, there are multiple criteria to determine individuals at risk. Most HNPCC cases go undetected.

1. Amsterdam I Criteria: The initial introduction of the Amsterdam I criteria determined those at risk for HNPCC. Later, it was changed to the Amsterdam II criteria to incorporate other cancers linked to HNPCC.

2. Amsterdam II Criteria: The Amsterdam II criteria are about 22 percent sensitive and 98 percent specific in diagnosing HNPCC. The presence of HNPCC should be suspected in anyone who meets all of the criteria listed below:

• Three or more relatives with clinically confirmed HNPCC-associated cancers, one of these relatives should be a first-degree relative of the other two, and in whom familial adenomatous polyposis has been ruled out.

• At least two generations should be affected by HNPCC-associated cancers.

• At least one cancer case should have been diagnosed before 50 years of age.

3. Bethesda Criteria: The Bethesda and revised Bethesda criteria were developed to help determine who needs tumor testing for microsatellite instability. Microsatellite instability is a kind of testing on malignant tissue or polyps. Strong family history and positive MSI test indicate a diagnosis of HNPCC. In addition, direct DNA sequencing genetic testing should confirm the diagnosis.

4. Genetic Testing: It may be advised to perform a DNA sequencing test for the gene mutations that cause HNPCC if there is a strong possibility that the family has an inherited colon cancer syndrome. In around half of the HNPCC families, a mutation has been found. If it is found in the family, testing may be done on other family members. It is important to note that a positive gene test merely verifies that an inherited gene mutation exists and cannot identify polyps or cancer.

How Is Hereditary Nonpolyposis Colon Cancer Treated?

The treatment modalities include:

Routine Measures: From the age of 25 to 30, people with HNPCC should get a physical examination every year.

Surgery: Several surgeries can be done depending on the severity of the condition:

1. Colon Neoplasia: Total abdominal colectomy with ileorectal anastomosis is the preferred surgery for individuals with HNPCC and colon cancer or an endoscopically unresectable adenoma, with yearly endoscopic surveillance of the residual rectum.

2. Segmental Colectomy: For patients who are not candidates for total colectomy, segmental colectomy with yearly post-operative colonoscopic surveillance is the treatment of choice.

3. Rectal Neoplasia: Total proctocolectomy with an ileal pouch-anal anastomosis is the preferred surgery for individuals with HNPCC and rectal cancer since proctectomy carries a high risk for metachronous colon cancer. After a proctectomy for rectal cancer, it is crucial to ensure yearly colonoscopic surveillance of the residual colon.

Chemotherapy: Advanced and metastatic (spreads to other body parts) colorectal cancer may benefit from immunotherapy using an immune checkpoint inhibitor therapy.

What Are the Complications of Hereditary Nonpolyposis Colon Cancer Diagnosed?

Complications associated with HNPCC are:

• Increased risk of synchronous and metachronous colorectal cancer. Synchronous cancers occur within six months of primary cancer, and metachronous cancers occur after six months.

• Women have an increased risk of endometrial cancer (cancer of the endometrial lining).

• In addition, people with HNPCC have a higher chance of developing pancreatic, prostate, breast, and cervical cancers. A few cases of sarcomas, hematologic malignancies, and laryngeal carcinoma have also been observed in people with HNPCC.

How Can Cancer Be Prevented in an HNPCC Family?

Colonoscopies must be performed regularly to prevent colorectal cancer. Adenomatous polyps, which can be removed via a colonoscopy, are the primary cause of cancer in most cases. Cancer in an HNPCC family is prevented in the following ways:

• A healthy diet and lifestyle can also help prevent colorectal cancer in addition to routine screening.

• The only definite method to stop colon cancer from returning is the surgical removal of the entire colon if cancer is discovered. Most patients can resume regular diets and daily activities after surgery.

Conclusion:

Hereditary nonpolyposis colorectal cancer is a rare genetic disorder that increases the risk of several other cancers, including colorectal cancer. However, individuals with HNPCC and colon cancer have a much better prognosis than individuals with colorectal cancer in the general population (sporadic colon cancer cases). In patients with HNPCC, the five-year survival rate is around 60 percent, compared to 40 to 50 percent in sporadic cases.