Lynch syndrome

Other Names: Colorectal cancer, hereditary nonpolyposis; Hereditary nonpolyposis colorectal cancer; HNPCC; Familial nonpolyposis colon cancer; Colon cancer, familial nonpolyposis; COCA1; Lynch syndrome 1; Lynch syndrome 2

Lynch syndrome is a genetic disorder that causes an increased risk of developing certain types of cancer such as colon and rectal cancer, as well as cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with Lynch syndrome also have a high risk of developing uterine cancer (also called endometrial cancer) and ovarian cancer. Even though the disorder was originally described as not involving noncancerous (benign) growths (polyps) in the colon, people with Lynch syndrome may occasionally have colon polyps.

Cause

Lynch syndrome is caused by mutations in at least 5 genes (MLH1, MSH2, MSH6, PMS2 or EPCAM). All of these genes are involved in the repair of mistakes made when DNA is copied (DNA replication) in preparation for cell division. Mutations in any of these genes prevent the proper repair of DNA replication mistakes. As the abnormal cells continue to divide, the accumulated mistakes can lead to uncontrolled cell growth and possibly cancer. Although mutations in these genes predispose individuals to cancer, not all people who carry these mutations develop cancerous tumors.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Lynch syndrome cancer risk is inherited in an autosomal dominant pattern, which means one inherited copy of the mutated gene in each cell is sufficient to increase a person's cancer risk. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop cancer.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Colon cancer
• Constipation
• Fatigue(Tired)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Glioblastoma multiforme
• Malabsorption(Intestinal malabsorption)
• Weight loss

30%-79% of people have these symptoms

• Anxiety(Excessive, persistent worry and fear)
• Attention deficit hyperactivity disorder(Attention deficit)
• Death in early adulthood
• Death in infancy(Infantile death)
• Depressivity(Depression)
• Hypertonia
• Increased intracranial pressure(Rise in pressure inside skull)
• IrritabilityJI(Irritable)
• Migraine(Intermittent migraine headaches)
• Muscular hypotonia
• Low or weak muscle tone
• Nausea and vomiting
• Neoplasm of the rectum(Rectal tumor)
• Seizure

Diagnosis

When a person is diagnosed with colorectal cancer, their tumor tissue is often screened to see if their cancer was caused by Lynch syndrome. In some cases, when a woman is diagnosed with uterine (endometrial) cancer, her tumor tissue may be screened as well. The tumor tissue used for screening comes from tissue removed during a biopsy or surgery. There are two types of Lynch syndrome tumor screening: Immunohistochemistry (IHC) and microsatellite instability (MSI) testing. Immunohistochemistry screening (IHC) IHC screening looks to see if certain proteins are absent in the tumor sample, indicating that one of the Lynch syndrome genes might not be working properly. Lynch syndrome mutations affect whether the MLHL, MSH2, MSH6, and PMS2 proteins are made and located in the correct place.

Microsatellite Instability (MSI) screening MSI screening is used to see if the Lynch syndrome genes are working properly. Microsatellites are regions of repeated DNA that change in length (show instability) when mismatch repair is not working properly. MSI testing looks at the length of certain DNA microsatellites from the tumor sample to see if they have gotten longer or shorter as a measure of instability. Not everyone with an abnormal IHC or MSI result will have Lynch syndrome, and additional testing may be necessary if a tumor screens positive. Genetic counseling and genetic testing for Lynch syndrome may be recommended if your tumor screening results are abnormal.

Treatment

Surgery remains the front-line therapy for HNPCC. There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II. Several medical options are available for managing cancer risks in people who have Lynch syndrome. These options all have risks and benefits, and should be discussed with a doctor before making any medical decisions.

Colonoscopies every 1-2 years starting between the ages of 20-25 (or 2-5 years before the earliest colorectal cancer in the family) are the most effective way to prevent colorectal cancer.

Other available options may reduce the chance of developing cancer or improve the likelihood of detecting it earlier, but the effectiveness of these options is less certain and should be discussed with a doctor:

Daily aspirin use to reduce the risk of colorectal cancer Transvaginal ultrasound and endometrial biopsy every 1–2 years, beginning at age 30–35 years, to detect endometrial cancer CA-125 blood tests every year to detect ovarian cancer Hysterectomy and bilateral salpingo-oophorectomy to prevent gynecologic cancers Upper endoscopies every 3-5 years starting between the ages of 30-35 to detect stomach and small bowel cancer Urinalysis every year starting between the ages of 30-35 to detect bladder cancer Physical and neurological exams starting between the ages of 25-30 every year to check for cancer in the central nervous system. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Leucovorin (Brand name: Leucovorin calcium®) For use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

Epidemiology

In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.

Also see

• Lynch Syndrome International

NIH genetic and rare disease info

• NIH info on Lynch syndrome

Lynch syndrome is a rare disease.

Lynch syndrome Resources
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