Henry T. Lynch, MD, PhD, , died in June . Dr. Lynch founded and directed the Hereditary Cancer Center at the Creighton University School of Medicine in Omaha, Nebraska. In the early 1960s, while still a medical student, Lynch began gathering evidence to show that some cancers had a genetic cause. The prevailing wisdom at the time was that cancer was a disease caused by environmental factors, not changes in DNA, and the U.S. National Institutes of Health repeatedly turned down funding for Lynch's work. But Dr. Lynch persisted, and his research laid one of the foundations for the way we understand cancer today.
His research, and therefore his discoveries, almost didn't happen for reasons other than lack of funding. After serving in WWII in the Pacific, Lynch was a professional boxer using the stage name "Hammerin' Hank." Perhaps this first career instilled in him the dogged determination he needed to overcome early rejection of his work by the established experts.
Over a career spanning five decades, Lynch studied the medical histories of more than 3,000 families, looking for potential hereditary causes of colon and breast cancer. In 1984, Lynch was given credit for his studies when a group of patients with a hereditary nonpolyposis colon cancer were then said to have "Lynch syndrome." Lynch also described a hereditary breast-ovarian cancer syndrome, later found to be related to BRCA mutations.
What Is Lynch Syndrome?
Lynch syndrome is a genetic condition affecting both men and women, which greatly increases their risks of developing several types of malignancies. The two most common are cancers of the colon and uterus but there may be an increased risk of developing cancers of other organs as well including stomach, small intestine, liver, pancreas, gallbladder ducts, upper urinary tract, kidney, brain, and skin -- and if you're male, the prostate gland. Some women with Lynch syndrome are also at increased risk of developing cancers of the ovary and breast. Men affected by Lynch syndrome have a 50%-80% chance of developing colon or rectal cancer in their lifetime, compared with only a 4.5% chance in unaffected individuals. In the U.S., about 140,000 new cases of colorectal cancer are diagnosed each year. Approximately 3%-5% of these cancers are caused by Lynch syndrome.
What Are the Genetics of Lynch Syndrome?
Parents who are Lynch carriers can pass this cancer susceptibility along to their children in an autosomal dominant pattern of inheritance. This means that there's a 50% chance of a child being affected if one of their parents has Lynch syndrome. Of the estimated 1 million Lynch carriers in the U.S., only about 5% know they carry a mutation. (See section on screening criteria below.)
Lynch syndrome is specifically caused by defects in the cellular machinery that repairs DNA damage in our cells and involves four DNA mismatch repair (MMR) genes -- named MLH1, MSH2, MSH6 and PMS2 -- and a fifth gene called EPCAM. Mutations in the EPCAM gene also lead to impaired DNA repair, although the gene is not itself involved in this process. The EPCAM gene lies next to the MSH2 gene on chromosome 2.
When even one of these genes is abnormal, the patient's DNA accumulates "stutters" that are short repetitions of the letters in their genetic code. These stutters are referred to as microsatellite instability, or MSI, and are surrogate markers for damage to proto-oncogenes and tumor suppressors that cause cancer.
Although mutations in these genes predispose individuals to cancer, not all people who carry these mutations develop cancerous tumors.
What Are the Risks for Individuals With Lynch Syndrome?
Individuals with Lynch syndrome have a 25% chance of developing colon cancer by age 50. That risk increases with age. By age 70, there is an 82% risk of colorectal cancer.
Lynch syndrome increases the risk of:
- Endometrial cancer by up to 71%
- Gastric cancer by up to 13%
- Ovarian cancer by up to 12%
- Lifetime risk of developing some type of cancer by up to 90%
Lynch syndrome can also lead to multiple cancer diagnoses. People with Lynch syndrome have a significantly increased risk of developing a second cancer within 15 years of their first cancer diagnosis.
What Are the "Red Flags" for Lynch Syndrome?
- A personal medical history is very important in diagnosing individuals with Lynch syndrome. These red flags can identify a person who may benefit from genetic testing:
- Having colorectal or endometrial cancer before the age of 50
- Having two or more Lynch syndrome-associated cancers at any age
- Having a known Lynch syndrome mutation in the family
Genetic testing can be used to assess the risk. It can be done either by a saliva sample or by drawing blood.
What Can Be Done to Help Individuals With Lynch Syndrome?
For those diagnosed with Lynch syndrome, preventive measures may significantly reduce the risk of cancer, delay the onset of cancer, or detect cancer at an earlier, more treatable, stage. Organizations such as the National Comprehensive Cancer Network recommend starting screening at a younger age (as young as age 25) and completing screenings more often than typically recommended (every 1 to 2 years).
Colonoscopy can reduce the risk of colorectal cancer in individuals with Lynch syndrome by more than 56%. Surgically removing the uterus and ovaries can reduce endometrial and ovarian cancer by up to 100% for at-risk women.
Who Should Be Screened for Lynch Syndrome?
Genetic testing for Lynch syndrome is available to individuals if they meet certain criteria. There are two different sets of criteria in current use. These are called the Amsterdam criteria and the Revised Bethesda guidelines. Details of these criteria may be found at the .
Michele R. Berman, MD, and Mark S. Boguski, MD, PhD, are a wife and husband team of physicians who have trained and taught at some of the top medical schools in the country, including Harvard, Johns Hopkins, and Washington University in St. Louis. Their mission is both a journalistic and educational one: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.