Lynch Syndrome: Causes, Risks, and Screening

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is one of the most common hereditary cancer syndromes. It is caused by inherited mutations in genes responsible for DNA mismatch repair — a quality-control system that corrects errors made during DNA replication. When this system is impaired, mutations can accumulate more rapidly, increasing the risk of several types of cancer.

Genes Associated with Lynch Syndrome

Lynch syndrome is primarily linked to mutations in four mismatch repair (MMR) genes:

• MLH1 — the most commonly affected gene
• MSH2 — the second most commonly affected
• MSH6 — associated with somewhat different cancer risk patterns
• PMS2 — generally associated with lower penetrance

Additionally, deletions in the EPCAM gene can lead to silencing of MSH2 and cause Lynch syndrome, though this is less common.

Cancer Risks

Individuals with Lynch syndrome have elevated lifetime risks for several cancers. The specific risks vary depending on which gene is affected:

• Colorectal cancer: Lifetime risk may range from 20 to 80 percent, depending on the gene involved. The general population risk is approximately 4.5 percent.
• Endometrial cancer: Women with Lynch syndrome may have a 25 to 60 percent lifetime risk.
• Ovarian cancer: Risk may be elevated to 4 to 24 percent, particularly with MLH1 and MSH2 mutations.
• Other cancers: Stomach, urinary tract, small bowel, brain, and sebaceous gland cancers are also associated with Lynch syndrome, though at lower frequencies.

Recognizing Lynch Syndrome in Your Family

Certain patterns in a family may suggest Lynch syndrome:

• Colorectal or endometrial cancer diagnosed before age 50
• Multiple family members on the same side with Lynch-associated cancers across generations
• An individual with more than one Lynch-associated cancer
• Colorectal polyps that show microsatellite instability (MSI-high) on tumor testing

Screening and Surveillance

For individuals confirmed to have Lynch syndrome, clinical guidelines recommend enhanced surveillance that can detect cancers at earlier, more treatable stages:

• Colonoscopy every 1 to 2 years, typically starting between ages 20 and 25 (or 2 to 5 years before the youngest colorectal cancer diagnosis in the family)
• Consideration of endometrial cancer surveillance for women, including endometrial sampling
• Discussion of risk-reducing surgery (such as hysterectomy and oophorectomy) after childbearing is complete
• Aspirin use, which some studies suggest may help reduce colorectal cancer risk in individuals with Lynch syndrome — discuss with your doctor

Testing for Lynch Syndrome

Lynch syndrome can be identified through genetic testing that examines the MMR genes. Multi-gene panel tests, like those used in hereditary cancer screening programs, typically include all four MMR genes alongside BRCA and other cancer genes.

If you have a family history that raises concern, our article on who should consider genetic testing can help you evaluate whether testing may be appropriate.