ConditionCancer
Lynch Syndrome
Lynch syndrome is the most common inherited cause of colorectal and endometrial cancer. It is caused by a faulty mismatch repair gene (MLH1, MSH2, MSH6, PMS2 or EPCAM) passed down in families, which stops cells fixing DNA copying errors. It affects about 1 in 280 people, most of whom do not know they have it. Lynch syndrome raises the lifetime risk of several cancers, often at younger ages. Regular colonoscopy and other screening greatly reduce cancer deaths.
Also called: Hereditary nonpolyposis colorectal cancer (HNPCC), mismatch repair deficiency syndrome, Lynch cancer syndrome
At a glance
- What it is
- An inherited mismatch repair gene mutation that raises cancer risk.
- How common
- About 1 in 280 people. Causes roughly 3% of colorectal and endometrial cancers.
- Inheritance
- Autosomal dominant. Each child of a carrier has a 50% chance of inheriting it.
- Main cancers
- Colorectal and endometrial. Also ovarian, stomach, small bowel, urinary tract, pancreas, biliary, brain, skin.
- Testing
- Tumor screening for mismatch repair deficiency, then genetic testing. Relatives can be tested once the family mutation is known.
- Prevention
- Colonoscopy every 1 to 2 years, aspirin discussion, and risk-reducing gynecologic surgery after childbearing.
When to get help
Call 911 or go to the ER
- Heavy rectal bleeding, or a swollen belly with vomiting and inability to pass stool or gas
- Heavy vaginal bleeding with dizziness or fainting
See a doctor within a day or two
- Rectal bleeding, a change in bowel habits, iron-deficiency anemia or unexplained weight loss in someone with Lynch syndrome
- Abnormal vaginal bleeding, bleeding between periods or after menopause in a woman with Lynch syndrome
- Blood in the urine
Book a routine appointment
- A family history of colorectal or endometrial cancer diagnosed before age 50, or several relatives with Lynch-associated cancers
- A cancer whose tumor testing showed mismatch repair deficiency or MSI-high
- A relative with known Lynch syndrome, to arrange genetic counseling and testing
- Missed or overdue surveillance colonoscopy
How Lynch syndrome causes cancer
Every time a cell divides, its DNA is copied, and small errors occur. Mismatch repair (MMR) genes fix these errors. People with Lynch syndrome inherit one faulty copy of an MMR gene. If the second copy is damaged in a cell, errors build up quickly, a state called microsatellite instability (MSI), and cancer can develop faster. In the colon, a polyp may become cancer within 1 to 3 years rather than the usual 10.
Genes involved
| Gene | Relative colorectal risk | Notes |
|---|---|---|
| MLH1 | Highest | Earlier onset |
| MSH2 and EPCAM | Highest | Also higher risk of urinary tract cancers |
| MSH6 | Lower, often later onset | Higher endometrial risk relative to colorectal |
| PMS2 | Lowest | Screening may start later |
Cancer risks
Lifetime risks vary by gene and studies, but approximate ranges are:
- Colorectal cancer: up to about 50% with MLH1 or MSH2, lower with MSH6 and PMS2 (compared with about 4% in the general population)
- Endometrial cancer: about 20 to 50% for women with MLH1, MSH2 or MSH6, often the first cancer in women
- Ovarian cancer: up to about 10 to 15% with some genes
- Stomach cancer and small bowel cancer
- urinary tract cancer (ureter and kidney pelvis), especially MSH2
- pancreatic, biliary, brain (glioblastoma) and prostate cancers
- sebaceous skin tumors (Muir-Torre variant)
Who should be tested
- All colorectal and endometrial cancers should have tumor screening for MMR deficiency or MSI, which is now standard practice. Abnormal results lead to genetic testing.
- People with a personal or family history of: - colorectal or endometrial cancer before 50 - multiple Lynch-associated cancers in one person - several relatives on the same side of the family with Lynch-associated cancers
- Relatives of someone with a known Lynch mutation (cascade testing)
- People whose risk models (such as PREMM5) estimate a significant chance of carrying a mutation
Testing is done after genetic counseling, usually with a blood or saliva test for a multigene panel.
Screening and prevention
Guidelines from NCCN and gastroenterology societies recommend:
- Colonoscopy every 1 to 2 years, starting at age 20 to 25 for MLH1 and MSH2 carriers, and somewhat later (often 30 to 35) for MSH6 and PMS2. Polyps are removed during colonoscopy, which prevents cancers
- Endometrial and ovarian cancer: awareness of symptoms and prompt evaluation of abnormal bleeding. Endometrial biopsy every 1 to 2 years from 30 to 35 may be considered
- Risk-reducing hysterectomy and removal of ovaries and fallopian tubes once childbearing is complete, often around age 40, which greatly reduces gynecologic cancer risk
- Upper endoscopy every 2 to 4 years from about age 30 to 40 in many carriers, with testing and treatment for H. pylori
- Urinalysis yearly in some, particularly MSH2 carriers
- Skin checks for sebaceous tumors
- Aspirin: the CAPP2 trial showed long-term aspirin reduced colorectal cancer in Lynch syndrome carriers. Discuss dose and bleeding risk with your doctor
Treatment of Lynch-associated cancers
- Surgery, chemotherapy and radiation as for other cancers, with some differences. More extensive colon surgery may be considered to reduce new cancers.
- Immunotherapy: MMR-deficient cancers respond particularly well to checkpoint inhibitors such as pembrolizumab and dostarlimab, including advanced colorectal and endometrial cancers.
Living with Lynch syndrome
- Share results with relatives so they can be tested. Genetic counselors can help with family letters.
- Each pregnancy has a 50% chance of passing on the gene. Options such as preimplantation genetic testing can be discussed.
- In the US, the Genetic Information Nondiscrimination Act (GINA) protects against genetic discrimination in health insurance and employment, but not life, disability or long-term care insurance.
Frequently asked questions
What is Lynch syndrome?
Lynch syndrome is an inherited condition caused by a mutation in a DNA mismatch repair gene. It greatly raises the risk of colorectal and endometrial cancer, as well as several others, often at a younger age than usual.
What cancers are linked to Lynch syndrome?
The main cancers are colorectal and endometrial. Others include ovarian, stomach, small bowel, urinary tract (ureter and kidney), pancreatic, bile duct, brain and certain skin tumors. Risks vary depending on which gene is affected.
How is Lynch syndrome diagnosed?
Tumors from colorectal and endometrial cancers are tested for mismatch repair deficiency. If abnormal, or if family history suggests Lynch syndrome, a genetic test on blood or saliva looks for mutations in MLH1, MSH2, MSH6, PMS2 or EPCAM.
How often do people with Lynch syndrome need a colonoscopy?
Usually every 1 to 2 years, starting between ages 20 and 35 depending on the gene involved. Regular colonoscopy with polyp removal significantly reduces the risk of developing and dying from colorectal cancer.
Can Lynch syndrome skip a generation?
The gene itself does not skip generations, because it is inherited in an autosomal dominant pattern. However, a carrier may never develop cancer, which can make it look as though it skipped a generation. Genetic testing clarifies who carries it.
Sources
This guide was written from current patient and clinical guidance, including:
- National Cancer Institute: Genetics of Colorectal Cancer (PDQ)
- NCCN Guidelines: Genetic/Familial High-Risk Assessment, Colorectal, Endometrial and Gastric
- American College of Gastroenterology: Clinical Guideline on Hereditary Gastrointestinal Cancer Syndromes
- CDC: Lynch Syndrome
- US Multi-Society Task Force on Colorectal Cancer: Guidelines on Lynch syndrome