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Sounding the alarm on Lynch syndrome

February 23, 2023 | Valerie Elwell
Concept illustration of cancer cells attacking the colon.

People with Lynch syndrome have a far greater risk for colon cancer, one of the leading causes of U.S. cancer deaths. But colon cancer is also one of the most preventable with regular screenings.

UCI Health researcher and gastroenterologist Dr. William E. Karnes is on a mission to raise awareness of Lynch syndrome, the most prevalent — and underdiagnosed — hereditary disorder that increases the risk for developing cancer.

People with this inherited genetic disorder have a significantly higher lifetime risk of developing cancers of the colon, uterus, ovaries, stomach and urinary tract, among others.

As director of high-risk colorectal cancer services at the UCI Health Digestive Health Institute, Karnes sees three to four patients a week who have Lynch syndrome and are returning for their annual colonoscopies, are coming to discuss genetic testing for the disorder or to get their results.

Lynch mutations affect an estimated one in 300 U.S. men and women vs. one in 500 for the better-known BRCA gene mutations implicated in breast and ovarian cancers, says Karnes. “That’s over 1.1 million people in the United States alone.”

It may be far more widespread than that. In Iceland, general population testing showed a carrier rate of one in 226 people tested, while a large registry study in the United States, Australia and Canada estimated a carrier rate of one in 279.

People with Lynch syndrome have a 50% chance of passing it to each of their children. By simply collecting detailed family histories and testing patients whose parents and close relatives had colorectal and other cancers before age 50, colorectal cancer can be prevented or caught at its earliest, most treatable stage with regular screenings, Karnes says.

“This genetic syndrome is a lot more common than anyone realizes and the vast majority of people have no clue they have it.”

What is Lynch syndrome?

Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is caused by mutations in genes responsible for repairing DNA mismatches — MLH1, MSH2, MSH6, PMS2 and EPCAM. It is characterized by early age onset of colorectal and endometrial (uterine) cancer, as well as ovarian, bladder, ureteral, stomach, pancreatic, bile duct and skin cancers.

Colorectal cancer, the fourth leading cause of U.S. cancer deaths, is expected to claim more than 50,000 lives in 2023, according to the Centers for Disease Control and Prevention. It is also one of the most preventable with regular screenings.

Men with Lynch syndrome have a 50% to 80% lifetime risk of developing colon cancer. Women have a 40% to 60% lifetime risk for colon cancer and a 40% to 60% chance of developing endometrial cancer. The risk of developing cancers of the small bowel, urethra and ovary are each between 5% and 10%.

Identifying who is at risk

Karnes laments the lack of awareness about Lynch syndrome — among the general public and doctors.

“While a complete family history is important to get, primary care practices are extremely busy and it often isn’t gathered,” says Karnes, a professor at the UCI School of Medicine.

He educates UCI fellows, residents and medical students about the prevalence of Lynch syndrome. But he also advocates that all physicians make gathering family histories from their patients a top priority. In particular, he calls for including Lynch syndrome prediction models in every patient’s electronic questionnaire.

A blue graphic showing the cancers associated with Lynch syndrome.

Short of that, key questions to ask include:

  • Are you aware of any family members who have been diagnosed with cancer?
  • If so, what is their relationship to you, what type of cancers did they have and at what age?
  • When was your last colonoscopy and what were the results?
  • Were you told when you should get your next one?
  • Do you have a personal history of cancer?
  • If so, what type and at what age? What was/is your treatment plan?

“Specifically, a physician should be looking to see if the patient has three or more relatives with cancer across a few generations,” he says.

“For instance, if a father, uncle and grandfather had colorectal cancer, especially if they were diagnosed under age 50, the patient should be referred immediately to a genetic counselor for testing and get scheduled for a colonoscopy."

If you see this within your family tree, advocate for yourself. Tell your doctor and ask for the genetic testing, Karnes advises.

Frequent screenings lower risk

“Knowing you have a higher risk for multiple cancers can be daunting for anyone,” says Karnes. “It’s important for people to know that regular physical exams and cancer screenings improve their odds for preventing cancer altogether or catching it in its earliest stages.”

If the person carries a Lynch-related gene mutation, screenings should begin at age 25 or as soon as it is detected.

Management plans should be tailored to each person based on their personal and family history. They generally include screenings for:

  • Colorectal cancer – People with Lynch syndrome undergo colonoscopy more frequently, annually in most cases, because benign polyps found in the colon can become cancerous far faster. Staying up-to-date with colonoscopies, the gold standard for detecting cancerous and pre-cancerous polyps, significantly lowers the risk for developing advanced colorectal cancer.
  • Gynecologic cancers – Women with Lynch syndrome also need regular screenings for gynecologic cancers because the risk of endometrial cancer is equal to or greater than the risk of colorectal cancer. Starting at age 30 to 35, a yearly pelvic exam, endometrial biopsy and vaginal ultrasound are recommended. Depending on a patient’s specific Lynch mutation, their personal and family history, some women may be advised to consider surgical removal of the uterus, ovaries and fallopian tubes to decrease the risk for endometrial and ovarian cancer.
  • Stomach and small intestine cancers – An upper endoscopy may be recommended every two to three years to check for polyps or tumors in the stomach and small intestine. This procedure can be performed at the same time as a colonoscopy.
  • Urinary tract cancers – Annual urinalysis with microscopy is recommended to check for urinary tract cancers.

Screening for skin and other cancers may also be advised, depending on a patient’s family history.

“Physicians can best help their Lynch syndrome patients by knowing the risk factors and scheduling the appropriate screening at the appropriate time,” says Karnes. “If caught early, all these cancers are survivable.”

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