Lynch Syndrome

Background

• Lynch syndrome is an autosomal dominant cancer syndrome which increases the risk of developing colorectal cancer up to 82% (compared to 5.5% in general population) and is characterized by increased risk of other cancers, including endometrial, gastric, and ovarian cancer.
• Lynch syndrome is caused by pathogenic variants in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and in the EPCAM gene.
• Factors associated with increased risk of developing cancer in persons with Lynch syndrome include obesity and smoking.

Evaluation

• Diagnosis of Lynch syndrome is important for patients with Lynch syndrome-related cancer due to the high risk of asynchronous cancers (such as second colorectal cancer or endometrial cancer following colorectal cancer), relatives of patients with Lynch syndrome due to autosomal dominant inheritance and potential for high penetrance, and Lynch syndrome mutation carriers to allow surveillance for early detection and prevention of Lynch syndrome-related cancers.
• Suspect Lynch syndrome in patients aged < 50 years presenting with diagnosis of Lynch syndrome-related cancer (typically colorectal or endometrial cancer), and/or with family history of Lynch syndrome or Lynch syndrome-related cancers.
• Diagnosis of Lynch syndrome is confirmed with genetic tumor testing and/or germline genetic testing to identify pathogenic variants in the MMR genes and the EPCAM gene:
  • For persons at risk of carrying Lynch syndrome mutations based on personal or family history, offer germline genetic testing (Strong recommendation);
  • For patients diagnosed with Lynch syndrome-related cancer, particularly colorectal and endometrial cancer, offer molecular tumor testing with immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing (Strong recommendation), or germline genetic testing (Strong recommendation), or multigene testing (Weak recommendation).
• Recommend genetic screening of all first-degree relatives (parents, siblings, and children) of patients with Lynch syndrome for early identification of individuals who would benefit from treatment and prevention (Strong recommendation).

Management

• Management of persons with Lynch syndrome consists of surveillance and prevention of Lynch syndrome-related cancers.
• Surveillance of Lynch syndrome-related cancers:
  • For colorectal cancer, perform colonoscopy with polypectomy beginning at age 20-25 years or 2-5 years before earliest familial diagnosis, whichever occurs first, and repeat every 1-2 years (Strong recommendation).
  • For endometrial cancer, consider endometrial biopsy every 1-2 years in women with Lynch syndrome (Weak recommendation) and pelvic/transvaginal ultrasound (Weak recommendation) starting at the age of 30-35 years.
  • For ovarian cancer, consider transvaginal ultrasound and serum cancer antigen (CA)-125 starting at the age of 30-35 years (Weak recommendation).
  • For gastric and small bowel cancers, consider upper endoscopy with visualization of upper duodenum every 3-5 years starting at age 30-35 years in patients with family history of gastric, duodenal, or small bowel cancer or those of Asian ancestry (Weak recommendation), and testing for Helicobacter pylori infection (Weak recommendation).
  • For other Lynch syndrome-related cancers, there is currently limited evidence supporting specific surveillance approaches.
• Prevention of Lynch syndrome-related cancers:
  • May consider chemoprevention of colorectal cancer with aspirin (Weak recommendation) and endometrial cancer with progestin-based contraceptives (Weak recommendation).
  • Prophylactic surgery:
    • prophylactic colectomy is generally not recommended in healthy persons with Lynch syndrome who have not yet developed colon cancer (Strong recommendation); screening colonoscopy with polypectomy is an effective preventive measure;
    • consider prophylactic hysterectomy and bilateral salpingo-oophorectomy for women with Lynch syndrome after completion of childbearing (Weak recommendation).
• Management of Lynch syndrome patients diagnosed with cancer should generally be same as for the general population.
  • Patients may benefit from consultation with a cancer clinical geneticist or a clinician with expertise in Lynch syndrome.
  • Special considerations for immunotherapy and surgery may apply to Lynch syndrome patients diagnosed with colorectal cancer.