What is Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC)?

From the Guidelines

Lynch syndrome is a highly penetrant genetic condition that significantly increases the risk of colorectal, endometrial, and other cancers, and thus, prompt identification and management are crucial to reduce morbidity and mortality. Lynch syndrome occurs due to mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) [ 1, 1 ]. When these genes don't work properly, errors accumulate in DNA, potentially leading to cancer. People with Lynch syndrome have a 20-80% lifetime risk of colorectal cancer and women have a 15-60% risk of endometrial cancer, with increased risks for ovarian, stomach, small intestine, pancreatic, urinary tract, and other cancers [ 1, 1 ]. Testing for Lynch syndrome involves genetic testing through blood samples, and sometimes tumor testing for mismatch repair deficiency 1.

Key Points to Consider

• The American Gastroenterological Association (AGA) and the National Comprehensive Cancer Network (NCCN) provide guidelines for the diagnosis and management of Lynch syndrome [ 1, 1 ].
• If diagnosed, increased cancer surveillance is recommended, including colonoscopies starting at age 20-25 and repeated every 1-2 years, as well as screening for other associated cancers 1.
• Some people may consider preventive surgeries like removal of the colon or uterus/ovaries to reduce cancer risk.
• Lynch syndrome follows an autosomal dominant inheritance pattern, meaning children of affected individuals have a 50% chance of inheriting the condition, making genetic counseling important for family members [ 1, 1 ].

Management and Screening

• The revised Bethesda criteria and Amsterdam II criteria can be used to identify individuals who warrant further genetic testing 1.
• Genetic testing and tumor testing for mismatch repair deficiency are essential for the diagnosis of Lynch syndrome 1.
• A study identified the following revised clinical/pathologic criteria to identify Lynch syndrome, including CRC diagnosed before age 50 years, synchronous or metachronous colorectal or other Lynch syndrome–associated tumor, and CRC with microsatellite instability–high histology 1.

From the Research

Definition and Causes of Lynch Syndrome

• Lynch Syndrome (LS) is also known as Hereditary Non-polyposis Colorectal Cancer (HNPCC) and is the most common hereditary colorectal cancer syndrome, accounting for 3-5% of CRC cases 2.
• It is caused by mutations in DNA mismatch repair (MMR) genes, which are inherited in an autosomal dominant pattern and are associated with accelerated development of cancers 2, 3.
• The MMR genes MLH1, MSH2, MSH6, and PMS2 are commonly mutated in families with Lynch Syndrome 2, 4.

Clinical Presentation and Diagnosis

• Families affected with Lynch Syndrome typically contain multiple individuals affected with CRC and/or endometrial cancer, with many of the cases diagnosed at younger ages 2.
• Clinical genetic testing has identified mutations in the MMR genes in many families with Lynch Syndrome 2.
• The criteria for the clinical diagnosis of LS and the procedures of the genetic testing for identification of pathogenetic mutations carriers in MMR genes have long been known 3.
• Variation exists regarding the optimum method for tracking and disclosing results, and international guidelines are necessary to standardize Lynch syndrome high-risk clinics 4.

Cancer Risks and Prevention

• Individuals with Lynch Syndrome have a 50%-70% lifetime risk of colorectal cancer, 40%-60% risk of endometrial cancer, and increased risks of several other malignancies 4.
• Women with Lynch syndrome have an additional need to address the substantial increased lifetime risk of endometrial and ovarian cancer, with a lifetime risk of endometrial cancer of approximately 40% 5.
• Colonoscopy at frequent intervals has been shown to be effective in reducing morbidity and mortality from Lynch-associated colorectal cancer 2.
• Prevention options include the use of oral contraceptives, which are known to be highly effective for decreasing risk of both endometrial and ovarian cancer, and prophylactic surgery to remove the uterus and ovaries 5.
• Immunotherapy represents a valid alternative to traditional therapeutic methods and extends the life expectancy of patients that have already developed LS-associated colorectal cancer 3.