From the Guidelines
Lynch syndrome is an inherited genetic condition that increases a person's risk of developing certain cancers, particularly colorectal cancer, at a younger age than the general population, caused by mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) 1.
Definition and Causes
Lynch syndrome is characterized by an increased risk of various cancers, including colorectal, endometrial, ovarian, stomach, small intestine, pancreatic, kidney, brain, and certain skin cancers. The syndrome is often underdiagnosed, with an estimated prevalence in the general population of 1 in 440 1. The genetic mutations associated with Lynch syndrome lead to errors in DNA repair, potentially resulting in cancer.
Cancer Risks and Screening
Individuals with Lynch syndrome have an estimated lifetime cumulative incidence of colorectal cancer up to 80% and endometrial cancer up to 60% 1. Enhanced cancer screening is essential for people with Lynch syndrome, including colonoscopies beginning at age 20-25 or 2-5 years before the earliest colorectal cancer diagnosis in the family. Genetic testing can confirm Lynch syndrome, and family members of affected individuals should consider testing since each child of a carrier has a 50% chance of inheriting the mutation 1.
Management and Prevention
Early identification of Lynch syndrome allows for appropriate surveillance and preventive measures to reduce cancer risk or detect cancers at earlier, more treatable stages. Aspirin therapy has been shown to decrease the incidence of colorectal cancer in adults with Lynch syndrome, but the recommended dose and frequency are unknown, and an individualized approach is best, considering the patient's personal risk of adverse events with aspirin therapy 1.
Key Points
- Lynch syndrome is an inherited genetic condition that increases cancer risk, particularly for colorectal cancer.
- Mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) cause Lynch syndrome.
- Enhanced cancer screening, including colonoscopies, is essential for individuals with Lynch syndrome.
- Genetic testing can confirm Lynch syndrome and identify family members at risk.
- Early identification and surveillance can reduce cancer risk and improve outcomes.
From the Research
Definition and Causes of Lynch Syndrome
- Lynch syndrome (LS) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes, resulting in an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts 2, 3.
- The mutations lead to frameshift alterations, causing the accumulation of errors within microsatellites, and individuals with LS have an elevated risk of developing colorectal and distant malignancies, including endometrial cancer (EC) 3.
Clinical Features and Cancer Risks
- LS is the most common inherited cause of colorectal (lifetime risk up to 70%) and endometrial cancer 4.
- The lifetime risk of each cancer in people with Lynch syndrome is gene-specific and may be modified by environmental factors 4.
- Individuals with LS are at an increased risk of developing various types of cancer, including colorectal, endometrial, ovarian, and other cancers 2, 5.
Diagnosis, Surveillance, and Prevention
- The diagnosis of Lynch syndrome facilitates preventive measures aimed at reducing the incidence and mortality of cancer 4.
- Colonoscopic surveillance for colorectal cancer, aspirin, and prophylactic hysterectomy and bilateral salpo-oopherectomy for endometrial and/or ovarian cancer have demonstrated to effectively reduce cancer mortality in this population 4.
- Aspirin use has been associated with reduced colorectal cancer risk in several studies, and low-dose aspirin is suggested by leading international guidelines for CRC prevention in Lynch syndrome carriers 6.
Management and Treatment
- People with Lynch syndrome may benefit from a personalized management approach, taking into account the gene-specific lifetime risk of each cancer and environmental factors 4.
- Recent advances in immunotherapy have revolutionized the treatment of advanced cancers with DNA mismatch repair defects, and genotype- and immunologic subtype-specific strategies for surveillance, cancer prevention, and treatment are being developed 5.