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

From the Guidelines

Lynch syndrome is an inherited genetic condition that significantly increases the risk of developing certain cancers, particularly colorectal cancer, at a younger age than the general population, and is caused by mutations in DNA mismatch repair genes. It's essential to understand that people with Lynch syndrome have a 20-80% lifetime risk of colorectal cancer and increased risks for endometrial, ovarian, stomach, small intestine, urinary tract, and other cancers 1. The identification of Lynch syndrome offers an opportunity for optimizing therapy and managing future risk for individuals with CRC or endometrial cancer, and for early detection and prevention of cancer for asymptomatic carriers of Lynch syndrome–associated mutations.

Key Points

• Lynch syndrome is associated with an increased risk of various cancers, including colorectal, endometrial, ovarian, stomach, small intestine, urinary tract, and other cancers 1.
• The syndrome is often underdiagnosed, and early detection through regular screening is crucial as it significantly improves outcomes for those with this condition 1.
• Management includes regular colonoscopies starting at age 20-25 (every 1-2 years), endometrial screening for women, and consideration of preventive surgeries 1.
• Family members should also be tested since Lynch syndrome has a 50% chance of being passed to children.
• The revised Bethesda guidelines and Amsterdam criteria II can be used to identify individuals who warrant further genetic testing 1.

Diagnosis and Management

• Tumor testing with IHC for MMR proteins and/or MSI is recommended in individuals with CRC 1.
• Full germline genetic testing should include DNA sequencing and large rearrangement analysis 1.
• Follow-up recommendations in mutation carriers include colonoscopy every 1–2 years, and gynaecological examination (with TV US, CA 125 and endometrial biopsy) on a yearly basis from age 30 to 35 years 1.

Screening and Prevention

• Regular screening is essential for early detection and prevention of Lynch syndrome-associated cancers.
• High-quality colonoscopy carried out in dedicated centers is advised 1.
• UGI endoscopy surveillance (every 1–3 years, from age 30–35 years) may be considered in patients at high risk 1.
• Prophylactic gynaecological surgery might be an option for female carriers who have completed childbearing or are postmenopausal 1.

From the Research

Definition and Characteristics of Lynch Syndrome

• Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is a genetic disorder characterized by an autosomal dominant inheritance of early-onset colorectal cancer and endometrial cancer, as well as increased risk for several other cancers 2, 3, 4, 5, 6.
• The syndrome is caused by a mutation in one of the four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2 2, 3, 4, 5, 6.
• Individuals with Lynch syndrome have a high lifetime risk of developing colorectal and endometrial cancers, with risks approaching 70-80% and 40-60%, respectively, in the absence of medical intervention 5.

Clinical Presentation and Diagnosis

• Lynch syndrome is often suspected in individuals who develop cancer at an unusually young age or in families with a history of clustering of certain types of cancer 6.
• Diagnosis involves analyzing tumor tissue for evidence of deficient mismatch repair, such as microsatellite instability or loss of mismatch repair protein expression, followed by genetic testing to identify a pathogenic mutation 6.
• Diagnostic evaluations for Lynch syndrome should be carried out with appropriate genetic counseling 6.

Management and Surveillance

• Regular surveillance for colorectal and endometrial cancer has been shown to be beneficial for mutation carriers, with colonoscopy at frequent intervals effective in reducing morbidity and mortality from Lynch-associated colorectal cancer 2, 5, 6.
• Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with Lynch syndrome 2.
• Annual colonoscopy and annual gynecological examination are recommended for patients with Lynch syndrome and healthy carriers of causative mutations 6.