What is Lynch syndrome?

Lynch Syndrome Definition

Lynch syndrome is an autosomal dominant genetic disorder caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene, leading to significantly increased lifetime risk of multiple cancers, most notably colorectal cancer (up to 80%) and endometrial cancer (up to 60%). 1

Genetic Basis and Pathophysiology

Lynch syndrome results from inherited defects in the DNA mismatch repair system that normally corrects errors during cell replication 2. The key pathogenic mechanisms include:

• Germline mutations in four primary MMR genes: MLH1, MSH2, MSH6, and PMS2, which are responsible for maintaining genomic stability during DNA replication 1, 3
• EPCAM gene deletions that cause hypermethylation of the MSH2 promoter, leading to MSH2 silencing 2, 1
• Accumulation of DNA errors in microsatellite regions, resulting in microsatellite instability (MSI) that drives cancer development 2, 4
• Autosomal dominant inheritance pattern, meaning affected individuals have a 50% chance of passing the mutation to offspring 1

Epidemiology and Clinical Significance

Lynch syndrome is one of the most common hereditary cancer syndromes:

• Affects approximately 1 in 440 Americans, making it far more prevalent than previously recognized 1
• Accounts for 2-4% of all colorectal cancers and 2-3% of endometrial cancers in the general population 2, 1
• Historically underdiagnosed, with many cases remaining unidentified despite national screening recommendations 5

Cancer Risk Profile

The syndrome confers substantially elevated lifetime risks for multiple malignancies:

Primary Cancer Risks

• Colorectal cancer: 22-80% lifetime risk (varies by specific gene mutation), with approximately 70% occurring proximal to the splenic flexure 1
• Endometrial cancer: up to 60% lifetime risk in women, making it the second most common Lynch syndrome-associated cancer 2, 1
• Ovarian cancer: 4-24% lifetime risk in women 1

Additional Associated Cancers

• Upper tract urothelial carcinoma: 2.9-28% lifetime risk, particularly underappreciated by urologists 2, 1
• Gastric, small intestinal, pancreatic, and biliary tract cancers all show increased incidence 2, 1
• Brain tumors (usually glioblastoma) 2, 1
• Sebaceous gland tumors (sebaceous adenomas, carcinomas, and keratoacanthomas) characteristic of Muir-Torre syndrome variant 2, 1

Distinctive Clinical Features

Lynch syndrome-associated cancers exhibit unique characteristics compared to sporadic cases:

Colorectal Cancer Characteristics

• Earlier age of onset, typically presenting before age 50 years 1
• Accelerated adenoma-to-carcinoma progression (approximately 35 months versus 10-15 years in sporadic cases) 1
• Predominantly right-sided location (proximal to splenic flexure) 1
• Distinctive histopathology: poor differentiation, signet cell features, abundant extracellular mucin, tumor-infiltrating lymphocytes, and lymphoid host response 1
• Better stage-for-stage survival compared to sporadic colorectal cancer 1

Upper Tract Urothelial Carcinoma Features

• Younger age at presentation than sporadic cases 2, 1
• Higher proportion of ureteral involvement (versus renal pelvis) 2, 1
• Female preponderance 2, 1
• Possible predisposition to bilateral disease 2, 1

Diagnostic Approach

Clinical Criteria for Suspicion

Suspect Lynch syndrome when patients meet any of the following criteria:

• "3-2-1 rule": 3 affected relatives with Lynch syndrome-associated cancer, across 2 generations, with 1 diagnosed before age 50 1
• Amsterdam II criteria: Family history of 3 relatives with Lynch syndrome-associated cancer, with one being a first-degree relative of the other two, at least 2 successive generations affected, and at least 1 cancer diagnosed before age 50 1
• Upper tract urothelial carcinoma presenting before age 60 years 2, 1
• Colorectal cancer diagnosed before age 50 years 2
• ≥10 adenomatous polyps in a lifetime (though Lynch syndrome typically presents with fewer polyps than FAP) 2

Diagnostic Testing Algorithm

The diagnosis is established through a stepwise approach 2:

1. Tumor tissue testing as initial screening:

   • Immunohistochemistry (IHC) to detect loss of MMR protein expression 1
   • Microsatellite instability (MSI) testing by PCR 2, 1

2. Germline genetic testing to identify pathogenic variants in MMR genes (MLH1, MSH2, MSH6, PMS2) or EPCAM deletions 1, 4

3. Risk assessment using prediction models based on personal and family cancer history 1

Important Clinical Pitfalls

The Amsterdam criteria are very stringent and miss up to 68% of patients with Lynch syndrome 2. Therefore, relying solely on these criteria will result in significant underdiagnosis. The Bethesda Guidelines provide broader screening criteria and should be preferentially used in clinical practice 2.

Data on breast and prostate cancer risk in Lynch syndrome remain emerging and inconsistent 2. Current major guidelines do not consider breast cancer part of the established Lynch syndrome tumor spectrum, and enhanced breast cancer surveillance beyond population-based screening is not recommended 6.