What is Lynch syndrome?

What is Lynch Syndrome

Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by inherited pathogenic germline mutations in DNA mismatch repair (MMR) genes—specifically MLH1, MSH2, MSH6, and PMS2—that dramatically increases lifetime risk of colorectal, endometrial, and other cancers. 1

Genetic Basis and Molecular Mechanism

• Lynch syndrome results from germline mutations in one of four DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 (deletions in EPCAM can also cause the syndrome) 2
• These mutations lead to defective DNA repair mechanisms and microsatellite instability (MSI), which accumulates genetic errors and drives cancer development 3
• The syndrome follows autosomal dominant inheritance, meaning each child of an affected parent has a 50% chance of inheriting the mutation 4

Cancer Risks by Gene Type

The cancer risk varies significantly depending on which MMR gene is mutated:

Colorectal Cancer Risk

• MLH1 and MSH2 carriers: >4% risk by age 40, requiring earlier surveillance 5
• MSH6 and PMS2 carriers: <2% risk by age 40, allowing delayed screening initiation 5

Endometrial Cancer Risk by Age 50

• MLH1: 8.3% 5
• MSH2: 8.7% 5
• MSH6: 5.2% 5
• PMS2: 3.0% 5

Ovarian Cancer Risk by Age 40

• MLH1: 1.2% 5
• MSH2: 0.9% 5

Other Associated Cancers

• Small intestine, stomach, hepatobiliary system, kidney, ureter, pancreas, and brain tumors also occur at increased rates 1

Clinical Significance and Prevalence

• Lynch syndrome accounts for approximately 3% of all colorectal cancers and 10-15% of DNA mismatch repair-deficient tumors 6
• It is one of the most prevalent hereditary cancer syndromes in humans, yet remains significantly underdiagnosed in the population 7, 4
• Early detection is crucial because affected individuals can benefit from intensive surveillance, chemoprevention, and risk-reducing surgeries that substantially reduce cancer mortality 1, 3

Terminology Evolution

• The term "Lynch syndrome" is now preferred over the older designation "hereditary nonpolyposis colorectal cancer (HNPCC)" 1, 3
• Lynch syndrome specifically refers to families with confirmed germline mutations in MMR genes, regardless of whether clinical pedigree criteria are met 1
• This molecular definition is more precise than historical clinical criteria like Amsterdam Criteria, which were based solely on family history patterns 1

Diagnostic Approach

All patients with newly diagnosed colorectal cancer should undergo tumor testing with either immunohistochemistry (IHC) for MMR proteins or microsatellite instability (MSI) testing to identify potential Lynch syndrome cases 8

Testing Algorithm

• IHC testing detects absence of MLH1, MSH2, MSH6, or PMS2 proteins in tumor tissue 8
• If MLH1 is absent, test for BRAF mutation or MLH1 promoter hypermethylation to distinguish Lynch syndrome from sporadic colorectal cancer 8
• Positive findings warrant germline genetic testing to confirm the diagnosis 8
• For patients with suggestive family history but no cancer, risk prediction models (PREMM1,2,6 or MMRpro) can guide decisions about proceeding to germline testing 8

Common Pitfalls

• Excluding older patients from testing: Lynch syndrome can present in elderly patients, and testing has implications for younger family members 8
• Relying solely on family history: Many Lynch syndrome patients lack classic family history patterns due to small family size, early deaths from other causes, or incomplete penetrance 4
• Missing structural variants: Standard exon sequencing and MLPA may miss large structural variants; optical genome mapping or long-read sequencing may be needed when clinical suspicion is high but standard testing is negative 9