What is Lynch syndrome (hereditary non‑polyposis colorectal cancer, HNPCC)?

What is Lynch Syndrome?

Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline mutations in DNA mismatch repair (MMR) genes—primarily MLH1, MSH2, MSH6, and PMS2—that dramatically increases lifetime risk of colorectal cancer (up to 80%) and endometrial cancer (up to 60%), along with other malignancies. 1, 2

Genetic Basis and Mechanism

The syndrome results from inherited defects in the DNA mismatch repair system, which normally functions as a "spell-check" mechanism during cell division. When this system fails, repetitive DNA sequences called microsatellites accumulate errors, producing microsatellite instability (MSI) in tumors—the molecular hallmark of Lynch syndrome 1. This defective repair mechanism leads to accelerated carcinogenesis, explaining why cancers develop at younger ages in affected individuals 3.

Clinical Features and Cancer Risks

Lynch syndrome accounts for 2-3% of all colorectal cancers with an estimated prevalence of 1 in 440 to 1 in 500 in the general population 2, 4. The syndrome is characterized by:

• Early-onset cancers: Colorectal cancers often develop before age 50
• Multiple primary tumors: Patients frequently develop more than one cancer over their lifetime
• Specific cancer spectrum: Beyond colon and endometrium, increased risks include cancers of the stomach, small intestine, pancreas, biliary tract, ovary, urinary tract (upper uroepithelial), and brain 1, 5

Terminology Evolution

The term "Lynch syndrome" should be reserved specifically for families with confirmed germline mutations in MMR genes, replacing the older term "hereditary nonpolyposis colorectal cancer (HNPCC)." 1, 6 This distinction matters because families meeting clinical criteria (Amsterdam criteria) without proven MMR deficiency represent a different entity called "familial colorectal cancer type X" with distinct clinical and molecular features 6.

Diagnostic Approach

Diagnosis follows a two-step process 4:

1. Tumor screening: When Lynch syndrome is suspected (young age at diagnosis, family clustering), tumor tissue is analyzed for:

   • Microsatellite instability (MSI)
   • Loss of MMR protein expression by immunohistochemistry

2. Genetic confirmation: If MMR deficiency is detected, germline genetic testing identifies the specific pathogenic mutation

Important caveat: High MSI alone does not diagnose Lynch syndrome, as approximately 15% of sporadic colorectal cancers show MSI due to acquired (not inherited) MLH1 changes 1. These sporadic cases often have BRAF mutations, which are rare in true Lynch syndrome 1.

Clinical Significance

The syndrome is frequently underdiagnosed despite its prevalence 2. Recognition is critical because it enables:

• Predictive testing of at-risk family members once a mutation is identified
• Implementation of intensive surveillance protocols that reduce cancer-related morbidity and mortality
• Informed surgical decision-making (extended resections due to high metachronous cancer risk)
• Risk-reducing prophylactic surgeries for gynecologic cancers

All diagnostic evaluations must be accompanied by appropriate genetic counseling 4.