Lynch Syndrome (HNPCC)

Lynch syndrome, historically called hereditary nonpolyposis colorectal cancer (HNPCC), is the most common inherited colorectal cancer syndrome. It results from germline alteration of a DNA mismatch repair gene, which leaves tumors unable to correct certain replication errors and confers an elevated lifetime risk of colorectal and several other cancers, typically without the profuse polyposis seen in FAP.

Definition

Lynch syndrome is an autosomal dominant cancer predisposition caused by germline pathogenic variants in DNA mismatch repair genes (such as MLH1, MSH2, MSH6, and PMS2) or in EPCAM, characterized by microsatellite-unstable tumors and increased lifetime risk of colorectal and other cancers without diffuse polyposis.

Scope

This topic covers the molecular basis of Lynch syndrome in DNA mismatch repair, the resulting tumor phenotype of microsatellite instability, the spectrum of associated cancers, and how the syndrome is identified. It is a reference overview and does not provide individualized surveillance schedules or treatment instructions.

Key concepts

• DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and EPCAM
• Microsatellite instability (MSI)
• Immunohistochemistry for mismatch repair proteins
• Spectrum of associated cancers (colorectal, endometrial, others)
• Amsterdam criteria and revised Bethesda guidelines
• Universal tumor testing and cascade genetic testing

Key theories

Mismatch repair deficiency and microsatellite instability

Loss of DNA mismatch repair function leaves replication errors at repetitive sequences uncorrected, producing microsatellite instability and a hypermutable phenotype that drives accelerated colorectal and extracolonic tumorigenesis.

Mechanisms

A germline pathogenic variant inactivates one allele of a mismatch repair gene; somatic loss of the second allele in a tumor cell abolishes the repair function, so errors introduced during DNA replication at short repetitive sequences go uncorrected. This produces microsatellite instability and a high mutational burden that accelerates progression of colorectal and other epithelial tumors. The mismatch-repair-deficient phenotype can be detected in tumors by molecular testing for microsatellite instability or by immunohistochemistry showing loss of the corresponding protein, which supports identification of the syndrome.

Clinical relevance

Lynch syndrome is identified within hereditary cancer programs because affected individuals and relatives carry elevated lifetime risk of colorectal, endometrial, and other cancers, and because the mismatch-repair-deficient phenotype has implications for tumor evaluation. This entry describes the syndrome as reference material and is not a source of individualized surveillance or treatment recommendations.

Epidemiology

Lynch syndrome is the most common hereditary colorectal cancer syndrome and accounts for a small but important proportion of all colorectal cancers, as well as a notable share of endometrial cancers. Many carriers remain unidentified, which has motivated approaches such as universal tumor testing of colorectal and endometrial cancers to find probands and prompt cascade testing of relatives.

Evidence & guidelines

The identification of MSH2 and MLH1 as mismatch repair genes underlying the syndrome established its molecular basis, and professional bodies such as the American College of Gastroenterology and collaborating UK societies publish guidelines on testing and management of hereditary gastrointestinal cancer syndromes including Lynch syndrome. These describe evidence and consensus rather than directing the care of any individual.

History

Henry Lynch's clinical descriptions of familial cancer clustering without polyposis defined the syndrome that bears his name. In the early 1990s the discovery that germline variants in DNA mismatch repair genes, beginning with MSH2 and MLH1, caused the condition explained the microsatellite-instability phenotype of the tumors and transformed diagnosis from purely clinical criteria toward molecular and genetic testing.

Debates

How should Lynch syndrome carriers be identified?

Clinical criteria such as the Amsterdam and Bethesda guidelines miss some carriers, prompting a shift toward universal tumor testing of colorectal and endometrial cancers for mismatch repair deficiency, an approach whose scope and implementation continue to be discussed.

Key figures

• Henry Lynch
• Richard Fishel
• Richard Kolodner
• Bert Vogelstein

Seminal works

• fishel-1993
• bronner-1994

Frequently asked questions

Why is Lynch syndrome called nonpolyposis?

Unlike familial adenomatous polyposis, Lynch syndrome does not usually produce hundreds of polyps; cancers arise from a small number of adenomas, so the older name emphasized the absence of diffuse polyposis.

What is microsatellite instability and why does it matter in Lynch syndrome?

Microsatellite instability is the accumulation of uncorrected errors at repetitive DNA sequences that results from defective mismatch repair; detecting it in a tumor is a key clue that helps identify Lynch syndrome.